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b1c15b08312573994fd5cd3d069012c46ba827ec	pubmed	COVID-19 Guidance for Triage of Operations for Thoracic Malignancies: A Consensus Statement From Thoracic Surgery Outcomes Research Network	COVID-19 Guidance for Triage of Operations for Thoracic Malignancies: A Consensus Statement From Thoracic Surgery Outcomes Research Network ## Covid-19 guidance documents ## Covid-19 guidance for triage of operations for thoracic malignancies: a consensus statement from thoracic surgery outcomes research network Thoracic Surgery Outcomes Research Network, Inc* The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital. (Ann Thorac Surg 2020;110:692-6) Ó 2020 by The Society of Thoracic Surgeons and the American Association for Thoracic Surgery T he COVID-19 pandemic has forced hospitals to progressively reduce surgical volumes to both minimize disease transmission within the hospital and to preserve human and personal protective equipment and other resources needed to care for COVID-19 patients. In response, many hospitals have abruptly reduced or eliminated elective operations. As the COVID-19 burden on a hospital increases, procedures that improve survival may similarly have to be reduced or eliminated (ie, semielective, urgent, and perhaps some emergent operations). For some cancer patients, surgery may be delayed for months or even years without negative consequences. In other scenarios, however, failure to perform an indicated cancer surgery in a timely fashion may have long-term implications on a patient's survivorship or significant permanent deficits in their quality of life. Therefore, cancer patients and the oncology teams that treat them are likely to face difficult decisions between suboptimal management strategies. Thoracic oncology decisions are further complicated by the fact most of the patients with lung, esophageal, and other thoracic malignancies would be considered to be a high-risk group for poor outcomes with COVID-19 (advanced age, emphysema, and heart disease). Further, the indicated therapeutic procedures can both impair lung function (ie, lung isolation, removal of lung tissue) and expose clinical teams to aerosolized viral load (bronchoscopy, double-lumen endotracheal tube placement, airway surgery, laparoscopy and possibly lung surgery particularly with parenchymal lung leaks). We have assembled a document to offer guidance intended to facilitate these difficult decisions when caring for patients with thoracic malignancies during the COVID-19 pandemic [fig_ref] Table 1: Guidance for the Triage of Patients With Thoracic MalignanciesCompass Statement [/fig_ref]. [bib_ref] Effects of delayed surgical resection on short-term and long-term outcomes in clinical..., Samson [/bib_ref] [bib_ref] Defining the ideal time interval between planned induction therapy and surgery for..., Samson [/bib_ref] [bib_ref] Delay in diagnostic workup and treatment of esophageal cancer, Grotenhuis [/bib_ref] [bib_ref] Does the timing of esophagectomy after chemoradiation affect outcome?, Kim [/bib_ref] [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] [bib_ref] A systematic review and metaanalysis of stereotactic body radiation therapy for colorectal..., Cao [/bib_ref] [bib_ref] Lobectomy versus stereotactic body radiotherapy in healthy patients with stage I lung..., Rosen [/bib_ref] [bib_ref] Survival of primary stereotactic body radiation therapy compared with surgery for operable..., Khorfan [/bib_ref] [bib_ref] Surveillance versus esophagectomy in esophageal cancer patients with a clinical complete response..., Semenkovich [/bib_ref] [bib_ref] Cincinnati Research in Outcomes and Safety in Surgery (CROSS) Group. Outcome of..., Levinsky [/bib_ref] Assumptions Much of the impact, timeline, duration, risks, and ultimate recovery from the COVID-19 pandemic remain unknown. In an effort to give context to this triage guide, several assumptions have been made: The risk of nosocomial infection (patients and clinicians infected while in hospital) [bib_ref] COVID-19: towards controlling of a pandemic, Bedford [/bib_ref] [bib_ref] Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia, Li [/bib_ref] [bib_ref] China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease..., Guan [/bib_ref] [bib_ref] Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington..., Arentz [/bib_ref] [bib_ref] Minimise nosocomial spread of 2019-nCoV when treating acute respiratory failure, Cabrini [/bib_ref] and competition for resources (surgical and medical patients) will increase in proportion to the prevalence of hospitalized COVID-19 patients. The duration of restriction on elective surgery will last approximately 3 months. Each facility's progression through the phases of care restriction will be variable, but surgeons should be prepared for rapid changes in hospital status (ie, consider what eligible operations could or should be performed as soon as possible). Surgical leadership are provided with daily updates regarding a hospital's COVID-19 population and resource status. ## Process of priority status determination for individual patients There are nuances to each patient's management approach, such as proceeding with surgery, delaying surgery, or pursuing alternative treatment, that will impact risk tolerance for both patient and surgeon. Ideally, when traditional cancer treatment is not logistically feasible, a patient's care plan will be made with input from a group of clinicians with expertise in thoracic malignancies, such as a case conference or tumor board. We encourage the use of this multidisciplinary strategy as guidance as appropriate for each individual hospital or clinic setting. Several considerations may cause a group's consensus approach to differ from what is proposed in [fig_ref] Table 1: Guidance for the Triage of Patients With Thoracic MalignanciesCompass Statement [/fig_ref] : The risk of delay may not be specifically captured by the outlined descriptors (ie, tumor may have aggressive growth kinetics or histology). Resource limitations (clinicians, supplies, facilities) affecting surgical, medical and radiation oncology departments may pose heterogeneous restrictions from hospital to hospital. Clinicians will need to keep in mind the important concept of social distancing in modifying management to limit the number of visits to the hospital for any reason. In addition, because the duration of surgical volume restriction is unknown (3 months is presumed), patients who are delayed or deferred should be tracked (ie, a patient registry or database). Considerations for the database should include the following: Indication if reassessment during the period of delay could influence care plan (ie, follow-up computed tomographic scan). This should be extremely selective, because access to imaging will likely be increasingly restricted with increased COVID-19 prevalence. An indication of case priority (ie, first group, second group, third group) for rescheduling when restrictions are lifted to best care for patients whose survival may be most impacted by additional delay. Alternative treatment strategies used in lieu of surgical resection (ie, systemic chemotherapy, stereotactic body radiotherapy, or other ablative strategies, palliative stent placement, etc) should also be tracked. ## Disclaimers This guidance document is meant to serve patients based on estimates of risk for average patients (in terms of tumor behavior, patient health, hospital resource availability) associated with each strategy. These should not be considered rigid guidelines. This guide is not intended to supplant clinical judgment or the development of consensus regarding institutional approaches to cancer treatment. There is a great deal of uncertainty around this evolving pandemic and information may change rapidly. Critical portions of the transition are not addressed. In reality, there is likely to be a Phase "1a," "1b," "1c," where only fraction of the priority cancer patients may have access to surgery. Clinicians may have to further restrict of surgery, likely across specialties (ie, colon cancer, breast, hepatobiliary) based on the perceived magnitude of risk of delay and over shorter time periods (ie, impact of 8-week delay, then 4 weeks, etc). Preoperative evaluation is likely to be impacted (ie, pulmonary function testing), and preoperative screening for COVID-19 is evolving (survey for symptoms, temperature assessment, possible selected testing for COVID-19 where available). It is possible that the strategies outlined in this document could be replaced as our understanding of unique challenges that COVID-19 poses within each country, state, and health care environment evolves. This document is not intended as a guide for other clinical scenarios, epidemics, or pandemics. ## Shared decision making and transparency Transparency regarding the potential risks of deferring or proceeding with an operation remains a priority. Surgeons should discuss these decisions individually with their patients. Multidisciplinary teams are encouraged to develop alternative treatment strategies if surgical resection is declined or infeasible. ## Origins of consensus statement This initiative is an extension of the American College of Surgeons and Commission on Cancer (CoC) effort to provide guidance for surgeons to make difficult triaging decisions in the face of progressively limited access to operating rooms, and there may be some slight differences in this document compared with the CoCpublished documents. A partnership was formed between the CoC (Tim Mullett, Larry Shulman, Linda Martin, and Matt Facktor), the Thoracic Surgery Outcomes Research Network (ThORN, a research collective of board-certified general thoracic surgeons), and leaders from the American College of Surgeons (Heidi Nelson, Valerie Rusch, and Douglas Wood), and reviewed by leadership from The Society of Thoracic Surgeons and the American Association of Thoracic Surgery (David Jones and Shaf Keshavjee). The limited data were discussed in an open exchange, and the resulting guide is best characterized as being based on "expert opinion" in terms of strength of evidence. The authors recognize that multiple resources are becoming available to triage all types of surgical treatment. We intentionally avoided language that is currently being used to structure guidance based on procedures (ie, tiers) or patient status (ie, emergent, urgent, and semiurgent) to avoid confusion, and have instead organized recommendations based on the conditions that exist within each hospital ("phases"). Availability of alternative treatments may vary across health systems and over time. The decision to pursue alternative treatment must balance risk of deferring alternative treatment (chemotherapy and radiotherapy) with risk of exposure of both patients and staff to COVID-19 infection. In Phase I, alternative treatments predominately considered in patients felt to be harmed by delay are listed (ie, the first column of table); c At the time of writing, the risk of death with COVID-19 infection is felt to be higher among patients receiving chemotherapy, but the data are incredibly limited (18 cancer patients in China); 5 d Although the accuracy of the clinical staging examination may be enhanced by invasive staging procedures, the magnitude of survival benefit from superior staging may be considered by some to be modest. In the setting of strained resources and potential exposure risk to clinical staff from staging procedures (bronchoscopy and mediastinoscopy), treating a patient based exclusively on a noninvasive staging evaluation (ie, imaging alone) is reasonable; e These procedures are currently felt to be associated with a particularly high potential to disseminate COVID-19. They should be done selectively and ideally in patients who have been screened for active COVID-19 infection; f There are incomplete data comparing surgery to stereotactic ablative radiotherapy for early-stage lung cancer in patients eligible for surgery. Observational data, which is likely biased with patients who were not surgical candidates, suggests a modest survival advantage of surgery (5%-15% higher 5-year survival); 6-8 g Among presumably highly selected patients, salvage resection has been associated with reasonable survivorship after definitive nonsurgical therapy for esophageal cancer, particularly if the patient has had a good response by imaging; [bib_ref] Surveillance versus esophagectomy in esophageal cancer patients with a clinical complete response..., Semenkovich [/bib_ref] [bib_ref] Cincinnati Research in Outcomes and Safety in Surgery (CROSS) Group. Outcome of..., Levinsky [/bib_ref] h Recommended for patients in whom a delay would likely compromise survival (ie, first column from Phase I section). [fig_ref] Table 1: Guidance for the Triage of Patients With Thoracic MalignanciesCompass Statement [/fig_ref] defines 3 phases of hospital status based on (A) the prevalence of COVID-19 patients within the hospital, (B) availability of hospital resources, and (C) the rate of change (in terms of increasing prevalence of infections and resource depletion). Because there are unique considerations for individual patients, each phase is accompanied by a "compass statement" that is meant to give additional direction to navigate volume restriction based on perceived risk to patients and hospital staff. For each phase, surgeons should operate for recommended scenarios (first column) but also for recommended scenarios from all higher phases (ie, appropriate operations during Phase II, include first column under both Phase II or Phase III). There are very limited data to inform many key decisions. The data and references in this section are meant to serve as an estimate of effect size, using the largest data sets available. They are not complete and, therefore, should not be used as definitive data but are only suggestive of the magnitude of effect. EBUS, endobronchial ultrasound; ICU, intensive care unit; PPE, personal protective equipment; VATS, video-assisted thoracoscopic surgery. ## Final thought There are times when the right decision becomes easieras the impact of the decision evaporates. This is one of those times. We hope that this document facilitates the timely execution of what are sure to be increasingly difficult decisions. ## Appendix of contributing authors in alphabetical order [table] Table 1: Guidance for the Triage of Patients With Thoracic MalignanciesCompass Statement: Surgery restricted to patients whose survivorship is likely to be compromised by surgical delay of 3 months Compass Statement: Surgery restricted to patients likely to have survivorship compromised if surgery not performed within the next few days [/table]	None	http://www.annalsthoracicsurgery.org/article/S0003497520304422/pdf	None
526602a7403c9f838db39c6f8f70f8986896b84a	pubmed	Guidelines on the treatment with integrated traditional Chinese medicine and western medicine for severe coronavirus disease 2019	Guidelines on the treatment with integrated traditional Chinese medicine and western medicine for severe coronavirus disease 2019 # Introduction Since the outbreak of Coronavirus Disease 2019 in December 2019, the epidemic has spread rapidly across several countries and regions worldwide. On January 30, 2020, the World Health Organization (WHO) announced that the outbreak of COVID-19 was classified as a Public Health Emergency of International Concern (PHEIC). Facing the severe global epidemic situation, WHO issued interim guidelines for severe acute respiratory infections caused by suspected novel coronavirus infectionson January 12, 2020, and the National Health Commission of the People's Republic of China (NHCPRC) updated the eighth edition of the Diagnosis and treatment of Coronavirus Disease-19on . Currently, the international epidemic situation is still not very optimistic. According to data from the official WHO outbreak report, by June 13, 2021, the total number of confirmed cases of novel coronavirus pneumonia was 174, 919,389 in 215 regions, countries, territories, and areas, with 410,909 new confirmed cases and 3782,619 cumulative deaths. Severe COVID-19 is characterized by numerous complications and complex conditions, and the mortality rate (12.4%) is about 5 times higher than the total mortality rate of COVID-19 (2.3%) [bib_ref] Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. Therefore, the treatment of severe patients is one of the top priorities in the treatment of COVID-19. Integrated traditional Chinese medicine (TCM) and western medicine played an important role in the prevention and treatment of COVID-19 during the epidemic. To scientifically summarize and evaluate the effect of integrated TCM and western medicine in the prevention and treatment of COVID-19, and to promote the successful experience to the international community, we developed this guideline based on a global perspective and systematic guideline methodology. We hope the guideline might potentially provide guidance to fully utilize the preventive and control role of TCM during the epidemic. ## Scope This guideline is intended for patients with COVID-19 who are at risk of severe conversion, have been diagnosed with severe disease, or patients that are recovering from severe COVID-19, including those who are suffering post-acute sequelae of COVID-19 (PASC, or long COVID). The guideline covers the prevention, treatment, rehabilitation, and psychological support of severe COVID-19 with integrated western medicine and TCM. This guideline applies to all healthcare providers, public health workers, and researchers involved in the diagnosis, treatment, and care of patients with COVID-19 in health care facilities and health administrations in all countries and regions. ## Guideline development process Guideline development was launched on May 4, 2020, and finalized on June 13, 2021. The guideline development followed the Institute of Medicine (IOM) definition of guidelines [bib_ref] Failure of clinical practice guidelines to meet institute of medicine standards: two..., Kung [/bib_ref] , the specification process recommended by the WHO handbook for guideline development, and the Basic methods and procedures for the development/revision of Clinical Practice Guidelines [bib_ref] Basic methods and procedures for the development/revision of Clinical Practice Guidelines, Jiang [/bib_ref]. The guideline used the grading of recommendation evaluation, development and evaluation (GRADE) [bib_ref] GRADE Guidelines: 16. GRADE evidence to decision frameworks for tests in clinical..., Schünemann [/bib_ref] [bib_ref] Rating the quality of evidence and the strength of recommendations using GRADE, Canfield [/bib_ref] method to rigorously determine the evidence quality and strength of recommendations. Guidelines were constructed based on the list of entries in the Appraisal of Guidelines for Research and Evaluation (AGREE II) [bib_ref] AGREE II: advancing guideline development, reporting, and evaluation in health care, Brouwers [/bib_ref] [bib_ref] Guidelines 2.0: systematic development of a comprehensive checklist for a successful guideline..., Schünemann [/bib_ref] tool. The complete guidelines were written according to the Reporting Items for Practice Guidelines in Healthcare (RIGHT) [bib_ref] A reporting tool for practice guidelines in health care: the RIGHT statement, Chen [/bib_ref]. The entire guideline development process is shown in [fig_ref] Figure 1: Guideline development process [/fig_ref]. ## Guideline panel The Guideline Panel includes the following five groups: The chief expert group (n = 2) includes one chief clinical expert and one chief methodologist. The chief clinical expert is the overall leader of the guideline, responsible for drafting the scope of the guideline, determining the composition of the guideline team, having decisionmaking authority at all stages of guideline development, finalizing the draft of the guideline, and being responsible for the clinical applicability of the guideline. The chief methodologist is responsible for the top-level design, guidance, training, and quality control of the guideline methodology and is responsible for the methodological quality. The steering committee (n = 4) is responsible for managing guideline conflicts of interest, approving guideline protocols, supervising the guideline development process, validating completed guidelines, and providing advice and guidance necessary for the guideline development. The guideline development group (GDG, n = 5) is responsible for coordinating the work of various working groups, drafting guideline protocols, conducting clinical question investigation, organizing consensus meetings/surveys on recommendations, documenting the entire guideline development process in detail, writing the guidelines draft, and submission of the guidelines. The evidence evaluation group (EEG, n = 12) is responsible for literature search, screening, inclusion, and quality evaluation; evidence extraction, synthesis, and grading; and creating the evidence profile. The consensus group (n = 27) is responsible for voting and consensus on clinical questions and recommendations. ## Registration This guideline has been registered bilingually on the International Practice Guidelines Registry Platform (http://www.guidelines-registry. org/) on May 4, 2020, with a unique registration number: IPGRP-2020CN062. ## Collection and determination of clinical questions EEG and GDG systematically reviewed and collected clinical questions from existing guidelines, systematic reviews, and clinical studies of COVID-19, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). Together with the clinical questions derived from the steering committee discussions, a total of 264 candidate clinical questions were obtained. After de-duplication, screening, and merging, 24 main clinical questions were determined. These 24 clinical questions were prioritized through an online questionnaire and supplemented with clinical questions that clinicians considered critical. We received questionnaire responses from 21 clinicians (three in TCM, four in respiratory medicine, four in critical care medicine, one in emergency medicine, three in rheumatology, three in nephrology, one in surgery, one in dermatology, and one in orthopedics) with experience in the prevention and treatment of COVID-19 from 17 medical institutions in ten provinces, cities, and autonomous regions in China. The importance of clinical questions was ranked according to the mean importance score (1-7 points) of each question. Finally, eight clinical issues were selected according to the results of the survey and the results of the discussion of the steering committee. ## Evidence collection Considering the suddenness of outbreaks, the evidence may not be sufficient. Systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies were included. Evidence-based guidelines and official treatment protocols issued by various national and regional health institutions were also included. Considering the characteristics of TCM, we also refer to the consensus opinions of TCM experts (famous and experienced TCM practitioners certified by the National Administration of TCM and have a wealth of experience in the treatment of SARS and influenza). The EEG deconstructed the final eight included clinical questions according to the PICO (participants, intervention, comparison, outcome) principle and conducted systematic searches according to topic terms combined with free words. We searched MEDLINE (via PubMed), Embase, the Cochrane Library, the China National Knowledge Infrastructure (CNKI), Wanfang, and the China Biology Medicine disc (CBM) for systematic reviews and meta-analyses, network meta-analyses, and clinical studies, supplemented by searches of Google Scholar (https:// scholar.google.com/) while tracing reference lists of the included literature; and searched WHO (https://www.who.int/), NICE (http://www. nice.org.uk/), NHCPRC (http://www.nhc.gov.cn/) and the National Administration of TCM (http://www.satcm.gov.cn/) for guidelines, treatment protocol, and consensus of TCM expert. The search period was from the establishment of the database to May 1, 2021, and the language of publication was limited to English and Chinese. Studies, guidelines, and treatment protocols were screened, identified, and checked to meet the inclusion criteria of every specific clinical question by two members of the EEG independently. Disagreements, if any, were resolved by discussion or consultation with a third party. ## Evidence evaluation and grading EEP applied the AMSTAR scale [bib_ref] AMSTAR is a reliable and valid measurement tool to assess the methodological..., Shea [/bib_ref] , the Cochrane Collaboration's tool for assessing risk of bias (ROB) scale [bib_ref] Risk of bias reporting in Cochrane systematic reviews, Hopp [/bib_ref] , the Newcastle-Ottawa Scale (NOS) [bib_ref] Appraising the quality of medical education research methods: the Medical Education Research..., Cook [/bib_ref] , the National Institutes of Health (NIH) Research Quality Assessment Tool, the Canadian Institute of Health Economics (IHE) Quality Assessment of Case Series Studies, the Agency for Health Care Research and Quality (AHRQ) Cross-sectional Study Quality Evaluation Tool, and AGREE II [bib_ref] AGREE II: advancing guideline development, reporting, and evaluation in health care, Brouwers [/bib_ref] to evaluate the quality of systematic reviews and meta-analyses (network meta-analysis), RCTs, cohort and case-control studies, before-after studies, case series, cross-sectional studies, and guidelines and consensus, respectively. The GRADE [bib_ref] GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables, Guyatt [/bib_ref] [bib_ref] Application of GRADE in systematic reviews:necessity, frequently-asked questions and concerns, Chin, Chen [/bib_ref] system was used to evaluate the evidence quality and recommendations [fig_ref] Table 1: Evidence quality grades and strength of recommendations [/fig_ref]. Two researchers independently extracted data and assessed the quality of studies. ## Formulation of recommendations The GDG initially developed appropriate recommendations for clinical practice based on the evidence included, with considering the preferences and values of patients, the costs of intervention, and the balance between pros and cons. Subsequently, the consensus group voted on every recommendation in Delphi surveys [bib_ref] Consensus methods for medical and health services research, Jones [/bib_ref] (selected one of "Not sure", "Disagree", or "Agree", reaching a consensus required 80% votes of "agree"). Additionally, the consensus group can propose modification suggestions to those recommendations that have reached a consensus. Two rounds of Delphi surveys were conducted on 8 February 2021 and 19 March 2021, with 22 recommendations reaching consensus and 99 modification suggestions collected. The GDG then completed the guidelines following the RIGHT report specifications. ## Dissemination and promotion of guidelines After publication, the guideline will be disseminated and promoted in the following ways: (1) health authorities; (2) publications and official networks; (3) academic conferences and forums in related fields; (4) social media platforms; (5) interpretation of the guideline by invited experts published on common medical websites. ## Definition of terms The definition of severe COVID-19 varies slightly around the world, but is primarily based on the presence of signs of pneumonia and severe dyspnea/hypoxemia. The definition of severe COVID-19 in this guideline follows both the WHO definition [fig_ref] Table 2: WHO severe COVID-19 definition [/fig_ref] and the definition of the Diagnosis and treatment of coronavirus disease-19 (8th trial edition)issued by the NHCPRC [fig_ref] Table 3: Definition of severe COVID-19 in the Diagnosis and treatment of COVID-19 [/fig_ref]. The term "usual care (UC)" (or usual treatment, standard care/ treatment, etc.) mentioned in different literature varies slightly depending on the center, region, and time, but mostly includes bed rest, supportive treatment, close monitoring of vital signs and indicators, symptomatic treatment, oxygen therapy, antibiotics (when there is evidence of a secondary bacterial infection) and sometimes empirical medications such as chloroquine phosphate or empirical antivirals (usually one or more of the following: IFN-α, ribavirin, abidol, or lopinavir/ritonavir). ## Recommendations Forty-seven articles were finally included in the study, including ten systematic reviews, 15 RCTs, nine cohort studies, two before-after studies, two cross-sectional studies, two case series, three guidelines, and four diagnosis and treatment protocols. A total of 22 recommendations were formed, and the essential points were summarized in [fig_ref] Table 4: Essential points of the recommendations [/fig_ref]. The following documents are included in the Supplementary Material: 1) Quality assessment of the included studies and guidelines; 2) the details and composition of TCM decoctions and Chinese patent medicines (CPM) mentioned in the recommendations and rationales; 3) the details, effect sizes, and safety data of the outcomes of the included clinical studies; 4) the GRADE evidence profile, which contains detailed information about the quality of evidence assessment and effect sizes of each clinical evidence. For COVID-19, supportive and symptomatic therapy is recommended (consensus recommendation). Triple therapy with interferon (IFN) β-1b, lopinavir/ritonavir (Lpv/R), and ribavirin is suggested to reduce the severe conversion rate of COVID-19 (weak recommendation, low evidence quality); for elderly patients with mild COVID-19, early treatment with high-titer convalescent plasma can be considered (weak recommendation, high evidence quality). ## Rationale Patients with COVID-19 should rest in bed and receive adequate supportive treatment, such as adequate nutrition and fluid support to ensure water-electrolyte balance and stability of the internal environment; symptomatic treatments such as antipyretic and analgesic treatment should also be given. One RCT [bib_ref] Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of..., Hung [/bib_ref] showed that, for mild and moderate COVID-19, the viral clearance time of nasopharyngeal swab was significantly reduced with the triple therapy of IFNβ-1b, Lpv/R, and ribavirin compared with Lpv/R alone (effect size and safety data of each study could be found in Supplementary Materials 3, while the effect size and GRADE assessment details of each evidence could be found in Supplementary Materials 4). Another RCTdemonstrated that early treatment with high-titer convalescent plasma significantly reduced the severe conversion rate in mild elderly patients with COVID-19 compared to placebo. Some treatments may have more impairments than benefits in reducing the severe COVID-19 conversion rate. Lpv/R or ribavirin alone may not reduce the rate of severe conversion in patients with COVID-19 or improve important outcomes (moderate evidence quality); Lpv/R may increase the risk of diarrhea and nausea/vomiting(very low evidence quality). An evidence-based guidelineand four systematic reviews [bib_ref] Hydroxychloroquine use and progression or prognosis of COVID-19: a systematic review and..., Zang [/bib_ref] [bib_ref] Hydroxychloroquine for treatment of nonsevere COVID-19 patients: systematic review and meta-analysis of..., Elsawah [/bib_ref] [bib_ref] Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: a systematic..., Sarma [/bib_ref] [bib_ref] The outcome of hydroxychloroquine in patients treated for COVID-19: systematic review and..., Mega [/bib_ref] showed that hydroxychloroquine (HCQ) can postpone pulmonary radiological progression in patients with COVID-19 compared to UC, but there were no significant differences in viral clearance rate, clinical progression, and length of hospital stay, and it may also increase the risk of death and invasive mechanical ventilation (IMV). Furthermore, HCQ may increase the risk of adverse events such as diarrhea and nausea/vomiting (very low to low evidence quality). Two evidence-based guidelinesand one RCT [bib_ref] Early use of corticosteroid may prolong SARS-CoV-2 shedding in non-intensive care unit..., Tang [/bib_ref] indicated that corticosteroid treatment has no significant effect on the rate of clinical deterioration and may prolong the time to viral clearance and increase 28-day mortality rate in patients with mild or moderate COVID-19 (low to moderate evidence quality). Antibiotic therapy or prophylaxis (especially in combination with broad-spectrum antibacterial drugs) is ## Rationale For COVID-19 treatment, the Diagnosis and treatment of COVID-19 (8th trial edition)recommended JHQG granules, LHQW capsules/granules, XBJ injection, QFPD decoction, HSBD decoction, and XFBD decoction based on phased syndrome differentiation, which is summarized as "three CPMs and three decoctions". JHQG granules and LHQW capsules (granules) are used mainly for fatigue with fever during the medical observation phase; XBJ injection is used mainly for the TCM syndrome of "overabundant beat in both Qifen and Yingfen" of severe COVID-19; QFPD decoction can be used for patients at any clinical stage; HSBD decoction is used mainly for the TCM syndrome of "epidemic toxin blocking lung" of severe COVID-19; XFBD decoction is mainly used for the TCM syndrome of "dampness toxin stagnant lung" of moderate COVID-19. Treatment of TCM decoctions or CPMs such as "three CPMs and three decoctions" based on syndrome differentiation in combination with UC (including EM such as Lpv/R, abidol, ribavirin, or interferon) can significantly reduce the severe COVID-19 conversion rate, improve symptoms, reduce complications, improve cardiopulmonary function, increase the cure rate, and reduce mortality compared with UC, with no statistical difference in the incidence of adverse events [bib_ref] Efficacy of Lianhua Qingwen Granules combined with Arbidol in the treatment of..., Yu [/bib_ref] [bib_ref] Retrospective analysis of 38 cases of COVID-19 treated by integrated traditional Chinese..., Lian [/bib_ref] [bib_ref] Analysis on clinical efficacy and liver injury of 100 cases of COVID-19..., Xia [/bib_ref] [bib_ref] Curative effects of integrated traditional Chinese and western medicine treatment regimens on..., Xie [/bib_ref] [bib_ref] Retrospective clinical analysis of traditional Chinese medicine Lianhua Qingwen in the treatment..., Yao [/bib_ref] [bib_ref] Chinese herbal medicine for coronavirus disease 2019: a systematic review and meta-analysis, Xiong [/bib_ref] [bib_ref] Chinese medical drugs for coronavirus disease 2019: a systematic review and metaanalysis, Pang [/bib_ref]. A cohort study [bib_ref] Hanshiyi Formula, a medicine for Sars-CoV2 infection in China, reduced the proportion..., Tian [/bib_ref] showed that the Hanshiyi formula can significantly reduce the severe conversion rate of patients with mild and moderate COVID-19 compared with UC (including antivirals such as oseltamivir or arbidol). ## Clinical question 2: How to treat severe COVID-19 with integrated TCM and western medicine ? ## Recommendation 3 For severe COVID-19, close monitoring for signs of clinical deterioration, aggressive management of complications and secondary infections, and timely supportive treatment are recommended; respiratory support such as oxygen therapy, noninvasive ventilation (NIV), IMV, and airway management should be given immediately (consensus recommendation). For patients with COVID-19 who receive high flow nasal cannula (HFNC) or NIV, concurrent awake prone ventilation is recommended (weak recommendation, low evidence quality). ## Rationale Close monitoring of clinical signs of deterioration such as rapid progressive respiratory failure and shock, active management of complications, treatment of underlying diseases, prevention of secondary infections, and timely support of organ function were considered the rules for treating severe COVID-19. Severe patients with PaO 2 /-FiO 2 less than 300 mmHg and those with emergency signs during resuscitation should immediately receive adjuvant oxygen therapy and airway management; after receiving a nasal catheter or mask oxygen inhalation, if respiratory distress or hypoxemia is not improved within 1~2 h, HFNC or NIV should be applied; if the condition is still not improved after 1~2 h, IMV should be performed in time; Extracorporeal membrane oxygenation (ECMO) could be administered if available. One evidence-based guidelineand one treatment protocolrecommended that patients with severe COVID-19 who require assisted oxygenation (including HFNC) or NIV should be placed in the awake prone position for > 12 h if there is no contraindication. ## Recommendation 4 Corticosteroids are recommended for the treatment of severe COVID-19 (strong recommendation, moderate evidence quality). For adult patients with high inflammatory markers, tocilizumab (TCZ) could be considered (strong recommendation, moderate evidence quality). For patients receiving oxygen therapy but not on IMV, 5 days of remdesivir treatment could be considered (weak recommendation, moderate evidence quality). For patients who fail to respond to initial therapy, appropriate treatment with intravenous immunoglobulin (IVIg) could be considered (strong recommendation, moderate evidence quality). ## Rationale Two evidence-based guidelines, one systematic review [bib_ref] Efficacy and safety of systematic corticosteroids among severe COVID-19 patients: a systematic..., Ma [/bib_ref] , and one RCT [bib_ref] Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results..., Edalatifard [/bib_ref] indicated that corticosteroid use in patients with severe or critical COVID-19 was associated with lower all-cause mortality and IMV requirements, higher disease improvement rates, and longer survival, with no increase in the incidence of serious adverse events except for a potential increase of hyperglycemia. One evidence-based guideline, two systematic reviews [bib_ref] Optimal use of tocilizumab for severe and critical COVID-19: a systematic review..., Nugroho [/bib_ref] [bib_ref] The efficacy of IL-6 inhibitor Tocilizumab in reducing severe COVID-19 mortality: a..., Kaye [/bib_ref] , and one RCT [bib_ref] Effect of Tocilizumab vs usual care in adults hospitalized with COVID-19 and..., Hermine [/bib_ref] showed that TCZ reduced the risk of all-cause mortality and 14-day requirements of NIV and IMV in moderate to critical COVID-19 patients (including those with high interleukin-6 or C-reactive protein [CRP]; on oxygen support; have extensive bilateral lung disease; or need cortisol therapy) compared with UC, and subgroup analyses showed lower mortality at higher CRP levels (≥ 100 mg/L). An RCT [bib_ref] The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus..., Gharebaghi [/bib_ref] showed that IVIg therapy was associated with a significant reduction in mortality compared with placebo in patients with severe COVID-19 that fail to respond to initial therapy. A cohort study [bib_ref] High-dose intravenous immunoglobulin in severe coronavirus disease 2019: a multicenter retrospective study..., Cao [/bib_ref] indicated that high-dose IVIg (total dose of 2 g/kg body weight, over 2-5 days) significantly reduced mortality at 28 days in patients with severe COVID-19 compared to UC. The overall benefit of some treatments for COVID-19 patients is not clear, but their use under specific conditions may be beneficial. One evidence-based guidelineindicated that remdesivir could not improve important outcomes in patients with COVID-19 (low certainty evidence). However, another evidence-based guidelinesuggested 5-days remdesivir treatment for COVID-19 patients (adults and young people aged 12 and over with a weight of 40 kg or more) who are in hospital and on supplemental oxygen but not on IMV, as there is evidence indicated that remdesivir can probably reduce the risk of death slightly (moderate certainty evidence). Some treatments may have more impairments than benefits for the treatment of severe COVID-19. One evidence-based guidelineand one RCT [bib_ref] A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19, Cao [/bib_ref] indicated that Lpv/R treatment was not significantly different from UC in terms of mortality, IMV requirements, clinical improvement time, and length of hospital stay of the patients, and was more likely to result in gastrointestinal adverse events (low certainty evidence). One evidence-based guidelineand four systematic reviews [bib_ref] Hydroxychloroquine use and progression or prognosis of COVID-19: a systematic review and..., Zang [/bib_ref] [bib_ref] Hydroxychloroquine for treatment of nonsevere COVID-19 patients: systematic review and meta-analysis of..., Elsawah [/bib_ref] [bib_ref] Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: a systematic..., Sarma [/bib_ref] [bib_ref] The outcome of hydroxychloroquine in patients treated for COVID-19: systematic review and..., Mega [/bib_ref] showed no significant differences in viral clearance rate, clinical progression, or length of hospital stay in patients with treatment of HCQ compared with UC, and it may increase the risk of death, IMV, and adverse effects such as diarrhea and nausea/vomiting. ## Recommendation 5 Severe COVID-19 belongs to the "damp toxin epidemic" in TCM theory, and its main TCM pathogenesis is "epidemic toxin blocking lung" (consensus recommendation). TCM medications based on syndrome differentiation, such as "three CPMs and three decoctions" that has the effect of "releasing pulmonary Qi and detoxicating", are recommended to treat severe COVID-19 in combination with UC; TCM medications such as Ma Huang Liu Jun decoction that has the effect of "nourishing the spleen and dissipating dampness" is also recommended (strong recommendation, low to moderate evidence quality). ## Rationale The Diagnosis and treatment of COVID-19 (8th trial edition)suggested that the main TCM pathogenesis of severe COVID-19 is "epidemic toxin blocking lung"; TCM decoctions including QFPD decoction, HSBD decoction, and Qingwen Baidu decoction, and CPMs such as XBJ injection, are suggested to treat severe COVID-19. Two systematic reviews [bib_ref] Chinese herbal medicine for coronavirus disease 2019: a systematic review and meta-analysis, Xiong [/bib_ref] [bib_ref] Chinese medical drugs for coronavirus disease 2019: a systematic review and metaanalysis, Pang [/bib_ref] and nine clinical studies [bib_ref] Retrospective analysis of 38 cases of COVID-19 treated by integrated traditional Chinese..., Lian [/bib_ref] [bib_ref] Integrated traditional Chinese and western medicine in the treatment of 40 cases..., Pan [/bib_ref] [bib_ref] Exploring an integrative therapy for treating COVID-19: a randomized controlled trial, Wang [/bib_ref] [bib_ref] Xuebijing injection in the treatment of COVID-19: a retrospective case-control study, Guo [/bib_ref] [bib_ref] Traditional Chinese Medicine decoctions significantly reduce the mortality in severe and critically..., Sun [/bib_ref] showed that CPMs (LHQW granules, JHQG granule, Tongjie Quwen granules, and XBJ injection) or TCM decoctions (Maxingshigan decoction, QFPD decoction, Qingfei Tongxie Fuzheng decoction, Maxing Xuanfei Jiedu decoction, and other decoctions based on syndrome differentiation) that have the efficacy of "detoxicating and releasing pulmonary Qi" could effectively ameliorate the symptoms of fever, cough, expectoration, shortness of breath, and fatigue; promote CT image improvement and viral clearance rate; shorten the length of hospital stay; and reduce the severe conversion rate and mortality, with no significant differences in safety compared to UC (including IFN-α, Lpv/R, abidol, ribavirin, or chloroquine phosphate). Severe COVID-19 belongs to the "damp toxin epidemic" in TCM theory [bib_ref] Discussion on traditional Chinese medicine prevention and treatment strategies of coronavirus disease..., Tong [/bib_ref] , therefore, "nourishing the spleen to dissipating dampness" was considered an important treatment method [bib_ref] Discussion on traditional Chinese medicine prevention and treatment strategies of coronavirus disease..., Tong [/bib_ref] [bib_ref] Differentiation reasoning for treatment of patients with difficulty in expectoration of sticky..., Liu [/bib_ref] [bib_ref] Discussion on the medical records of COVID-19 from the perspective of dampness-toxin..., Ding [/bib_ref]. A cohort study [bib_ref] Chinese herbal medicine reduces mortality in patients with severe and critical Coronavirus..., Chen [/bib_ref] demonstrated that UC (including IFN and ribavirin) combined with Mahuang Liujun decoction based on syndrome differentiation significantly reduced the mortality of patients with severe COVID-19 compared with UC alone. Another cohort study [bib_ref] Curative effects of integrated traditional Chinese and western medicine treatment regimens on..., Xie [/bib_ref] showed that the TCM decoctions based on syndrome differentiation, which has the effect of "detoxicating and releasing pulmonary qi, nourishing spleen, and dissipating dampness", could significantly improve the CT score of pneumonia, improve symptoms and inflammatory indicators, and reduce the incidence of adverse events in patients with severe COVID-19 compared with UC (including Lpv/R). ## Clinical question 3: how to treat elderly patients with severe covid-19 with integrated tcm and western medicine? ## Recommendation 6 For elderly patients with COVID-19, polypharmacy should be appropriately reduced; drug dose should be adjusted according to the condition, organ function, and drug interactions; and adverse events should be prevented. (consensus recommendation). ## Rationale Older people are more likely to have deteriorated liver and kidney function, a low drug clearance rate, and a high risk of adverse events and liver/kidney damage. The Pharmacopoeia of the People's Republic of China (2015 edition)stipulates that elderly people (60-80 years old) should be given 3/4-4/5 of the dose as adults (18-60 years old), and the dose for elderly people over 80 years old should be reduced to 1/2 of that for adults. For elderly patients with COVID-19, medication prescriptions should be reviewed to reduce polypharmacy and prevent drug interactions and adverse events; community workers, doctors, nurses, pharmacists, physiotherapists, occupational therapists, mental health and psychosocial care providers, and other health care professionals should facilitate multidisciplinary collaboration in the decision-making process to solve multimorbidity and hypofunction problems in elderly patients. ## Recommendation 7 For elderly patients with severe COVID-19, potential complications such as secondary infection and disseminated intravascular coagulation should be closely monitored and actively prevented; treatments should focus on supportive, symptomatic treatment and TCM treatment with syndrome differentiation. (consensus recommendation). ## Rationale Elderly COVID-19 patients are characterized by numerous underlying diseases, multiple complications, variable conditions, and limited nutritional intake [bib_ref] Analysis of clinical characteristics of elderly patients with novel coronavirus pneumonia, Zhang [/bib_ref] , suggesting that their management should be focused on supportive, symptomatic treatment, and TCM treatment based on syndrome differentiation. The neutrophil ratio in elderly patients with COVID-19 was significantly higher than that in non-elderly patients [bib_ref] Analysis of clinical characteristics of elderly patients with novel coronavirus pneumonia, Zhang [/bib_ref] , suggesting that elderly patients may be more susceptible to secondary infections. Therefore, respiratory pathogen monitoring should be actively performed, and targeted anti-infective treatment should be performed timely. D-dimer is significantly elevated in elderly patients [bib_ref] Analysis of clinical characteristics of elderly patients with novel coronavirus pneumonia, Zhang [/bib_ref] , suggesting a higher risk of disseminated intravascular coagulation; thus, close monitoring of coagulation indicators and timely implementation of interventions as well as symptomatic, supportive therapies and TCM treatment with syndrome differentiation are recommended. A cohort study on SARS [bib_ref] Clinical study on the treatment of elderly patients with SARS by integrated..., Huang [/bib_ref] showed that TCM decoction treatment with phased syndrome differentiation could significantly reduce the mortality of elderly patients and increase the improvement rate of clinical symptoms, which may provide a reference for the treatment of elderly COVID-19 patients. ## Recommendation 8 Elderly patients with COVID-19 showed more significant signs of the TCM pathogenesis of "deficiency" and "stasis" than non-elderly patients; therefore, the TCM therapeutic method of "strengthening healthy energy and removing blood stasis" is suggested (consensus recommendation). ## Rationale Elderly patients with COVID-19 are characterized by reduced physiological and immune function. Their peripheral blood albumin and prealbumin are significantly lower than those of non-elderly patients, and the number of patients with inappetence is significantly larger than that of non-elderly patients, which might be related to the TCM pathogenesis of "deficiency". Compared to non-elderly patients, elderly patients with COVID-19 are more likely to have combined cardiovascular disease and significantly higher D-dimer, which might be due to the TCM pathogenesis of "stasis" [bib_ref] Analysis of clinical characteristics of elderly patients with novel coronavirus pneumonia, Zhang [/bib_ref]. Accordingly, the treatment should focus on "strengthening healthy energy and removing blood stasis" based on syndrome differentiation. ## Clinical question 4: how to mitigate the adverse effects of medications with integrated tcm and western medicine in the treatment of severe covid-19? ## Recommendation 9 Use the medications that carries the lowest risk of drug-drug interactions with other medications that the patient may be receiving; for medications with dose-dependent negative effects, minimum effective doses should be used for the shortest duration (consensus recommendation). ## Rationale Careful consideration should be given to the numerous side effects of medications that may be used in the treatment of COVID-19, as well as drug-drug interactions between medications, both of which may affect COVID-19 symptomatology (including effects on respiratory, cardiac, immune, and mental or neurological function). Both pharmacokinetic and pharmacodynamic effects should be considered. ## Recommendation 10 Symptomatic treatment combined with TCM treatment based on syndrome differentiation is recommended for reducing potential adverse events in patients with severe COVID-19 (consensus recommendation). For liver damage, the combination of symptomatic treatment with TCM decoction based on the therapeutic strategy of "strengthening primordial energy, releasing pulmonary qi, nourishing spleen, and detoxification" is recommended (weak recommendation, low evidence quality). ## Rationale A cohort study [bib_ref] Curative effects of integrated traditional Chinese and western medicine treatment regimens on..., Xie [/bib_ref] showed that TCM decoctions based on the therapeutic method of "strengthening primordial energy, releasing pulmonary qi, nourishing spleen, and detoxification" in combination with symptomatic treatment could significantly reduce the incidence of adverse events (especially elevated liver enzymes) of severe COVID-19. ## Recommendation 11 TCM treatment for severe COVID-19 based on syndrome differentiation could reduce adverse events by shortening the application time and total dose of other medications, such as antivirals or corticosteroids (strong recommendation, low evidence quality). ## Rationale TCM medications based on syndrome differentiation could increase the treatment efficacy for severe COVID-19 with good safety , and therefore may reduce the adverse events by shortening the application time and total amount of other medications, such as antivirals or corticosteroids. ## Clinical question 5: how to treat the complications of severe covid-19 with integrated tcm and western medicine? ## Recommendation 12 For all potential complications of severe COVID-19, active monitoring and evaluation should be carried out according to the TCM theory of "treating the disease before it occurs (preventive treatment of disease)"; if complications have already occurred, it is recommended to immediately follow local treatment protocols for symptomatic treatment (consensus recommendation). ## Rationale Two evidence-based guidelinesand one treatment protocolsuggested active monitoring of COVID-19 patients for signs or symptoms of thromboembolism, such as stroke, deep vein thrombosis, pulmonary embolism, or acute coronary syndrome; if clinically suspected, an appropriate diagnostic and management pathway needs to be initiated immediately. Adolescent and adult patients with COVID-19 should be evaluated for the risk of hemorrhage immediately after admission. For patients with suspected or confirmed myocardial injury, high-sensitivity troponin measurements and continuous ECG monitoring should be repeated daily, and blood pressure, heart rate, and fluid balance should be measured. ## Recommendation 13 For fatigue, chest distress, shortness of breath, loss of appetite, limb pain, and other complications in patients with severe COVID-19, it is recommended to use HXZQ capsule/dropping pill combined with LHQW capsule/granule based on syndrome differentiation (strong recommendation, moderate evidence quality). For digestive system complications, including anorexia, diarrhea, and constipation, TCM decoctions based on syndrome differentiation may be more effective than CPMs (strong recommendation, moderate evidence quality). For abdominal fullness, anorexia, and nausea, TCM herbs, such as Magnolia Bark (Houpu), Cablin patchouli herb (Huoxiang), and Atractylodes Rhizome (Cangzhu), that have the effect of "regulating stomach and dissipating dampness" or TCM herbs, such as roasted Endothelium Corneum Gigeriae Galli (Jineijin), fire-dried Fructus Crataegi (Shanzha), and Fructus Amomi (Sharen), that have the effect of "tonifying spleen and appetizing" could be considered based on syndrome differentiation (consensus recommendation). For constipation, dry stool, and abdominal distension, the Chengqi decoction series based on syndrome differentiation are suggested (consensus recommendation). For pulmonary function damage including pulmonary fibrosis, the TCM herbs, such as Circada Moulting (Chantui), Body of sick Silkworm (Jiangcan), and lumbricus (Dilong), that have the effects of "dispelling wind, dredging collaterals, and resolving hard lumps" could be considered; or Guizhi Fuling decoction (pill) could be considered for those who do not have high fever (consensus recommendation). ## Rationale One RCTindicated that, HXZQ dripping pills combined with LHQW granules can effectively improve nausea, vomiting, limb pain, loss of appetite, limb pain, fatigue, chest tightness, shortness of breath, and other symptoms in patients with COVID-19, and meanwhile reduce the use of antibiotics. With the treatment of UC combining CPMs based on syndrome differentiation, some patients showed improvement in symptoms such as fever, cough, sore throat, and fatigue, while digestive symptoms such as poor appetite, diarrhea, or constipation did not improve significantly; after changing the CPMs to TCM decoctions with syndrome differentiation, the aforementioned symptoms improved [bib_ref] Analysis on clinical efficacy and liver injury of 100 cases of COVID-19..., Xia [/bib_ref]. TCM herbs, such as Magnolia Bark (Houpu), Cablin patchouli herb (Huoxiang), Atractylodes Rhizome (Cangzhu), with the effects of "regulating stomach and dissipating dampness" and TCM herbs, such as roasted Endothelium Corneum Gigeriae Galli (Jineijin), fire-dried Fructus Crataegi (Shanzha) and Fructus Amomi (Sharen), with the effects of "tonifying spleen and appetizing" based on syndrome differentiation can improve abdominal fullness, anorexia, nausea, diarrhea, and other gastrointestinal symptoms in patients with severe COVID-19 [bib_ref] Analysis on clinical efficacy and liver injury of 100 cases of COVID-19..., Xia [/bib_ref]. Treatment of Chengqi decoction series including Da Chengqi decoction, Xuanbai Chengqi decoction, and Jiedu Chengqi decoction based on syndrome differentiation can improve constipation, dry stool, abdominal distension, and other symptoms in patients with severe COVID-19 [bib_ref] Analysis on clinical efficacy and liver injury of 100 cases of COVID-19..., Xia [/bib_ref]. Early use of TCM medications such as Circada Moulting (Chantui), Body of Sick Silkworm (Jiangcan), and lumbricus (Dilong), Red Peony Root (Chishao), Peach Kernel (Taoren), and the Salvia Root (Danshen), with the effects of "dispelling wind, dredging collaterals, and resolving hard lumps" may reduce the severity of pulmonary fibrosis; for those who do not have high fever, Guizhi Fuling decoction (pill) could also be considered for treatment [bib_ref] Deciphering the potential pharmaceutical mechanism of GUI-ZHI-FU-LING-WAN on systemic sclerosis based on..., Wang [/bib_ref]. 6.6. 6.6Clinical Question 6: How to carry out integrated TCM and western medicine treatment for patients recovering from severe COVID-19? ## Recommendation 14 All patients before hospital discharge or those experienced persistent symptoms and/or functional limitations after hospital discharge should be screened for rehabilitation needs in terms of physical, cognitive, and mental disorders, to facilitate onward referral and/or be managed timely (consensus recommendation). ## Rationale All patients with COVID-19 before hospital discharge should be screened for rehabilitation needs (including physical deconditioning, and respiratory, swallow, cognitive or mental health disorders) to facilitate onward referral; patients who have been discharged from the hospital and experienced persistent symptoms and/or functional limitations should also be screened for rehabilitation needs to be managed in a timely manner. ## Recommendation 15 All severe COVID-19 patients should be provided with education and support for self-management of breathlessness and resumption of activities. (consensus recommendation). ## Rationale Patients with severe COVID-19 are more likely to have severely impaired pulmonary diffusion capacity and abnormal chest imaging manifestations, and therefore, are the main target population for longterm recovery intervention [bib_ref] Cao, 6-month consequences of COVID-19 in patients discharged from hospital: a cohort..., Huang [/bib_ref]. All severe COVID-19 patients should be educated and supported. Education on breathing control, such as high side lying, forward lean sitting, pursed lip breathing, and square box breathing, can support patients recovering from respiratory illness. Appropriate walking pace regulation is recommended to reduce breathlessness and prevent oxygen desaturation on exertion. All rehabilitating patients should be educated to resume daily activities conservatively at an appropriate pace that is safe and manageable, and the increase of exercise should be gradual and based on symptoms. ## Recommendation 16 The general TCM pathogenesis of patients recovering from severe COVID-19 is "unexhausted evil Qi and unrecovered healthy Qi", and the specific pathogenesis is mainly characterized by "deficiency, stasis, and dampness". The basic TCM syndromes are "Qi deficiency of the lung and spleen, and Qi and Yin deficiency", which are conditionally combined with "uncleared toxin and phlegm-stasis blocking collaterals" (consensus recommendation). ## Rationale The general pathogenesis of patients recovering from severe COVID-19 is characterized by "unexhausted evil Qi (epidemic toxin) and unrecovered healthy Qi". Although the epidemic toxin has been attenuated, the body's Yin and Yang were both damaged, both Qi and Yin were injured, and the epidemic toxin was difficult to be dispelled, which results in the TCM syndrome of "origin deficiency and superficial actuality" or "a mixture of deficiency and actuality". Specific pathogenesis is mainly "deficiency, stasis, and dampness". The pathogenesis "Qi deficiency, Yin deficiency, lung and spleen deficiency" belongs to "origin deficiency", and the pathogenesis "stasis, dampness, and unexhausted epidemic toxin" belongs to "superficial actuality". The basic TCM syndrome can be summarized as "Qi deficiency of the lung and spleen, and deficiency of both Qi and Yin" combined with "uncleared toxin" or "phlegm-stasis blocking collaterals" [bib_ref] Analysis of TCM syndrome types in the recovery period of novel coronavirus..., Min [/bib_ref]. ## Recommendation 17 For the management of function disorders, pulmonary fibrosis, mental health problems, decreased mobility, glucocorticoids sequelae, and recurrence of positive RT-PCR test results that patients who recovering from severe COVID-19 may experience, TCM decoctions and CPMs with syndrome differentiation are recommended (strong recommendation, low evidence quality). TCM therapy such as acupuncture and moxibustion, manipulation, auricular points therapy, skin-scraping therapy, cupping, foot bath, diet therapy, and emotional therapy, or traditional Chinese excises such as Baduanjin and Tai-chi, are also recommended (strong recommendation, moderate evidence quality). ## Rationale A cohort study [bib_ref] Clinical study on integrated traditional Chinese and western medicine therapy to improve..., Zhang [/bib_ref] showed that, in combining with UC, the TCM decoction series of Yiqi Yangyin (YQYY) decoction, Bufei Jianpi (BFJP) decoction, and Yangyin Qingre (YYQR) decoction, together with Xiaoyao powder, which has the effect of "soothing the liver to relieve depression", "nourishing spleen and harmonizing Ying", and "eliminating the remaining evil Qi (epidemic toxin)", were used with modification according to the patient's specific condition; they significantly improved the life quality of patients recovered from SARS in ten aspects, including asthmatic, cycling, shopping, stairs climbing, chest tightness, melancholy, anger, restricted activity, worrying about the present, and worrying about the future. A treatment protocolrecommended that patients recovered from COVID-19 can be treated with acupuncture and moxibustion, manipulation, auricular points therapy, skin-scraping therapy, cupping, and other non-oral drug TCM therapies; diet therapy and emotional therapy; or traditional Chinese excises including the Baduanjin and Tai-chi. A cohort studyshowed that the comprehensive treatment based on syndrome differentiation, including TCM decoction, CPM, acupuncture, foot bath, and Baduanjin exercise, can significantly reduce the recurrence of positive RT-PCR test results of the viral nucleic acid in patients recovered from COVID-19. For patients with severe COVID-19 treated with glucocorticoids, sequela may occur after discontinuation, such as femoral head necrosis (FHN), which is the most common and should be prevented early. The main TCM syndrome of FHN is "fire excess from Yin deficiency" and "deficiency of both Yin and Yang" combined with "blood stasis and phlegm-dampness", which can be treated with Liuwei Dihuang pill, Jinkui Shenqi pill, or Jisheng Shenqi pill based on syndrome differentiation [bib_ref] Concerns and suggestions for management of coronavirus disease 2019 in convalescence with..., Wang [/bib_ref]. For convalescent patients with severe COVID-19, prompt identification and assessment as well as early warning mechanism for possible adverse mental states should be established, and psychosocial support strategies and first-line intervention should be initiated for management. (consensus recommendation). ## Rationale More than 60% of COVID-19 patients may experience adverse mental states such as anxiety and depression [bib_ref] Investigation of psychological status of patients with COVID-19 and analysis of related..., Chen [/bib_ref] [bib_ref] Mental health status and psychological intervention of patients with new coronavirus pneumonia..., Yang [/bib_ref]. An evidence-based guidelineand a treatment protocolsuggested establishing a dynamic evaluation and warning mechanism for prompt identification, assessment, and intervention of possible psychological crises. For patients with mild adverse mental states, psychological self-adjustment including breath relaxation training and mindfulness training is recommended. For patients with moderate to severe adverse mental states, intervention by combining medication and psychotherapy is suggested. For patients experiencing anxiety and depression, basic psychological interventions such as psychological first aid, stress management, and brief psychological interventions based on the principles of cognitive behavior therapy should be considered. For severe anxiety, medications, especially those with a short half-life and low risk of drug-drug interactions, at the lowest possible dose and the shortest possible duration as can be considered. ## Recommendation 19 It is recommended to provide basic mental health and psychosocial support to all patients with severe COVID-19 by asking and addressing their needs and concerns. (consensus recommendation). ## Rationale Basic mental health and psychosocial support is essential for the treatment of patients and is an indispensable part of medical care for different groups affected by COVID-19, including severe patients. Patients should continue receiving mental health and psychosocial support and be followed up after hospital discharge to ensure that their symptoms continue being improved. ## Recommendation 20 For anxiety, fear, depression, somatization symptoms, and other adverse mental states that severe COVID-19 patients may experience, psychological counseling, mental health education, and non-drug treatment such as Tai Chi, breathing relaxation training, mindfulness training, cognitive behavioral therapy, and group intervention are recommended (strong recommendation, low evidence quality). Symptomatic treatment combined with TCM decoctions based on syndrome differentiation, which follows the therapeutic method of "soothing the liver and relieve depression, reinforcing earth (spleen) to strengthen metal (lung)" and "eliminating the remaining evil Qi", is also suggested (weak recommendation, low evidence quality). ## Rationale Two before-after studies [bib_ref] Mental health status and psychological intervention of patients with new coronavirus pneumonia..., Yang [/bib_ref] [bib_ref] The influence of Taijiquan on depression and hope level of patients with..., Xu [/bib_ref] showed that psychological counseling, mental health education, cognitive behavioral therapy, mindfulness therapy, group intervention, and Tai Chi can significantly improve the adverse mental status of COVID-19 patients, such as anxiety, fear, depression, and somatization symptoms. Furthermore, two RCTs [bib_ref] Clinical study on integrated traditional Chinese and western medicine therapy to improve..., Zhang [/bib_ref] [bib_ref] Effect of integrated traditional Chinese and western medicine treatment on 85 cases..., Bian [/bib_ref] showed that symptomatic treatment combined with TCM decoctions, including YQYY decoction, BFJP decoction, and YYQR decoction, based on syndrome differentiation, which has the effect of "soothing the liver and relieve depression, reinforcing earth (spleen) to strengthen metal (lung)" and "eliminating the remaining evil Qi", can significantly improve sadness, depression, anger, worry, and other adverse mental states of COVID-19 patients. Rehabilitation care should be implemented as soon as possible for patients with severe COVID-19, which could be carried out in parallel with the treatment of the disease according to the correct assessment (consensus recommendation). ## Rationale In case of stable oxygenation and hemodynamics, passive and active activities should be carried out as soon as possible to promote sputum drainage and pulmonary rehabilitation. Interventions could be initiated by rehabilitation professionals in the acute phase of the disease to reduce respiratory distress, prevent complications, and support communication. The timing of the start of rehabilitation care should be decided by the multidisciplinary team based on the medical condition of the patient. ## Recommendation 22 For potential impaired pulmonary function and pulmonary fibrosis in convalescent patients with severe COVID-19, pulmonary rehabilitation training and TCM decoction according to syndrome differentiation, which follows the therapy method of "reinforcing earth (spleen) to strengthen metal (lung), eliminating phlegm to dredging collaterals" and "eliminating the remaining evil Qi (epidemic toxin)", are suggested (weak recommendation, low evidence quality); Baduanjin, Tai-chi, 6character breathing exercise, posture management, breathing exercise management, and other Chinese and western non-drug treatments are also suggested (strong recommendation, low evidence quality). ## Rationale A systematic review [bib_ref] Effectiveness of pulmonary rehabilitation in interstitial lung disease including coronavirus diseases: a..., Reina-Gutiérrez [/bib_ref] of interstitial lung disease (including pulmonary fibrosis after severe COVID-19 infection) showed that pulmonary rehabilitation training, including combined exercise (aerobic with strength), combined exercise with specific respiratory exercises, and aerobic exercise with specific respiratory muscle training, significantly improved pulmonary function (forced vital capacity), exercise capacity (6-minute walking distance), and health-related quality of life of convalescent patients with severe COVID-19. Three RCTs [bib_ref] Clinical study on integrated traditional Chinese and western medicine therapy to improve..., Zhang [/bib_ref] [bib_ref] Effect of traditional Chinese medicine treatment on lung function and quality of..., Chen [/bib_ref] [bib_ref] Clinical observation on intervention of series of Chinese herbal medicines on pulmonary..., Bian [/bib_ref] showed that, for SARS convalescent patients, TCM decoctions such as YQYY decoction, BFJP decoction, and YYQR decoction, based on syndrome differentiation and following the therapy strategy of "reinforcing earth (spleen) to strengthen metal (lung), eliminating phlegm to dredging collaterals" and "eliminating the remaining evil Qi (epidemic toxin)", can significantly improve the chest x-ray manifestations of pulmonary fibrosis (blindly scored by the specialized radiologist, in principle based on the density and extent of shadows on chest radiographs), total lung capacity, diffusion capacity for carbon monoxide, and symptoms such as dyspnea and chest distress. Two treatment protocolssuggested using posture management, breathing exercise management, or TCM health-preserving exercises such as Baduanjin and Tai-chi, and 6-character breathing exercise for pulmonary function recovery. # Conclusion This is the first guideline for the management of severe COVID-19 by integrated Chinese and western medicine, based on a systematic search of evidence applying the GRADE classification system. As there is still a discrepancy between existing studies and clinical practice due to the suddenness of the epidemic, a large number of high-quality studies are needed in the field of integrated Chinese and western medicine for severe COVID-19, especially for the old patients, as they are the main focus of the severe COVID-19. Because of the inadequacy or lack of clinical evidence, some of the recommendations are of weak recommendation level. Therefore, we suggest physicians make appropriate choices when applying them in clinical practice by considering the actual conditions and values of the patients. Moreover, as the population of patients grows, the rehabilitation of COVID-19, including the management of long-COVID/PACS, has become a facing challenge, while high quality studies remain inadequate. TCM has advantages in long-COVID management for its strengths in rehabilitation, individualized treatment, and self-immunity enhancement, and therefore, will be the focus of the guideline update. In addition, users of this guidelines are welcome to provide valuable suggestions and comments through clinical practice, and we will continue improving them in the next edition. # Funding This work was supported by the Key Project "Emergency Prevention and Treatment of COVID-19 ′′ of the Zhejiang Provincial Natural Science Foundation of China (grant number LEZ20H190001). # Declaration All authors declare that there is no conflict of interest. The opinions covered in this guide should not be used for commercial promotion or publicity. [fig] Figure 1: Guideline development process. [/fig] [fig] 6. 7: Clinical Question 7: How to improve the mental health of patients recovering from severe COVID-19 with integrated TCM and western medicine? 6.7.1. Recommendation 18 [/fig] [fig] 6. 8: Clinical Question 8: How to help rehabilitate pulmonary function in patients with severe COVID-19 with integrated TCM and western medicine? 6.8.1. Recommendation 21 [/fig] [table] Table 1: Evidence quality grades and strength of recommendations. [/table] [table] Table 2: WHO severe COVID-19 definition. [/table] [table] Table 3: Definition of severe COVID-19 in the Diagnosis and treatment of COVID-19 (8th trial edition). meet any of the following criteria:1. Shortness of breath, respiratory rate (RR) ≥ 30 breaths/min; 2. Oxygen saturation ≤ 93% on air inhalation at rest state; 3. Arterial partial pressure of oxygen (PaO 2 )/inhaled oxygen concentration (FiO 2 ) Refusal of food or feeding difficulties, with signs of dehydration. [/table]	None	None	None
159c2d5c6d31c313bc72f933955ab4d903e2eee9	pubmed	American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period	American College of Gastroenterology-Canadian Association of Gastroenterology Clinical Practice Guideline: Management of Anticoagulants and Antiplatelets During Acute Gastrointestinal Bleeding and the Periendoscopic Period We conducted systematic reviews of predefined clinical questions and used the Grading of Recommendations, Assessment, Development and Evaluations approach to develop recommendations for the periendoscopic management of anticoagulant and antiplatelet drugs during acute gastrointestinal (GI) bleeding and the elective endoscopic setting. The following recommendations target patients presenting with acute GI bleeding: For patients on warfarin, we suggest against giving fresh frozen plasma or vitamin K; if needed, we suggest prothrombin complex concentrate (PCC) compared with fresh frozen plasma administration; for patients on direct oral anticoagulants (DOACs), we suggest against PCC administration; if on dabigatran, we suggest against the administration of idarucizumab, and if on rivaroxaban or apixaban, we suggest against andexanet alfa administration; for patients on antiplatelet agents, we suggest against platelet transfusions; and for patients on cardiac acetylsalicylic acid (ASA) for secondary prevention, we suggest against holding it, but if the ASA has been interrupted, we suggest resumption on the day hemostasis is endoscopically confirmed. The following recommendations target patients in the elective (planned) endoscopy setting: For patients on warfarin, we suggest continuation as opposed to temporary interruption (1-7 days), but if it is held for procedures with high risk of GI bleeding, we suggest against bridging anticoagulation unless the patient has a mechanical heart valve; for patients on DOACs, we suggest temporarily interrupting rather than continuing these; for patients on dual antiplatelet therapy for secondary prevention, we suggest temporary interruption of the P2Y 12 receptor inhibitor while continuing ASA; and if on cardiac ASA monotherapy for secondary prevention, we suggest against its interruption. Evidence was insufficient in the following settings to permit recommendations. With acute GI bleeding in patients on warfarin, we could not recommend for or against PCC administration when compared with placebo. In the elective periprocedural endoscopy setting, we could not recommend for or against temporary interruption of the P2Y 12 receptor inhibitor for patients on a single P2Y 12 inhibiting agent. We were also unable to make a recommendation regarding same-day resumption of the drug vs 1-7 days after the procedure among patients prescribed anticoagulants (warfarin or DOACs) or P2Y 12 receptor inhibitor drugs because of insufficient evidence. SUPPLEMENTARY MATERIAL accompanies this paper at # Introduction Antithrombotic drugs including vitamin K antagonists (VKAs; warfarin and acenocoumarol), direct oral anticoagulants (DOACs; apixaban, dabigatran, edoxaban, and rivaroxaban), antiplatelet drugs such as the P2Y 12 receptor inhibitors (clopidogrel, prasugrel, and ticagrelor), and acetylsalicylic acid (ASA) [bib_ref] Risk of gastrointestinal bleeding increases with combinations of antithrombotic agents and patient..., Abraham [/bib_ref] are used in the management of patients with atrial fibrillation, ischemic heart disease, venous thromboembolism, and valvular heart disease. These drugs also increase the risk of gastrointestinal (GI) bleeding from luminal sources such as ulcers or diverticula and after endoscopic procedures [bib_ref] Gastrointestinal safety of direct oral anticoagulants: A large population-based study, Abraham [/bib_ref] [bib_ref] Endoscopy-related bleeding and thromboembolic events in patients on direct oral anticoagulants or..., Rodríguez De [/bib_ref]. Standardized, evidencebased protocols are lacking to inform best practices before and after endoscopic procedures in urgent and elective settings. Furthermore, uncertainty regarding best practice recommendations and associated levels of evidence has led to significant variation in adherence to guideline-directed practices [bib_ref] Clinical practice and guidelines for managing antithrombotics before and after endoscopy: A..., Jeon [/bib_ref]. The American College of Gastroenterology (ACG) and the Canadian Association of Gastroenterology (CAG) convened an international, multisociety, and multidisciplinary working group to create a focused, pragmatic guideline after distillation of published literature to inform clinical practice in the periendoscopic period. In keeping with the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach (5), the most pertinent clinical questions guided the systematic review of the literature, with the resulting rigorous methodological evaluation of the available published data informing recommendations. In this document, we propose an evidence-based approach to periprocedural antithrombotic drug management in common emergent and elective settings addressing clinical questions related to (i) temporary interruption of anticoagulant and antiplatelet drugs; (ii) reversal of anticoagulant and antiplatelet drugs; (iii) periprocedural heparin bridging; and (iv) postprocedural resumption of anticoagulant and antiplatelet drugs. This document does not cover all possible clinical situations where multidisciplinary guidance may be necessary to manage periendoscopic antithrombotic therapy. Nor does it address the rapidly evolving menu of endoscopic approaches developed to minimize intraprocedural and postprocedural bleeding in situations such as removing large colonic polyps [bib_ref] Prophylactic clipping after colorectal endoscopic resection prevents bleeding of large, proximal polyps:..., Spadaccini [/bib_ref]. Because of insufficient evidence, the panel could not recommend a best practice for all clinical questions. These clinical situations are identified as priorities for future research. # Methods These guidelines are established to support clinical practice and suggest preferable approaches to a typical patient with a particular medical problem based on the currently available published literature. When exercising clinical judgment, particularly when treatments pose significant risks, healthcare providers should incorporate this guideline in addition to patient-specific medical comorbidities, health status, and preferences to arrive at a patientcentered care approach. The methods for this guideline were agreed on a priori by the ACG and the CAG with the express intent to codevelop highquality multisociety guidelines that reduce duplication of effort and improve impact. The methods have followed the GRADE approach [bib_ref] GRADE: An emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref]. The target population of this guideline is patients receiving anticoagulants or antiplatelet drugs who are (i) hospitalized or under observation with acute GI bleeding or (ii) undergoing inpatient or outpatient elective GI endoscopic procedures. The target audience for this guideline includes healthcare providers, public health policymakers, patients, and caregivers. The guideline panel was led by 2 gastroenterology cochairs (N.S.A. and A.N.B.). It included 6 voting content experts-4 gastroenterologists (N.S.A., A.N.B., L.L., and J.T.), 1 cardiologist (P.A.N.), 1 thrombosis expert (J.D.), and 2 nonvoting gastroenterologists who served as the GRADE methodologists (G.I.L. and B.S.). No patients were included in the guideline process. The panel developed, prioritized, and finalized the clinical questions in Population, Intervention, Comparator, and Outcome (PICO) format through teleconferences before systematic literature reviews. The critical outcomes were 7-day further bleeding and 30-day thrombotic events for patients with acute GI bleeding and 30-day bleeding and 30-day thrombotic events after elective endoscopic procedures. The final PICO questions were shared with the leadership of the ACG Practice Parameters Committee and the CAG Clinical Affairs Committee. The editorial office of the Cochrane Gut Group at McMaster University developed and ran searches in MEDLINE, EMBASE, and CENTRAL for randomized controlled trials (RCTs), controlled or uncontrolled observational studies, and systematic reviews of any study design published in the English language as full text (conference abstracts were not included) between January 1, 1995 (January 1, 1985, for some searches), and August 13, 2020. Full details of search strategies can be found in Supplementary Digital Content (see Appendix 1, http://links.lww.com/AJG/ C416). Each identified abstract was screened for eligibility in duplicate by at least 2 of the 4 voting gastroenterologists. Potentially eligible studies were assessed as full-text articles by the GRADE methodologists or 1 of the 4 voting gastroenterologists. A GRADE methodologist verified data extraction. An evidence map was prepared for each PICO question. The panel reviewed the preliminary evidence map, proposed additional articles, and assisted in supplementary literature searches targeting broader populations when gaps in the evidence were identified. Where appropriate, more recent publications available after the formal literature search and evidentiary review are discussed for contextual information if deemed to provide critical additional contemporary insight. The 2 GRADE methodologists prepared assessments of the risk of bias of each included study and developed complete evidence reports, including a summary of evidence tables (see Appendix 2, Supplementary Digital Content, http://links.lww.com/ AJG/C417). The certainty of the evidence for each PICO question was categorized as very low, low, moderate, or high depending on the assessment of (i) limitations in the design and execution of the studies, (ii) indirectness, (iii) inconsistency, (iv) imprecision, and (v) other considerations including publication bias, according to the GRADE approach [bib_ref] GRADE guidelines: 4. Rating the quality of evidence: Study limitations (risk of..., Guyatt [/bib_ref]. Manuscripts initially deemed potentially eligible but eventually excluded are listed in Supplementary Digital Content (see Appendix 3, http://links.lww.com/ AJG/C418) with reasons for exclusion. Each GRADE methodologist, in turn, prepared half of the evidence reports, whereas the other methodologist double-checked them, providing feedback until agreement was achieved. For each PICO, 3 versions of the wording of the potential recommendation were prepared a priori (in favor, against, or unable to recommend). The opinions of individual content experts were sought for specific issues. The evidence reports and risk of bias tables were shared with the whole panel on , and discussed by e-mail. The finalized document was shared before the voting videoconference meetings on May 8 and 15, 2021. One cochair (A.N.B.) and 1 GRADE methodologist (G.I.L.) moderated the voting videoconference meetings. For each PICO, the GRADE methodologist presented a summary of the evidence, including the direction and magnitude of effect for desirable and undesirable outcomes and the certainty of the evidence. After The American Journal of GASTROENTEROLOGY ACG-CAG Clinical Practice Guideline which, the panel discussed results. All domains of the Evidenceto-Decision Framework [bib_ref] GRADE evidence to decision (EtD) frameworks: A systematic and transparent approach to..., Alonso-Coello [/bib_ref] , including the certainty of evidence on the balance between desirable and undesirable outcomes, evidence and assumptions about patient values and preferences, feasibility, acceptability, and resource use associated with alternative management options, were reviewed, agreed on, summarized, and tabulated in real time for the PICO question being assessed [bib_ref] GRADE evidence to decision (EtD) frameworks: A systematic and transparent approach to..., Alonso-Coello [/bib_ref]. Notes were taken with regards to qualifiers and dissenting opinions. The 6 voting panel members then voted on the direction of the recommendation (in favor vs against) for that PICO question with its corresponding wording. The predetermined threshold vote for consensus was 75% (i.e., 5 of 6 panel members). If consensus was not reached, the topic was further discussed, and reasons for disagreement were sought, with the panel voting for a second time. If the 75% threshold could still not be reached, the conclusion that "we could not reach a recommendation for or against" the intervention was assigned to that PICO question. ## Direct thrombin inhibitor reversal (dabigatran) 5. For patients on dabigatran who are hospitalized or under observation with acute GIB, we suggest against the administration of idarucizumab (conditional recommendation, very low certainty of evidence). Reversal of rivaroxaban/apixaban with andexanet alfa 6. For patients on rivaroxaban or apixaban who are hospitalized or under observation with acute GIB, we suggest against andexanet alfa administration (conditional recommendation, very low certainty of evidence). ## Reversal of direct oral anticoagulant with pcc 7. For patients on DOACs who are hospitalized or under observation with acute GIB, we suggest against PCC administration (conditional recommendation, very low certainty of evidence). ## Reversal of antiplatelet with platelet transfusion 8. For patients on antiplatelet agents who are hospitalized or under observation with acute GIB, we suggest against platelet transfusions (conditional recommendation, very low certainty of evidence). Holding ASA vs continuing ASA 9. For patients with GI bleeding on cardiac ASA for secondary prevention, we suggest against holding the ASA (conditional recommendation, very low certainty of evidence). ## Resumption of asa after endoscopic hemostasis 10. For patients with GI bleeding on ASA for secondary cardiovascular prevention whose ASA was held, we suggest the ASA be resumed on the day hemostasis is endoscopically confirmed (conditional recommendation, very low certainty of evidence). ASA, acetylsalicylic acid; FFP, fresh frozen plasma; DOAC, direct oral anticoagulant; GI, gastrointestinal; GIB, GI bleeding; PCC, prothrombin complex concentrate. . Guideline statements, the strength of recommendation, and certainty of the evidence for the management of antithrombotic agents in the elective endoscopy setting Management of antithrombotic agents in the elective endoscopy setting Anticoagulant interruption vs continuation 11. For patients on warfarin undergoing elective/planned endoscopic GI procedures, we suggest warfarin be continued, as opposed to temporarily interrupted (1-7 d) (conditional recommendation, very low certainty of evidence). 12. For patients on warfarin, who hold warfarin in the periprocedural period for elective/planned endoscopic GI procedures, we suggest against bridging anticoagulation (conditional recommendation, low certainty of evidence). 13. For patients on DOACs who are undergoing elective/planned endoscopic GI procedures, we suggest temporarily interrupting DOACs rather than continuing DOACs (conditional recommendation, very low certainty of evidence). ## Antiplatelet interruption vs continuation 14a. For patients on dual antiplatelet therapy for secondary prevention who are undergoing elective endoscopic GI procedures, we suggest temporary interruption of the P2Y 12 receptor inhibitor while continuing ASA (conditional recommendation, very low certainty of evidence). 14b. For patients on single antiplatelet therapy with a P2Y 12 receptor inhibitor who are undergoing elective endoscopic GI procedures, we could not reach a recommendation for or against temporary interruption of the P2Y 12 receptor inhibitor. [bib_ref] Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage..., Steiner [/bib_ref]. For patients on ASA 81-325 mg/d (i.e., cardiac ASA monotherapy) for secondary prevention, we suggest against interruption of ASA (conditional recommendation, very low certainty of evidence). Timing of anticoagulant resumption after endoscopy [bib_ref] Use of factor IX complex in warfarin-related intracranial hemorrhage, Boulis [/bib_ref]. In patients who are undergoing elective endoscopic GI procedures whose warfarin was interrupted, we could not reach a recommendation for or against resuming warfarin the same day vs 1-7 d after the procedure. [bib_ref] Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in..., Karaca [/bib_ref]. In patients who are undergoing elective endoscopic GI procedures whose DOAC was interrupted, we could not reach a recommendation for or against resuming the DOAC on the same day of the procedure vs 1-7 d after the procedure. Timing of P2Y 12 inhibitor resumption after endoscopy 18. In patients who are undergoing elective endoscopic GI procedures whose P2Y 12 inhibitor was interrupted, we could not reach a recommendation for or against resuming P2Y 12 inhibitor on the same day of the procedure vs 1-7 d after the procedure. ASA, acetylsalicylic acid; DOAC, direct oral anticoagulant; GI, gastrointestinal. The American Journal of GASTROENTEROLOGY VOLUME 117 \| APRIL 2022 www.amjgastro.com If the 75% threshold was reached, provided the certainty of the evidence was moderate or high, panel members intended to discuss and vote on the strength of recommendation (strong vs conditional). If 75% of the members voted for strong, the recommendation would begin with "we recommend that …." Strong recommendations imply that most informed patients would choose the recommended course of action, and clinicians should provide it to most patients [bib_ref] GRADE evidence to decision (EtD) frameworks: A systematic and transparent approach to..., Alonso-Coello [/bib_ref]. If less than 75% of the members voted for strong, the recommendation would be considered conditional and began with the words "we suggest that…." Conditional recommendations indicate that most individuals in this situation would want the suggested course of action. Still, others would not, and clinicians should help each patient make decisions consistent with their risks, values, and preferences, ideally using decision aids. Recommendations with low or very low certainty of evidence were designated as conditional by default (without voting on the strength), although such recommendations could have still been considered as strong if they had fulfilled criteria for 1 of the 4 "paradigmatic situations" [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref]. A search of contemporary studies and recent systematic reviews was also performed and detailed in the evidence profile to inform the panel deliberations concerning the preferences of providers and patients for a cardiovascular event vs a GI bleeding event (see Appendix 2, Supplementary Digital Content, http://links.lww.com/AJG/C417 pages 3-6). Each voting panel member, including the 2 cochairs, prepared a draft for designated sections after the voting videoconference meeting. The 2 cochairs subsequently edited and merged these into a single manuscript. The final version was reviewed and approved unanimously. The final manuscript was peer-reviewed by the ACG Practice Parameters Committee, CAG Clinical Affairs Committee, the ACG Board of Trustees, the CAG chair of Clinical Practice, the CAG vice president for Clinical Affairs, the CAG Board of Directors, and the CAG membership at large (to whom the document was made available for 2 weeks). For each PICO question, the evidence table that summarizes the data and the grading of that evidence is in Supplementary Digital Content (see Appendix 2, http://links.lww.com/AJG/C417). A complete list of guideline statements, the strength of recommendation, and the certainty of the evidence is found in Tables 1 and 2. # Guideline statements ## Management of antithrombotic agents in the setting of acute gi bleeding The first 10 guideline statements address the management of antithrombotic agents in the setting of acute GI bleeding. Acute GI bleeding is defined as patients hospitalized or under observation with acute overt GI bleeding (upper and/or lower) manifesting as melena, hematochezia, or hematemesis. Life-threatening hemorrhage is defined as major clinically overt or apparent bleeding, resulting in hypovolemic shock or severe hypotension requiring pressors or surgery; or associated with a decrease in hemoglobin of .5 g/dL, or requiring transfusion of $ 5 units of packed red blood cells, or causing death [bib_ref] Standardized bleeding definitions for cardiovascular clinical trials: A consensus report from the..., Mehran [/bib_ref]. ## Vka reversal. Summary of evidence. For this recommendation, no eligible studies specifically addressing patients with GI bleeding were identified by literature searches. The observational studies identified were cohort studies without a comparator arm, or the study did not report separate results for clinical outcomes in patients with GI bleeding. It is thus not possible to infer with any certainty whether administering FFP can benefit, harm, or make no difference in these patients compared with no reversal. Pertinent studies included a small cohort of 41 warfarintreated patients requiring rapid reversal [bib_ref] Emergency oral anticoagulant reversal: The relative efficacy of infusions of fresh frozen..., Makris [/bib_ref] , with 12 receiving FFP, 29 receiving clotting factor concentrates, and all receiving vitamin K 1-5 mg intravenously. No clinical outcomes were measured, but in the 12 patients given FFP, the international normalized ratio (INR) did not normalize (range 1.6-3.8, mean 2.3), indicating an ongoing anticoagulated state in all patients. In a case-control study of 267 patients with major bleeding prescribed VKA for venous thromboembolism, 78 patients had GI bleeding, but no results were reported for the GI bleeding outcomes [bib_ref] Management and outcome of major bleeding in patients receiving vitamin K antagonists..., Moustafa [/bib_ref]. In a multivariable analysis that failed to adjust sufficiently for confounding, FFP use was associated with a higher risk of thrombotic events (OR: 4.22; 95% CI: 1.25-14.3) [bib_ref] Management and outcome of major bleeding in patients receiving vitamin K antagonists..., Moustafa [/bib_ref]. Three additional RCTs which lacked the comparator of interest (i.e., placebo) provide cohort-type data that further inform this recommendation. Sarode et al. randomized 202 patients on a VKA with an INR $2.0 and major bleeding to FFP (n 5 104) vs 4-factor prothrombin complex concentrate (PCC), while both arms received vitamin K (5-10 mg intravenously). In the FFP arm, 58 patients had GI bleeding with excellent or good hemostatic efficacy achieved in 75.9% [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref]. Conclusions. Although there is biological plausibility of FFP administration to reverse VKA in patients with GI bleeding, there exists only very low certainty evidence, given serious concerns of risk of bias, imprecision, and indirectness. The panel also considered the low cost of FFP, relevant patient utilities, and the potential increased risk of transmission of infectious agents with FFP administration. The panel suggested that FFP should not be used routinely but could be considered for patients with a lifethreatening GI bleed or a supratherapeutic INR substantially exceeding the therapeutic range. Its use could also be considered in those for whom massive blood transfusion is undesirable because of its effect on coagulopathy or dilution of blood components when PCC is unavailable (see below). 1. For patients on warfarin who are hospitalized or under observation with acute GI bleeding, we suggest against fresh frozen plasma (FFP) administration (conditional recommendation, very low certainty of evidence). 2. For patients on warfarin who are hospitalized or under observation with acute GI bleeding, we could not reach a recommendation for or against prothrombin complex concentrate administration. ## Acg-cag clinical practice guideline Summary of evidence. The panel made an a priori decision to consider 3-factor PCC and 4-factor PCC equivalent for the intervention (PCC for reversal of warfarin and other VKAs). No eligible studies were identified exclusively in patients with GI bleeding. A backward (snowballing) citation search of previous guidelines was used to identify supporting evidence, including noncomparative cohort data derived from the PCC arms of 2 RCTs that compared PCC vs FFP [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref] [bib_ref] Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage..., Steiner [/bib_ref]. We also considered a cohort study of GI patients, which provided clinical outcomes and results on the indirect outcome of INR reversal [bib_ref] Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in..., Karaca [/bib_ref]. This study was regarded as noncomparative data with the inclusion of the PCC group only. From 7 studies, there were 223 patients on warfarin, all experiencing major bleeding and treated with PCC [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref] [bib_ref] Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage..., Steiner [/bib_ref] [bib_ref] Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in..., Karaca [/bib_ref] [bib_ref] Beriplex P/N reverses severe warfarininduced overanticoagulation immediately and completely in patients presenting..., Evans [/bib_ref] [bib_ref] Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal..., Lubetsky [/bib_ref] [bib_ref] Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage, Vigué [/bib_ref] [bib_ref] Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation, Yasaka [/bib_ref]. Of these, 38.6% had GI bleeding. All patients received 4-factor PCC at various doses, with vitamin K administered to most patients. Further bleeding was observed in 25.5%, with a 7.2% incidence of thrombotic events and 30-day mortality of 7.0% [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref] [bib_ref] Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage..., Steiner [/bib_ref] [bib_ref] Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in..., Karaca [/bib_ref] [bib_ref] Beriplex P/N reverses severe warfarininduced overanticoagulation immediately and completely in patients presenting..., Evans [/bib_ref] [bib_ref] Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal..., Lubetsky [/bib_ref] [bib_ref] Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage, Vigué [/bib_ref] [bib_ref] Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation, Yasaka [/bib_ref]. One study estimated transfusion-related events (fluid overload) of 4.9% within 7 days of PCC use [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref]. All studies demonstrated consistently rapid INR reduction of a large magnitude. Given the pharmacodynamics of warfarin treatment, it was implausible that this dramatic INR change could have occurred because of bias, confounding, or chance. Studies were downrated for serious or very serious risk of bias (no comparator cohorts), indirectness of the outcome ("hemostatic efficacy" or active bleeding visualized at the time of endoscopy), and the concomitant use of vitamin K. The small number of events contributed to serious imprecision. Only a small proportion of the patients had GI bleeds, although the type of bleed would not have influenced the effect of PCC on the INR. Finally, the speed of INR correction is a surrogate outcome, not a clinical outcome. Conclusions. There is insufficient evidence to judge the balance between desirable and undesirable effects with PCC administration; thus, the panel was unable to issue a recommendation. The guideline panel implicitly considered evidence from the comparison of PCC with FFP for warfarin reversal that did reveal a favorable profile for PCC use and benefit in studies using the surrogate endpoint of INR correction. PCC is not necessary for most patients on warfarin with a GI bleed. PCC administration could be considered in patients with a lifethreatening GI bleed, those with a supratherapeutic INR substantially exceeding the therapeutic range, or in patients in whom massive blood transfusion is undesirable because of its effect on coagulopathy or dilution of blood components. Summary of evidence. We identified 2 randomized trials [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref] [bib_ref] Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage..., Steiner [/bib_ref] and 1 cohort study [bib_ref] Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in..., Karaca [/bib_ref] comparing PCC with FFP in patients on warfarin with bleeding. The 2 studies that included patients with GI bleeding reported inconsistent results [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref] [bib_ref] Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in..., Karaca [/bib_ref]. The RCT by Sarode et al. [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref] did not find a difference in further bleeding among patients with acute GI bleeding with PCC (25.4%) compared with FFP (24.1%) (relative risk [RR] 1.05, 95% CI: 0.55-2.00). However, the study's definition of successful hemostasis allowed for up to 2 additional units of blood products after receiving FFP or PCC. It did not report whether this cointervention differed between the 2 groups. Furthermore, a higher proportion of patients in the FFP arm received vitamin K, including intravenously. A prospective cohort study of patients with acute upper GI bleeding who received intravenous vitamin K and either FFP or PCC found that the absolute risk of further bleeding was numerically lower in the PCC arm with zero of 20 patients diagnosed with bleeding compared with 7 of 20 patients (35%) in the FFP arm but without statistical significance (RR 0.07, 95% CI: 0-1.09) [bib_ref] Use and effectiveness of prothrombin complex concentrates vs fresh frozen plasma in..., Karaca [/bib_ref]. An additional 3 patients in the FFP arm developed recurrent bleeding, but it was unclear whether these 3 patients were independent of the 7 patients already attributed. Regardless, their inclusion would not change the direction of the effect nor certainty of evidence. The risk of thromboembolic events in patients on warfarin randomized to receive either FFP or PCC was evaluated in 2 studies. In 1 study, the bleeding site was intracranial, whereas in the second study, the bleeding site varied and included GI bleeding in some patients [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref] [bib_ref] Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage..., Steiner [/bib_ref]. Combining results from both studies, although not significant, the absolute risk of thromboembolic events was numerically higher in the PCC arm (RR 5 1.60, 95% CI: 0.70-3.62), whereas the 30-day mortality (RR 5 0.64, 95% CI: 0.17-2.49) and transfusionrelated adverse events (1 transfusion-related anaphylaxis in the FFP group) [bib_ref] Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on..., Sarode [/bib_ref] were numerically lower in the PCC arm. Both studies demonstrated a more rapid INR reduction in patients receiving PCC than FFP (RR 5 6.99, 95% CI: 3.61-13.53). The heterogeneous study populations, variability in outcome definition and timing of assessment, and the wide confidence intervals for clinical outcomes led to a very low certainty of evidence. Conclusions. The effect of PCC compared with FFP on further GI bleeding in patients on warfarin is unknown; however, the more rapid and reliable correction of the INR provides for a biological rationale supporting the efficacy of PCCs. Although there was a very low certainty of evidence, the panel determined that the anticipated desirable effects of PCC compared with FFP were greater than the undesirable effects in patients with acute GI bleeding. The panel concluded that although most patients with acute GI bleeding on warfarin would not require PCC administration, PCC use could be considered in patients with a life-threatening GI bleed, in those with a supratherapeutic INR substantially exceeding the therapeutic range, or those in whom massive blood transfusion is undesirable because of its effect on coagulopathy or dilution of blood components. Summary of evidence. In patients receiving a VKA such as warfarin, low-dose oral vitamin K 1-2 mg can be used when there is an elevated INR (typically an INR $10) to restore therapeuticlevel anticoagulation (i.e., INR 2.0-3.0) [bib_ref] Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, Holbrook [/bib_ref]. In the setting of clinically significant GI bleeding requiring therapeutic intervention, vitamin K 2-5 mg (oral or intravenous) [bib_ref] Endoscopy-related bleeding and thromboembolic events in patients on direct oral anticoagulants or..., Rodríguez De [/bib_ref]. For patients on warfarin who are hospitalized or under observation with acute GI bleeding, we suggest prothrombin complex concentrate administration compared with FFP administration (conditional recommendation, very low certainty of evidence). 4. For patients on warfarin who are hospitalized or under observation with acute GI bleeding, we suggest against the use of vitamin K (conditional recommendation, very low certainty of evidence). reverses anticoagulant effect (to INR #1.3) in 24-48 hours. Vitamin K use does not achieve rapid hemostasis in patients with acute bleeding [bib_ref] Evidence-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, Holbrook [/bib_ref]. Consequently, the clinical value of vitamin K is limited in most patients with acute GI bleeding, especially if the bleed is self-limiting, treatable through direct endoscopic hemostatic intervention, or if the INR is mildly elevated (e.g., INR 1.5-2.5). Vitamin K can be administered in patients with a supratherapeutic INR if the intent is to reverse the effect of a VKA over an extended period (i.e., 2-4 weeks) or if the objective is to stop the VKA altogether. This decision should be undertaken in consultation with hematologists, cardiologists, or other clinicians involved in patients' anticoagulant management. No prospective studies have assessed whether giving vitamin K in VKA-treated patients with acute bleeding affects clinically meaningful outcomes. In a meta-analysis involving nonbleeding patients on a VKA with a supratherapeutic INR, administration of vitamin K was associated with small, nonsignificant increases in mortality (RR 5 1.24; 95% CI: 0.62-2.47) and thrombotic events (RR 5 1.29; 95% CI: 0.35-4.78) (23). One retrospective case-control study involving patients with VKA-associated bleeding (from both GI and non-GI sites) found vitamin K administration was associated with a significant decrease in mortality (adjusted OR 5 0.47; 95% CI: 0.24-0.92). However, this study had significant methodological limitations, including cointerventions that confounded an association between vitamin K administration and clinical outcomes [bib_ref] Management and outcome of major bleeding in patients receiving vitamin K antagonists..., Moustafa [/bib_ref]. Conclusions. Overall, there is no clinical evidence that vitamin K administration in VKA-treated patients with acute GI bleeding prevents further bleeding or improves mortality or other clinically meaningful outcomes. Moreover, evidence is very weak that giving or not giving vitamin K will affect the risk of thromboembolism, such as stroke or venous thrombosis, presumed to be because of normalization of the INR. ## Direct thrombin inhibitor reversal. Summary of evidence. The available evidence addressing this recommendation included 1 cohort study that compared idarucizumab with no treatment and 2 additional cohort studies without a comparator. Singh et al. [bib_ref] Real world outcomes associated with idarucizumab: Population-based retrospective cohort study, Singh [/bib_ref] performed a retrospective cohort study in the United States that included patients hospitalized for dabigatran-associated major nontraumatic GI bleeding or intracranial bleeding. Among those with GI bleeding (159 who received idarucizumab vs 1124 who did not), nonsignificant differences in mortality (OR: 1.39, 95% CI: 0.51-3.45) and venous thromboembolism (OR: 0.35, 95% CI: 0.08-1.58) were observed. In the Reversal Effects of Idarucizumab on Active Dabigatran study [bib_ref] Idarucizumab for dabigatran reversal: Full cohort analysis, Pollack [/bib_ref] [bib_ref] Idarucizumab for dabigatran reversal, Pollack [/bib_ref] , Pollack et al. examined patients on dabigatran with multiple causes of acute bleeding, including GI (45.5%) and other patients on dabigatran about to undergo an urgent surgery or procedure. The reversal of dabigatran anticoagulant effect (before and up to 24 hours after the administration of idarucizumab) was assessed by dabigatranspecific coagulation function tests (dilute thrombin time or ecarin clotting time), and the reduction in the concentration of unbound dabigatran, both indirect measures of the outcome of interest. In a subgroup analysis of 137 patients with GI bleeding [bib_ref] Idarucizumab for dabigatran reversal in the management of patients with gastrointestinal bleeding, Van Der Wall [/bib_ref] , Van der Wall et al. reported 30-day mortality and thrombotic event rates of 11.1% and 3.6%, respectively, among patients receiving idarucizumab. Conclusions. Given the limited evidence of benefit and the high cost of idarucizumab, the panel felt it could not recommend routine use of idarucizumab for patients with GI bleeding who have taken dabigatran. However, selective use may be appropriate in patients with a life-threatening GI bleed who have taken dabigatran within the past 24 hours. Reversal of rivaroxaban or apixaban with andexanet alfa. Summary of evidence. Andexanet alfa, or "coagulation factor Xa (recombinant) inactivated-zhzo," is a modified recombinant human factor Xa decoy protein that binds and sequesters apixaban and rivaroxaban. It also binds and inhibits tissue factor pathway inhibitor and has an elimination half-life of 5 hours [bib_ref] What is the role of andexanet alfa in the reversal of anticoagulant..., Sewell [/bib_ref]. In clinical trials, andexanet alfa decreased apixaban activity by 94% and rivaroxaban activity by 92%. It restored thrombin generation in 100% of patients within 2-5 minutes. A prospective, single-group cohort of 352 patients with major bleeding within 18 hours of factor Xa inhibitor administration (rivaroxaban n 5 128, apixaban n 5 194, enoxaparin n 5 20, or edoxaban n 5 10) examined outcomes after giving andexanet alfa. A subgroup (90 patients) suffered an episode of GI bleeding with all contributing to the "safety group," whereas 62 contributed to the "efficacy group" (those with a baseline anti-Xa activity of at least 75 ng/mL and confirmed major bleeding) [bib_ref] Full study report of andexanet alfa for bleeding associated with factor Xa..., Connolly [/bib_ref]. Overall, the surrogate marker of median anti-F Xa activity decreased from 149.7 to 11.1 ng/mL (92% reduction; 95% CI: 91-93) in the apixaban group and from 211.8 to 14.2 ng/mL (92% reduction; 95% CI: [bib_ref] Continuation of low dose aspirin during per-gastric endoscopic submucosal dissection period and..., Dohi [/bib_ref] [bib_ref] To continue or discontinue aspirin in the perioperative period: A randomized, controlled..., Oscarsson [/bib_ref] [bib_ref] A randomised controlled trial to evaluate and optimize the use of antiplatelet..., Antolovic [/bib_ref] [bib_ref] Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding..., Mantz [/bib_ref] [bib_ref] The effect of low-dose acetylsalicylic acid on bleeding after transurethral prostatectomy-a prospective,..., Nielsen [/bib_ref] [bib_ref] Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: Assessment of a..., Douketis [/bib_ref] [bib_ref] Bridging therapy in patients on long-term oral anticoagulants who require surgery: The..., Dunn [/bib_ref] in the rivaroxaban group. Among the 62 patients with GI bleeding, excellent or good hemostatic efficacy was noted 12 hours after the andexanet alfa infusion in 85% (95% CI: 76-94), although the clinical applicability of the chosen criteria may not reflect contemporary clinical standards in GI bleeding. In addition, methodological limitations included the absence of an intention-to-treat analysis, possible confounding covariates, and insufficient reporting of resuscitative, endoscopic, and pharmacological management. Surprisingly, there was no significant relationship between hemostatic efficacy and a reduction in anti-FXa activity during andexanet alfa treatment. Adverse events were reported only at the whole group level and included thrombotic events and mortality within 30 days in 9.7% of 352 patients and 13.9%, respectively. Infusion-related events at 7 days were noted in 2 patients but not in the 90 patients with GI bleeding. Conclusions. The only published study presents a serious risk of bias because it lacks a control group. Indirectness of the outcomes is also a significant concern because data on patients with GI bleeding are limited, with missing information concerning specific management. Additional methodological limitations include very serious imprecision as event rates are low and the use of 5. For patients on dabigatran who are hospitalized or under observation with acute GI bleeding, we suggest against the administration of idarucizumab (conditional recommendation, very low certainty of evidence). 6. For patients on rivaroxaban or apixaban who are hospitalized or under observation with acute GI bleeding, we suggest against andexanet alfa administration (conditional recommendation, very low certainty of evidence). Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology. The American Journal of GASTROENTEROLOGY ACG-CAG Clinical Practice Guideline surrogate laboratory rather than clinical outcomes. Notably, the cost of using the drug is high (up to $49,500 at high-dose regimen, with the low-dose regimen costing half as much). Accordingly, the panel could not recommend the routine use of andexanet alfa in patients with GI bleeding. This intervention could be considered in the setting of life-threatening GI bleeding in hospitalized patients who have taken apixaban or rivaroxaban within the past 24 hours. ## Reversal of doacs with pcc. Summary of evidence. The literature search identified only 2 cohort studies with comparator arms (no PCC) [bib_ref] Reversal of dabigatranassociated major bleeding with activated prothrombin concentrate: A prospective cohort..., Schulman [/bib_ref] [bib_ref] Dabigatran versus warfarin major bleeding in practice: An observational comparison of patient..., Smythe [/bib_ref] , both of which have limitations. Schulman et al. [bib_ref] Reversal of dabigatranassociated major bleeding with activated prothrombin concentrate: A prospective cohort..., Schulman [/bib_ref] examined the reversal of dabigatran-associated major bleeding with activated prothrombin concentrate in a small prospective cohort study . Among the 5 patients with GI bleeding compared with matched patients (N 5 28) from 5 Phase III trials, the "effectiveness" rating was assessed at 24 hours by the treating physicians for GI bleeding. The effectiveness was considered good in 4 patients and moderate in 1, which was not statistically different from the comparator group. Smythe et al. [bib_ref] Dabigatran versus warfarin major bleeding in practice: An observational comparison of patient..., Smythe [/bib_ref] reported that among 28 patients with GI bleeding on dabigatran, 2 received 4-factor PCC, and both (100%) died within 30 days. However, the mortality results were not adjusted for confounding, and the comparator group's death rate is unknown. Several systematic reviews [bib_ref] The reversal of bleeding caused by new oral anticoagulants (NOACs): A systematic..., Udayachalerm [/bib_ref] [bib_ref] Efficacy and safety of the drugs used to reverse direct oral anticoagulants:..., Da Luz [/bib_ref] [bib_ref] Quality evaluation of case series describing four-factor prothrombin complex concentrate in oral..., Costa [/bib_ref] have reported mainly on low-quality, single-arm cohort studies. Conclusions. Given the uncertainty of the available evidence, the panel felt they could not recommend routine use of PCC for patients with GI bleeding who have taken DOACs. However, selective use may be clinically justifiable in some patients who have taken DOACs within the past 24 hours with a lifethreatening GI bleed. ## Reversal of antiplatelet with platelet transfusion Summary of evidence. ASA and the thienopyridine P2Y 12 receptor inhibitors clopidogrel and prasugrel irreversibly block platelet function for the 7-10-day life span of platelets, whereas ticagrelor is a reversible nonthienopyridine P2Y 12 receptor inhibitor (a cyclopentyltriazolopyrimidine) that impairs platelet function for 3-5 days. For this guideline, we refer most frequently to thienopyridine antiplatelet agents in discussing P2Y 12 receptor inhibitors because the evidence reviewed examined clopidogrel or prasugrel. However, the mechanism of action of the nonthienopyridine P2Y 12 receptor inhibitor, ticagrelor, is similar, permitting reasonable extrapolation of results. Previous guidelines have suggested platelet administration as a therapeutic option in patients on antiplatelet agents with severe GI bleeding [bib_ref] No benefit from platelet transfusion for gastrointestinal bleeding in patients taking antiplatelet..., Zakko [/bib_ref] [bib_ref] The management of antithrombotic agents for patients undergoing GI endoscopy, Acosta [/bib_ref]. However, the possibility of thrombotic events with an infusion of functional platelets in patients taking antiplatelet drugs, who are at higher cardiovascular risk, along with potential risks related to the transfusion of blood products, also needs to be considered. A single fully published study directly relevant to this PICO was identified: a cohort study in patients without thrombocytopenia taking antiplatelet agents and admitted with GI bleeding. This study compared 204 patients who received platelet transfusion with a matched control group of 204 patients who did not. Conclusions. Given a possible mortality increase in patients with GI bleed and other medical conditions, and the lack of benefit in decreasing further bleeding in patients with GI bleeding, the panel suggests against platelet transfusion in patients with antiplatelet-related GI bleeding who are not thrombocytopenic. Holding ASA vs continuing ASA. Summary of evidence. Current recommendations suggest that patients with upper GI bleed undergo endoscopy within 24 hours, and in those with a lower GI bleed, diagnostic testing be performed within ;24-36 hours [bib_ref] ACG clinical guideline: Upper gastrointestinal and ulcer bleeding, Laine [/bib_ref] [bib_ref] ACG clinical guideline: Management of patients with acute lower gastrointestinal bleeding, Strate [/bib_ref] [bib_ref] Early colonoscopy does not improve outcomes of patients with lower gastrointestinal bleeding:..., Tsay [/bib_ref]. In addition, hemostasis generally occurs before endoscopy or, in the minority with active bleeding identified endoscopically, at the time of endoscopy after hemostatic therapy is applied. ASA's pharmacodynamic effect occurs through irreversible inhibition of platelet cyclooxygenase-1, which mediates thromboxane synthesis. After ASA ingestion, thromboxane synthesis normalizes by 7-10 days, although in vitro studies suggest 70% of arachidonic acid-mediated platelet function may normalize by 3 days after ASA ingestion [bib_ref] Management of plateletdirected pharmacotherapy in patients with atherosclerotic coronary artery disease undergoing..., Becker [/bib_ref] [bib_ref] Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet..., Santilli [/bib_ref]. Therefore, interruption of ASA in patients presenting with GI bleeding will have little impact on the initial clinical course 7. For patients on direct oral anticoagulants who are hospitalized or under observation with acute GI bleeding, we suggest against prothrombin complex concentrate administration (conditional recommendation, very low certainty of evidence). 8. For patients on antiplatelet agents who are hospitalized or under observation with acute GI bleeding, we suggest against platelet transfusions (conditional recommendation, very low certainty of evidence). 9. For patients with GI bleeding on cardiac ASA for secondary cardiovascular prevention, we suggest against holding the ASA (conditional recommendation, very low certainty of evidence). 10. For patients with GI bleeding on ASA for secondary cardiovascular prevention whose ASA was interrupted, we suggest the ASA be resumed on the day hemostasis is endoscopically confirmed (conditional recommendation, very low certainty of evidence). The American Journal of GASTROENTEROLOGY VOLUME 117 \| APRIL 2022 www.amjgastro.com because of the persistent antiplatelet effect of ASA in the first day or 2 after the patient's presentation. Furthermore, the suggestion to resume ASA immediately after hemostasis means that ASA resumption will occur in most cases well before the antiplatelet effect has substantially waned. Thus, the initial interruption of ASA after presentation would not be expected to have much impact on either bleeding or cardiovascular clinical outcomes if ASA is restarted once endoscopic hemostasis is established. Only 1 study was identified relevant to the PICO regarding interruption vs continuation of ASA when patients present with GI bleeding (GIB); this was a retrospective study in patients hospitalized with acute myocardial infarction who subsequently developed ulcer bleeding during hospitalization [bib_ref] Acetylsalicylic acid use in patients with acute myocardial infarction and peptic ulcer..., Cheung [/bib_ref]. This comparison of 64 patients interrupting ASA vs 38 continuing ASA reported similar 30-day rates for both further bleeding and for mortality of 16% (10/64) vs 11% (4/38) (RR 5 1.48, 0.50-4.41), respectively. The results for further bleeding are opposite than expected for interruption of ASA (i.e., slightly more bleeding reported with interrupted ASA), although confidence intervals are wide and consistent with benefit or harm. No statistical adjustments were made for potential confounders, limiting the utility of the results. Furthermore, since outcomes were at 30 days, the results may be viewed as primarily relevant to the timing of ASA resumption after bleeding stops. The most pertinent study relevant to the PICO regarding resumption of ASA after hemostasis is an RCT in patients taking ASA for secondary cardiovascular protection with high-risk ulcer bleeding requiring endoscopic therapy. In this RCT, 156 patients with peptic ulcer bleeding and high-risk endoscopic stigmata treated with successful endoscopic therapy and proton pump inhibitor were randomized to continued low-dose ASA for secondary prevention vs placebo for the 8 weeks of the study (a much longer interruption than typical in current clinical practice) [bib_ref] Continuation of low-dose aspirin therapy in peptic ulcer bleeding: A randomized trial, Sung [/bib_ref]. Recurrent bleeding rates at 30 days were not significantly greater in the ASA group (10.3% vs 5.4%); difference 4.9% (95% CI: 23.6 to 13.4), whereas 8-week mortality attributable to cardiovascular, cerebrovascular, or GI complications was significantly greater in the placebo group (1.3% vs 10.3%; difference 9% [95% CI: 1.7-16.3]). Thrombotic events at 30 days did not differ between groups (3/78 vs 9/78 favoring early ASA resumption, RR 5 0.33 [95% CI: 0.09-1.19]) with 6 nonfatal, recurrent acute ischemic events reported (2 in the ASA and 4 in the placebo group). However, the 2-month interruption of ASA in the placebo group imparts serious indirectness of observed outcomes. There also exists very serious imprecision because of very low event rates. Two additional cohort studies that compared patients who continued ASA after GIB to others who discontinued ASA and did not resume ASA could not be included. In 1, the life-table analysis curves did not permit accurate extraction of results for the first 1-7 days (the relevant timeframe for this recommendation) [bib_ref] Discontinuation of low-dose aspirin therapy after peptic ulcer bleeding increases risk of..., Derogar [/bib_ref]. The second study was unclear when patients along the x axis were on or off ASA [bib_ref] Risks of bleeding recurrence and cardiovascular events with continued aspirin use after..., Chan [/bib_ref]. We wish to stress that our recommendations do not apply to patients taking ASA for primary cardiovascular prevention. Recent RCTs suggest little if any benefit of primary prevention for reduction of cardiovascular outcomes despite significant increases in serious GI bleeding [bib_ref] Effect of aspirin on cardiovascular events and bleeding in the healthy elderly, Mcneil [/bib_ref] [bib_ref] ASCEND: A study of cardiovascular events in diabetes: Characteristics of a randomized..., Bowman [/bib_ref] [bib_ref] Use of aspirin to reduce risk of initial vascular events in patients..., Gaziano [/bib_ref] , and current guidelines suggest ASA for primary prevention be considered only in a very limited population and should not be used in those with increased risk of bleeding [bib_ref] Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer:..., Bibbins-Domingo [/bib_ref] [bib_ref] ACC/AHA guideline on the primary prevention of cardiovascular disease: A report of..., Arnett [/bib_ref]. Conclusions. The panel weighed the important and welldocumented cardiovascular benefit of secondary preventive ASA therapy and the potential risk of further GI bleeding with continued ASA therapy. The trend to reduced mortality in an observational study of patients with myocardial infarction with continued aspirin [bib_ref] Acetylsalicylic acid use in patients with acute myocardial infarction and peptic ulcer..., Cheung [/bib_ref] coupled to the significant reduction in mortality among patients with high-risk ulcer bleeding who had aspirin resumed immediately after endoscopic hemostasis [bib_ref] Continuation of low-dose aspirin therapy in peptic ulcer bleeding: A randomized trial, Sung [/bib_ref] were important considerations in the panel's decision to recommend continuation rather than an interruption of aspirin therapy. If ASA is discontinued at clinical presentation, we recommend rapid resumption within 24 hours of successful endoscopic hemostasis. Increased further bleeding with continued ASA at presentation was not shown in the observational study, but results of the RCT did raise the possibility of increased rebleeding with early Management of antithrombotic agents in the elective endoscopy setting. The 9 remaining statements inform antithrombotic therapy management in patients undergoing scheduled, elective endoscopic procedures. These recommendations exclude patients at high risk of thromboembolic events in whom elective procedures should be deferred. Such high-risk patients include those within 3 months of acute venous thromboembolism (comprising lower-limb deep vein thrombosis or pulmonary embolism), stroke, or transient ischemic attack [fig_ref] Table 4: Empiric periprocedural thromboembolic risk stratification for patients receiving anticoagulant therapyThe sources used... [/fig_ref] ; and patients within 3 months of acute coronary syndrome (ACS) event, within 6 months of a drug-eluting stent or 1 month of a bare-metal coronary stent placement without ACS history (54); or after ACS event within 12 months of a drug-eluting stent placement or 2 months of bare-metal stent placement [bib_ref] ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients..., Levine [/bib_ref]. Recent data suggest that dual antiplatelet therapy (DAPT) with ASA and P2Y 12 receptor inhibitor can be converted to platelet P2Y 12 receptor inhibitor monotherapy among patients at 3 months or less in patients with a drugeluting stent placed after ACS event [bib_ref] Meta-analysis of dual antiplatelet therapy versus monotherapy with P2Y12 inhibitors in patients..., Malik [/bib_ref] [bib_ref] Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and..., Kim [/bib_ref]. A review of published guidelines highlights the lack of consensus regarding high vs low baseline risk of endoscopic procedures [fig_ref] Table 3: Empiric endoscopic procedural bleeding risk stratification Copyright © 2022 The American College... [/fig_ref] [bib_ref] The management of antithrombotic agents for patients undergoing GI endoscopy, Acosta [/bib_ref] [bib_ref] European Society of Gastrointestinal endoscopy (ESGE) guideline, Boustière [/bib_ref] [bib_ref] Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment, Fujimoto [/bib_ref] [bib_ref] Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants:..., Veitch [/bib_ref]. Procedural bleeding risk and patient-specific thromboembolic risk were empirically framed using the risk stratification endorsed by the International Society on Thrombosis and Haemostasis Guidance Statement (60), the BRIDGE Trial (61), previously published guidelines, and expert opinion [fig_ref] Table 4: Empiric periprocedural thromboembolic risk stratification for patients receiving anticoagulant therapyThe sources used... [/fig_ref] [bib_ref] The management of antithrombotic agents for patients undergoing GI endoscopy, Acosta [/bib_ref] [bib_ref] European Society of Gastrointestinal endoscopy (ESGE) guideline, Boustière [/bib_ref] [bib_ref] Guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment, Fujimoto [/bib_ref] [bib_ref] Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants:..., Veitch [/bib_ref] [bib_ref] Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had..., Douketis [/bib_ref]. A structured and exhaustive GRADE assessment of procedural bleeding risk is beyond the scope of this clinical practice guideline. Also pertinent to this section are considerations of patient preference. The targeted review performed for this guideline initiative (see Appendix 2, Supplementary Digital Content, http://links.lww.com/ AJG/C417) demonstrated substantial variability in the threshold number of bleeds observed for oral anticoagulation therapy to be considered acceptable both within individuals and between different studies [bib_ref] Patient preferences for oral anticoagulation therapy in atrial fibrillation: A systematic literature..., Wilke [/bib_ref]. Furthermore, country-specific differences exist in patients' perceptions of atrial fibrillation, concerns about stroke, and preference for involvement in oral anticoagulation therapy treatment decisions, with recent experience of stroke and GI bleeding both significantly influencing patient values and preferences [bib_ref] Patients' perceptions of atrial fibrillation, stroke risk, and oral anticoagulation treatment: An..., Lane [/bib_ref] [bib_ref] Management of antithrombotic therapy after gastrointestinal bleeding: A mixed methods study of..., Little [/bib_ref]. Indeed, patients placed more weight (more disutility) on stroke prevention than GI bleeding unless they had previously experienced a GI bleed [bib_ref] Management of antithrombotic therapy after gastrointestinal bleeding: A mixed methods study of..., Little [/bib_ref]. Among the latter, 87% placed the highest utility on rebleeding risk followed by thrombosis risk [bib_ref] Management of antithrombotic therapy after gastrointestinal bleeding: A mixed methods study of..., Little [/bib_ref]. The panel members concluded that for most PICOs, there is possibly significant uncertainty about or variability in how much people value the critical outcomes. ## Anticoagulant interruption vs continuation. Summary of evidence. The published data examining uninterrupted warfarin before endoscopic procedures and associated GI bleeding risk is heterogeneous and methodologically flawed. When formulating our recommendation, we considered 3 cohort studies with a control group (temporary interruption of warfarin) (65-67) and 2 cohort studies without a control group [bib_ref] Removal of small colorectal polyps in anticoagulated patients: A prospective randomized comparison..., Horiuchi [/bib_ref] [bib_ref] Safety of cold snare polypectomy in patients receiving treatment with antithrombotic agents, Arimoto [/bib_ref]. These 5 studies provided very low certainty of evidence because of imprecision of the results, lack of adjustment for confounders, lack of standardized procedure technique (e.g., biopsy, cold snare polypectomy, hot snare polypectomy, and routine hemostatic clipping), comparator groups that differ in prognostic factors for bleeding, differences in population, lack of blinding of the endoscopist, and incomplete follow-up. The desirable anticipated effect with continued warfarin (compared with interrupted warfarin) is reduced thromboembolic events. A single small cohort study without adjustment for confounding Our ability to estimate the direction and magnitude of the effect of uninterrupted warfarin (compared with interrupted warfarin) on GI bleeding and mortality using data from the 3 cohort studies with controls [bib_ref] Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of..., Ara [/bib_ref] [bib_ref] Adverse events associated with anticoagulation therapy in the periendoscopic period, Gerson [/bib_ref] [bib_ref] Post-polypectomy bleeding and thromboembolism risks associated with warfarin vs direct oral anticoagulants, Yanagisawa [/bib_ref] is limited by small sample size and few events, resulting in extremely wide confidence intervals compatible with considerable benefit and considerable harm. When the continuous warfarin arms from all 5 studies are pooled (65-69), we observe 0/239 bleeding events (95% CI: 0%-12.5%), suggesting a risk of postprocedural bleeding with continuous warfarin as low as 0% and as high as 12.5%. Conclusions. It is impossible to confidently estimate the GI procedural bleeding risk associated with uninterrupted warfarin therapy (vs warfarin interruption), given the limitations of the published literature, heterogeneity of patient populations and procedure type, and imprecision of the results. The absence of studies in advanced endoscopic procedures (with higher baseline bleeding risk), and differences in clinical consequences of luminal and extraluminal bleeding associated with such endoscopic GI procedures, limits our ability to comment on the safety of proceeding without interrupting warfarin. The evolving role of mechanical hemostasis may render some advanced procedures safer with continued warfarin in the future; however, current evidence supporting this strategy is scant. The planned procedure type [fig_ref] Table 3: Empiric endoscopic procedural bleeding risk stratification Copyright © 2022 The American College... [/fig_ref] and its associated risk of postprocedural bleeding, and the baseline risk of thromboembolism will influence the recommendation, as will resource requirements associated with discontinuation and reinitiation of anticoagulation (e.g., laboratory tests and clinic visits). For patients on warfarin who are undergoing elective and planned outpatient endoscopic GI procedures, we suggest warfarin be continued unless they are undergoing an advanced endoscopic procedure [fig_ref] Table 3: Empiric endoscopic procedural bleeding risk stratification Copyright © 2022 The American College... [/fig_ref] , which may incur a higher risk of procedural bleeding, in which case 5 days of temporary interruption without bridging heparin would be appropriate, as discussed in PICO 12. Summary of evidence. In patients receiving warfarin who require its temporary interruption, heparin bridging, typically with subcutaneous, full-dose low-molecular-weight heparin (LMWH), is sometimes used for 3 days before and 3-5 days after the surgery or procedure. The premise for heparin bridging is that by minimizing the time patients are not therapeutically anticoagulated periprocedurally during warfarin interruption and resumption, the risk of stroke and other thromboembolic events will be reduced. However, heparin bridging may not affect the pathophysiologic pathway that mediates periprocedural stroke and thromboembolism and may place patients at increased risk of procedure-site bleeding, especially if heparin bridging is administered in too close proximity to the time of the procedure [bib_ref] Perioperative management of anticoagulant and antiplatelet therapy, Tafur [/bib_ref] [bib_ref] Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, Douketis [/bib_ref]. Two randomized trials assessed heparin bridging among warfarintreated patients who required anticoagulant interruption for elective surgery/procedure, including GI procedures. One randomized, doubleblind, placebo-controlled trial (BRIDGE) assessed the need for heparin bridging in patients with atrial fibrillation who required temporary warfarin interruption for an elective surgical procedure, including 758 GI procedures (98.7% were minor or low bleeding risk procedures) [bib_ref] Perioperative bridging anticoagulation in patients with atrial fibrillation, Douketis [/bib_ref]. Excluded from the BRIDGE trial were patients with a very high thrombotic risk (i.e., a mechanical heart valve; stroke, systemic embolism, or transient ischemic attack within the past 12 weeks) or significant risk factors for major bleeding (i.e., history of a bleeding event within the past 6 weeks; creatinine clearance ,30 mL/min; and thrombocytopenia , 100,000 per microliter). Patients with planned cardiac, intracranial, or intraspinal surgeries were also excluded [bib_ref] Perioperative bridging anticoagulation in patients with atrial fibrillation, Douketis [/bib_ref]. There were 1,813 patients enrolled in the BRIDGE trial, of whom 918 were allocated to receive bridging with therapeutic-dose LMWH before and after the surgical procedure, and 895 to matching placebo, with a 30-day follow-up period after procedure. Forgoing bridging anticoagulation was noninferior to perioperative bridging with LMWH for the prevention of arterial thromboembolism (0.4% vs 0.3%, respectively, with a risk difference, of 0.1%; 95% CI: 20.6 to 0.8; P 5 0.01 for noninferiority) and decreased the risk of major bleeding (1.3% vs 3.2%, respectively, P 5 0.005) [bib_ref] Perioperative bridging anticoagulation in patients with atrial fibrillation, Douketis [/bib_ref]. Another randomized trial of bridging (Postoperative low molecular weight heparin bridging treatment for patients at high risk of arterial thromboembolism [PERIOP-2]) was performed in 1,471 warfarin-treated patients who required an elective surgery or procedure in which all patients received preprocedure LMWH bridging and were randomly allocated to receive bridging, with either a therapeutic-dose or low-dose LMWH regimen (determined by the procedure bleed risk) or no bridging after procedure [bib_ref] Postoperative low molecular weight heparin bridging treatment for patients at high risk..., Kovacs [/bib_ref]. This study was unique in that it included patients with mechanical heart valve (n 5 304) in addition to patients with atrial fibrillation (n 5 1,167). PERIOP-2 was not included in the evidence profile because it had only been published in abstract form. A few weeks after the final panel voting meeting, the PERIOP-2 trial was published as full text showing similar results to the BRIDGE trial [bib_ref] Perioperative bridging anticoagulation in patients with atrial fibrillation, Douketis [/bib_ref]. Two additional observational studies of lower methodological quality involving only warfarin-treated patients who required an elective GI procedure further suggest that the use of periprocedural heparin bridging increases the risk of postprocedure bleeding [bib_ref] Clinical features of postpolypectomy bleeding associated with heparin bridge therapy, Inoue [/bib_ref] [bib_ref] Continuous anticoagulation and cold snare polypectomy versus heparin bridging and hot snare..., Takeuchi [/bib_ref]. Conclusions. Overall, evidence is lacking that routine periprocedural heparin bridging during VKA interruption provides a therapeutic benefit to reduce thromboembolism and seems to increase patients' risk of postprocedural bleeding. Periprocedural bridging may be appropriate in the subset of patients with mechanical valves, atrial fibrillation with CHADS 2 score .5, patients with previous thromboembolism during temporary interruption of VKAs, or those patients undergoing certain types of surgery (e.g., cardiac valve replacement, carotid endarterectomy, and major vascular surgery). Consultation with a cardiologist and hematologist is recommended in these high-risk thromboembolic patients. Summary of evidence. No RCTs addressed this clinical question. However, 3 cohort studies with control arms [bib_ref] Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of..., Ara [/bib_ref] [bib_ref] Post-polypectomy bleeding and thromboembolism risks associated with warfarin vs direct oral anticoagulants, Yanagisawa [/bib_ref] [bib_ref] Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: Results from the..., Heublein [/bib_ref] and 2 cohort studies without control arms [bib_ref] Safety of cold snare polypectomy in patients receiving treatment with antithrombotic agents, Arimoto [/bib_ref] [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] were used to indirectly estimate the risk of GIB with continuous DOAC 12. For patients on warfarin, who hold warfarin in the periprocedural period for elective/planned endoscopic GI procedures, we suggest against bridging anticoagulation (conditional recommendation, low certainty of evidence). 13. For patients on direct oral anticoagulants (DOACs) who are undergoing elective/planned endoscopic GI procedures, we suggest temporarily interrupting DOACs rather than continuing DOACs (conditional recommendation, very low certainty of evidence). Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology. The American Journal of GASTROENTEROLOGY ACG-CAG Clinical Practice Guideline anticoagulation (3.6%; 8/224) vs that with temporary interruption (3.1%; 18/578). In the PAUSE study [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] , the incidence of 30-day thrombotic events and mortality was 0.7% and 0.5%, respectively, after DOAC temporary interruption [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref]. The absolute risk of increased delayed bleeding with continuous DOAC anticoagulation could not be reliably calculated nor the results reliably pooled, given the zero event rates in one or both arms of comparative studies [bib_ref] Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of..., Ara [/bib_ref] [bib_ref] Post-polypectomy bleeding and thromboembolism risks associated with warfarin vs direct oral anticoagulants, Yanagisawa [/bib_ref] [bib_ref] Safety of cold snare polypectomy in patients receiving treatment with antithrombotic agents, Arimoto [/bib_ref] [bib_ref] Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: Results from the..., Heublein [/bib_ref] , the unclear denominator for patient numbers [bib_ref] Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: Results from the..., Heublein [/bib_ref] , and the absence of control arms [bib_ref] Safety of cold snare polypectomy in patients receiving treatment with antithrombotic agents, Arimoto [/bib_ref] [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref]. Furthermore, we noted a lack of adjustment for known confounders [bib_ref] Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of..., Ara [/bib_ref] [bib_ref] Post-polypectomy bleeding and thromboembolism risks associated with warfarin vs direct oral anticoagulants, Yanagisawa [/bib_ref] [bib_ref] Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: Results from the..., Heublein [/bib_ref] , limited sample sizes, and low event rates. In addition, there was a diversity of GI procedure types, endoscopic techniques, and protocols for DOAC interruption. These factors contribute to the serious risk of bias, inconsistency, indirectness, and imprecision in estimates, leading to the very low certainty of evidence. The most informative study was the prospective PAUSE cohort study [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] , which provided a standardized protocol for DOAC interruption, complete follow-up, and valid outcome assessment. However, there was no comparator of interest (i.e., uninterrupted anticoagulation). The panel was provided with the raw data for the subgroup of patients undergoing GI procedures enrolled in this cohort study. The calculated GI bleeding incidence rate was 2.5% (95% CI: 1.4%-4.2%), with 35.7% of GI bleeding events considered major bleeding episodes (Jim Douketis, Alan Barkun, written communication, . The 30-day thromboembolic (0.7%; 95% CI: 0.3%-1.8%) and mortality (0.5%; 95% CI: 0.2%-1.6%) incidence rates were also very low and nonsignificant with temporary DOAC interruption. Of the 556 endoscopic procedures performed, most were colonoscopies, gastroscopies, and flexible sigmoidoscopies with and without biopsy or polypectomy. Before endoscopic procedures, the duration of DOAC interruption was 2.0 6 0.5 days (including the day before the procedure and the day of the procedure in 91.7%). Only 8.1% of patients undergoing scheduled endoscopic procedures held their DOACs for .2 days before the procedure. DOAC resumption after procedure was 1.9 6 1.5 days providing endoscopic hemostasis had been achieved, for a total time off DOACs of 3.9 6 1.6 days in the periendoscopic period (Jim Douketis, Alan Barkun; personal communication). Conclusions. From the limited available data, for patients on DOACs undergoing elective, planned endoscopic GI procedures, we suggest temporary interruption of the DOACs is preferred over continued DOAC administration. The duration of temporary DOAC interruption before endoscopic procedures associated with favorable outcomes is between 1 and 2 days, excluding the day of the procedure, which permits the shortest preprocedural duration of DOAC interruption while balancing bleeding and thromboembolism risk. As the window of temporary interruption evaluated in this clinical question was 1-5 days before endoscopy, the panel discussed if withholding DOACs for 1-5 days could trigger a prothrombotic state that might result in thrombosis with any subsequent postendoscopic delays in DOAC resumption. It was argued that the prothrombotic risks seem to be more related to the periprocedural milieu (e.g., nature of the intervention such as vascular surgery vs nonvascular surgery and patient characteristics) than the brief interruption of DOACs [bib_ref] Risk of stroke after surgery in patients with and without chronic atrial..., Kaatz [/bib_ref]. Furthermore, given the rapid action of onset and half-life of DOACs, the thrombotic risk of interruption is anticipated to be lower than with interruption of warfarin [bib_ref] Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had..., Douketis [/bib_ref] [bib_ref] Periprocedural heparin bridging in patients receiving vitamin K antagonists: Systematic review and..., Siegal [/bib_ref]. ## Antiplatelet interruption vs continuation. Summary of evidence. The panel considered 2 RCTs and numerous observational studies that examined the temporary interruption of DAPT (stopping the P2Y 12 inhibitor while continuing ASA) in patients undergoing elective endoscopic GI procedures. Chan et al. [bib_ref] Risk of post-polypectomy bleeding with uninterrupted clopidogrel therapy in an industryindependent, double-blind,..., Chan [/bib_ref] conducted a double-blinded RCT to examine the bleeding and thrombosis rates among patients treated with either clopidogrel 75 mg or placebo for 7 days before the colonoscopy (N 5 387; of which N 5 216 had cold snare polypectomy). Of the 387 patients enrolled, 78.5% were on continuous ASA. There were similar rates of immediate and delayed postpolypectomy bleeding and a modest trend toward fewer cardiothromboembolic events with thienopyridine interruption: 1.3% (95% CI: 0.3%-5.0%) of patients receiving placebo vs 2.7% (95% CI: 1.0%-7.0%) in those with continued clopidogrel; RR 5 0.47 (95% CI: 0.09-2.55). By contrast, Won et al. [bib_ref] Cold snare polypectomy in patients taking dual antiplatelet therapy: A randomized trial..., Won [/bib_ref] reported no thrombotic events with similar bleeding rates among 87 patients randomized to continue DAPT through a scheduled cold snare polypectomy (0/45 with placebo and 1/42 [formula] [2.4%] with DAPT). [/formula] The numerous observational studies examining periprocedural antiplatelet regimens have been summarized in a systematic review by Eisenberg et al. [bib_ref] Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents, Eisenberg [/bib_ref]. They assessed the time to late stent thrombosis (occurring between 30 days and 1 year after stent implantation) in patients with drug-eluting stents on DAPT after discontinuing thienopyridine alone or discontinuing both thienopyridine and ASA. However, the absolute risk of stent thrombosis within 10 days when a P2Y 12 inhibitor is discontinued while continuing ASA cannot be calculated because the denominator (patients at risk) is unknown. Nonetheless, among the 94 patients with stent thrombosis after discontinuing a P2Y 12 inhibitor but continuing ASA, only 6 cases (6%) occurred within 10 days, suggesting that late stent thrombosis is a greater problem than immediate stent thrombosis. There were no events reported in the 3-4 days after coronary intervention in this study. We note that this PICO considered only data regarding events occurring in the first 30 days after the intervention. Conclusions. Among patients on DAPT (P2Y 12 inhibitor [clopidogrel, prasugrel, or ticagrelor and ASA 81-325 mg/d]) for secondary cardiovascular prevention, we suggest temporary interruption of the P2Y 12 inhibitor. This recommendation applies only to elective and not emergency procedures. Summary of evidence. We identified 1 randomized trial and 1 cohort study evaluating patients on P2Y 12 inhibitors undergoing elective endoscopic procedures that compared interruption with the continuation of antithrombotic therapy [bib_ref] Risk of post-polypectomy bleeding with uninterrupted clopidogrel therapy in an industryindependent, double-blind,..., Chan [/bib_ref] [bib_ref] Effect of antiplatelet agent number, types, and pre-endoscopic management on post-polypectomy bleeding:..., Watanabe [/bib_ref]. In their study, Chan et al. randomized 216 patients on clopidogrel, with or 14B. For patients on single antiplatelet therapy with P2Y 12 inhibitor agents who are undergoing elective endoscopic GI procedures, we could not reach a recommendation for or against temporary interruption of the P2Y 12 inhibitor. 14A. For patients on dual antiplatelet therapy for secondary cardiovascular prevention who are undergoing elective endoscopic GI procedures, we suggest temporary interruption of the P2Y 12 inhibitor while continuing ASA (conditional recommendation, very low certainty of evidence). without concomitant ASA, to continued medication or placebo. The method of polypectomy included cold snare, hot snare, cold biopsy, and hot biopsy without a prophylactic clip or endoscopic loop placement. None of the 46 patients on clopidogrel alone were diagnosed with GIB; however, the study was underpowered to detect a difference in this subgroup [bib_ref] Risk of post-polypectomy bleeding with uninterrupted clopidogrel therapy in an industryindependent, double-blind,..., Chan [/bib_ref]. A retrospective cohort study of 1,050 patients on antiplatelet therapy undergoing colonoscopy with hot snare polypectomy and, in most cases, prophylactic clip placement included 37 patients receiving P2Y 12 inhibitors [bib_ref] Effect of antiplatelet agent number, types, and pre-endoscopic management on post-polypectomy bleeding:..., Watanabe [/bib_ref] [bib_ref] Risk of post-polypectomy bleeding with uninterrupted clopidogrel therapy in an industryindependent, double-blind,..., Chan [/bib_ref] [bib_ref] Effect of antiplatelet agent number, types, and pre-endoscopic management on post-polypectomy bleeding:..., Watanabe [/bib_ref]. One study reported 30-day mortality, and there were no deaths in either group [bib_ref] Effect of antiplatelet agent number, types, and pre-endoscopic management on post-polypectomy bleeding:..., Watanabe [/bib_ref]. Conclusions. Although interruption of a P2Y 12 inhibitor should decrease a patient's risk of bleeding, the available evidence reported a nonsignificant increased bleeding risk in patients who stop a P2Y 12 inhibitor for an elective endoscopic procedure compared with those who continue the medication. This result is biologically implausible and, coupled to the very large confidence intervals, speaks to the very low certainty of evidence. Ultimately, the panel was unable to make a recommendation. Summary of evidence. The risk of clinically significant bleeding with diagnostic endoscopic procedures and standard biopsies is so low that the panel agreed that ASA does not need to be held for these procedures [fig_ref] Table 3: Empiric endoscopic procedural bleeding risk stratification Copyright © 2022 The American College... [/fig_ref]. A prospective observational study of the risk of clinical bleeding (.2-g/dL hemoglobin drop necessitating endoscopic hemostasis) after endoscopic biopsies revealed bleeding events in 0 of 142 patients continuing ASA and 1 of 61 (1.6%) interrupting ASA [bib_ref] Prospective analysis of risk for bleeding after endoscopic biopsy without cessation of..., Ara [/bib_ref]. Using the ASA arm of an RCT comparing clopidogrel with ASA in healthy volunteers undergoing duodenal and antral biopsies, none of the 280 biopsies on ASA led to bleeding events [bib_ref] Is gastroduodenal biopsy safe in patients receiving aspirin and clopidogrel? A prospective,..., Whitson [/bib_ref]. The risk of bleeding with polypectomy is higher than biopsies, especially for larger polyps and with the use of cautery rather than a cold snare. A case-control study examined 81 patients with postpolypectomy bleeding matched to 81 patients who had polypectomies without complication. In this study, 87% of polypectomies were performed with cautery, and 3% of polyps were .10 mm in size [bib_ref] Postpolypectomy lower gastrointestinal bleeding: Potential role of aspirin, Yousfi [/bib_ref]. ASA use within 3 days before polypectomy exhibited a small, nonsignificant trend to being more common in the bleeding group (40% vs 33%; OR 5 1.41, 95% CI: 0.68-3.04). Several factors limit the utility of this study, including the indirectness of the population studied and lack of adjustment for confounding factors. For example, the number of polyps removed was ;2-fold higher in the postpolypectomy bleeding group, which might suggest ASA use was less commonly associated with postpolypectomy bleeding when assessed on a per-polyp rather than per-patient basis. The cases and controls were derived from different databases, and the data are not generalizable to current practice in which most polyps ,10 mm are removed with a cold snare. Furthermore, it is not clear that DAPT was excluded. An observational study with information on a control group of 297 patients undergoing 867 polypectomies (mean size of largest polyp 6.5 mm; 29% hot snare, 4% cold snare, and 71% cold forceps) revealed delayed rebleeding in 0 (95% CI: 0%-3%) of the 119 patients on ASA monotherapy [bib_ref] Low rate of postpolypectomy bleeding among patients who continue thienopyridine therapy during..., Feagins [/bib_ref]. Procedures with the highest bleeding risk include wide-field endoscopic mucosal resection, endoscopic submucosal dissection (ESD), biliary or pancreatic sphincterotomy, and ampullectomy [bib_ref] Continuation of low dose aspirin during per-gastric endoscopic submucosal dissection period and..., Dohi [/bib_ref]. As the study was available only in abstract form, it was not included in the formal evidence report. Given the extremely limited evidence from studies in GI bleeding, especially on our critical outcome of thrombotic events, we also assessed studies in non-GI procedures to assess the impact of ASA interruption vs continuation on thrombotic events. A meta-analysis of 4 RCTs in patients undergoing noncardiac surgery revealed a nonsignificant increase in thrombotic events (RR 5 1.49; 95% CI: 0.56-3.96) with ASA interruption [bib_ref] To continue or discontinue aspirin in the perioperative period: A randomized, controlled..., Oscarsson [/bib_ref] [bib_ref] A randomised controlled trial to evaluate and optimize the use of antiplatelet..., Antolovic [/bib_ref] [bib_ref] Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding..., Mantz [/bib_ref] [bib_ref] The effect of low-dose acetylsalicylic acid on bleeding after transurethral prostatectomy-a prospective,..., Nielsen [/bib_ref]. Meta-analysis with these 4 RCTs and a 5th RCT (99) revealed a nonsignificant decrease in postprocedural bleeding when ASA is interrupted (RR 5 0.81; 95% CI: 0.66-1.01); the panel did not believe that bleeding rates with surgery could be generalized to GI endoscopic procedures. Conclusions. The panel weighed the potential desirable effects (reduction in thrombotic events) and undesirable effects (increased bleeding) of continuing ASA, limited by the availability of only scant, very low certainty evidence. The known important benefit of ASA for secondary cardiovascular prevention and the possible reduction in thrombotic events seen in RCTs of nonendoscopic surgical procedures led the panel to conditionally suggest the continuation of ASA for endoscopic procedures, in general. However, a blanket recommendation cannot be made for all procedures and patients, given that bleeding risk varies markedly among endoscopic procedures, and cardiovascular risk also varies among patients. The panel felt comfortable that the bleeding risk was very low in diagnostic endoscopic procedures, biopsies, and most polypectomies. Nevertheless, when removing larger and more complex polyps and other procedures with the highest bleeding risk (e.g., ESD, biliary or pancreatic sphincterotomy, ampullectomy, peroral endoscopic myotomy, and radiofrequency ablation), the panel felt that interruption of ASA could be considered. Such decisions require consideration of other factors such as cardiovascular risk and patient preference regarding cardiovascular vs bleeding events. Patients taking ASA as primary prevention should have ASA [bib_ref] Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage..., Steiner [/bib_ref]. For patients on ASA 81-325 mg/d (monotherapy) for secondary cardiovascular prevention, we suggest against interruption of ASA (conditional recommendation, very low certainty of evidence). Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology. The American Journal of GASTROENTEROLOGY ACG-CAG Clinical Practice Guideline stopped before higher-risk endoscopic procedures because the bleeding risk outweighs the minimal cardiovascular benefit. ## Timing of anticoagulant resumption after endoscopy Summary of evidence. The appropriate timing of warfarin resumption after an elective endoscopic procedure is not known. No prospective trials exist comparing different strategies. Three single-arm prospective cohort studies were identified that reported outcomes of interest, grouped by the timing of warfarin resumption. Douketis et al. [bib_ref] Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: Assessment of a..., Douketis [/bib_ref] evaluated 650 consecutive patients who required interruption of warfarin for an invasive procedure, including 5 patients undergoing colonoscopic polypectomy and 65 patients undergoing endoscopy with or without biopsy. All patients resumed warfarin on the procedure day and received standardized LMWH bridging therapy. The endoscopic procedures were analyzed as part of a subgroup of 542 patients undergoing non-high bleeding risk procedures (e.g., cholecystectomy, bowel resection, angiography, and joint replacement). There were 4 (0.74%; 95% CI: 0.20-1.47) cases of major bleeding, none of which were GI bleeding. Dunn et al. [bib_ref] Bridging therapy in patients on long-term oral anticoagulants who require surgery: The..., Dunn [/bib_ref] studied 260 patients, including 46 GI invasive procedures, who resumed warfarin the day of their procedure. All patients received a standardized LMWH bridging therapy. One of the 46 patients (2%; 95% CI: 0-13) undergoing colonoscopy was diagnosed with GI bleeding during the follow-up period of 28 days. Paik et al. [bib_ref] Optimal time of resuming anticoagulant after endoscopic sphincterotomy in patients at risk..., Paik [/bib_ref] reported on 96 patients undergoing endoscopic sphincterotomy who interrupted their warfarin therapy before the procedure and, we assume, resumed warfarin on the day of the procedure. Patients received different regimens of bridging therapy with heparin. The study may be further limited in generalizability because of the high rate of biliary stent placement (75% of cases) and precut sphincterotomy (23% of cases). Including the 6 patients excluded for postprocedural bleeding before the resumption of heparin, 11 of 102 patients (11%; 95%: CI 6%-19%) had postprocedure bleeding within the 14 days after endoscopic retrograde cholangiopancreatography. Thromboembolic events were reported in all 3 studies but assessed at different times. There were 2 thromboembolic events in the 542 patients (0.37%; 95% CI: 0.04%-1.32%) undergoing non-high bleeding risk procedures at a median of 13.8 days, including 1 event in a patient undergoing endoscopy [bib_ref] Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: Assessment of a..., Douketis [/bib_ref]. Dunn et al. [bib_ref] Bridging therapy in patients on long-term oral anticoagulants who require surgery: The..., Dunn [/bib_ref]. reported 5 thromboembolic events in 260 patients (1.9%; 95% CI: 0.6%-4.4%) within 28 days of their procedure, none occurring in the 46 who underwent GI procedures. Finally, among the 96 patients undergoing endoscopic sphincterotomy, 3 thromboembolic events (3.4%; 95% CI: 0.7%-8.9%) were diagnosed within the 30 days after procedure [bib_ref] Optimal time of resuming anticoagulant after endoscopic sphincterotomy in patients at risk..., Paik [/bib_ref]. Two studies reported mortality, and there were no deaths in either study at 13.8 or 28 days, respectively [bib_ref] Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: Assessment of a..., Douketis [/bib_ref] [bib_ref] Bridging therapy in patients on long-term oral anticoagulants who require surgery: The..., Dunn [/bib_ref]. The lack of a comparator group limited these studies, as did the diversity of the populations studied, the small proportion of patients undergoing endoscopic procedures, the use of bridging therapy, and the outcomes assessment occurring at variable follow-up times. The 2016 American Society for Gastrointestinal Endoscopy clinical practice guidelines (37) recommend resuming warfarin the day of an elective endoscopic procedure while referencing 2 studies lacking valid comparator arms and unclear resumption timing; these studies were excluded from the current evidence profile. Conclusions. We could not find studies comparing same-day resumption of warfarin with resumption in 1-7 days after the temporary interruption of warfarin before an elective endoscopic procedure. Therefore, the panel was unable to make a recommendation. In PICO 11, the panel suggested continuing warfarin in patients undergoing elective endoscopic procedures considered to be at low risk of postprocedural bleeding [fig_ref] Table 3: Empiric endoscopic procedural bleeding risk stratification Copyright © 2022 The American College... [/fig_ref]. However, we recognize that there may be a clinical concern of delayed procedural bleeding in a subgroup of patients undergoing advanced endoscopic procedures. In those patients, decisions regarding warfarin resumption should be informed by achieving adequate hemostasis at the time of the procedure, the risk of delayed bleeding associated with the endoscopic procedure performed, the patient's risk of thrombosis, and patient preferences in consultation with a cardiologist and hematologist. Summary of evidence. One prospective cohort study was identified that compared the risk of bleeding based on the timing of DOAC resumption but did not compare same day with 1-7 days. Radaelli et al. [bib_ref] Periendoscopic management of direct oral anticoagulants: A prospective cohort study, Radaelli [/bib_ref] evaluated 529 patients who interrupted DOAC therapy for an elective endoscopic procedure, including 327 with a low bleeding risk procedure and 202 with a high bleeding risk procedure, with 18 in the latter group receiving LMWH bridging therapy, and were then followed for 30 days. Comparing patients who resumed the DOAC on day 0-3 vs those who resumed the DOAC after day 3, the risk of bleeding was 2.3% and 11.5%, respectively (RR 0.20; 95% CI: 0.08-0.52). The patients receiving LMWH were not reported separately, and this use of bridging anticoagulation may have increased the bleeding risk in patients in whom DOAC was resumed after day 3. The PAUSE study was a single-arm, prospective cohort study that included 3,007 patients with atrial fibrillation undergoing elective surgery or procedures requiring DOAC interruption [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref]. The panel was provided the raw data for the subgroup of patients undergoing a GI procedure, as described in PICO 13. All GI procedures were classified as a low bleeding risk in the PAUSE study. The DOAC was resumed at 1.9 6 1.5 days after the procedure. Fourteen patients developed GI bleeding after endoscopy (2.5%, 95% CI: 1.4-4.2; n 5 554) during the 30 days of follow-up after the resumption of DOACs, of which 5 were considered major bleeding episodes [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref]. Radaelli et al. [bib_ref] Periendoscopic management of direct oral anticoagulants: A prospective cohort study, Radaelli [/bib_ref] reported thromboembolic events in 1 of 477 patients resuming DOACs on day 0-3 and 1 of 52 patients resuming DOACs after day 3 (RR 0.11; 95% CI: 0.01-1.57). Douketis et al. [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] reported an overall rate of thromboembolic events of 21 in the entire cohort of 3,007 (0.7%; 95% CI: 0.45%-1.09%) and 5 in the subgroup of patients undergoing GI endoscopic procedures (0.7%; 95% CI: 0.3%-1.8%). Mortality ranged from 0 in both arms of the Radaelli study to 0.3% (95% CI: 0.15%-0.59%) among all patients in the PAUSE cohort, to 0.5% In patients who are undergoing elective endoscopic GI procedures whose DOAC was interrupted, we could not reach a recommendation for or against resuming the DOAC on the same day of the procedure vs 1-7 days after the procedure. [bib_ref] Use of factor IX complex in warfarin-related intracranial hemorrhage, Boulis [/bib_ref]. In patients who are undergoing elective endoscopic GI procedures whose warfarin was interrupted, we could not reach a recommendation for or against resuming warfarin the same day vs 1-7 days after the procedure. (95% CI: 0.2%-1.6%) in the post hoc analysis of the GI PAUSE data [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] [bib_ref] Periendoscopic management of direct oral anticoagulants: A prospective cohort study, Radaelli [/bib_ref]. Previously published clinical practice guidelines have made informal and formal recommendations regarding DOAC resumption after elective endoscopic procedures; however, none were informed by studies that evaluated the timing of DOAC resumption [bib_ref] The management of antithrombotic agents for patients undergoing GI endoscopy, Acosta [/bib_ref] [bib_ref] Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants:..., Veitch [/bib_ref] [bib_ref] Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: Joint..., Chan [/bib_ref]. Conclusions. We did not identify a study comparing the timing of DOAC resumption proposed in this recommendation. Hence, the panel was unable to make a recommendation. Decisions regarding resumption of DOAC therapy should consider the rapid onset of action, achievement of adequate hemostasis at the time of the procedure, the risk of delayed bleeding for the endoscopic procedure performed, the patient's risk of thrombosis, and patient preferences in consultation with a cardiologist and hematologist. Timing of P2Y 12 inhibitor resumption after endoscopy. Summary of evidence. Theoretically, earlier resumption of P2Y 12 inhibitor monotherapy would tend to reduce thrombotic events and increase postprocedure bleeding. However, we did not identify any studies providing evidence relevant to this PICO. Thus, we cannot estimate the potential thrombotic or bleeding risk and cannot assess the balance between the desirable and undesirable effects of earlier resumption. Patients on P2Y 12 inhibitor monotherapy are at lower cardiovascular risk than those on DAPT because cardiovascular events are generally more remote in those on monotherapy. For example, US guidelines recommend patients remain on DAPT for at least 12 months after ACS before the transition to antiplatelet monotherapy, with a reduction to monotherapy considered after 6 months in those with high bleeding risk [bib_ref] ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients..., Levine [/bib_ref]. P2Y 12 inhibitor monotherapy can also substitute for ASA monotherapy in those with ASA hypersensitivity or GI intolerance [bib_ref] Aspirin and clopidogrel in acute coronary syndromes: Therapeutic insights from the CURE..., Jneid [/bib_ref] [bib_ref] ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable..., Fihn [/bib_ref]. Recent RCTs in patients with percutaneous coronary intervention for ACS have shown that DAPT for 1-3 months followed by P2Y 12 inhibitor monotherapy reduces major bleeding with no increase in cardiovascular events compared with continuation of DAPT for 12-24 months [bib_ref] Meta-analysis of dual antiplatelet therapy versus monotherapy with P2Y12 inhibitors in patients..., Malik [/bib_ref] [bib_ref] Effect of ticagrelor monotherapy vs ticagrelor with aspirin on major bleeding and..., Kim [/bib_ref]. Thus, patients now placed on P2Y 12 inhibitor monotherapy may have higher CV risk (because of more recent ACS), preventing extrapolation of baseline thrombotic risk in patients on ASA monotherapy to those on P2Y [bib_ref] Emergency oral anticoagulant reversal: The relative efficacy of infusions of fresh frozen..., Makris [/bib_ref] inhibitor monotherapy. Similarly, we may not be able to extrapolate bleeding risk with ASA to P2Y 12 inhibitor monotherapy. Although studies have not assessed postendoscopic procedural bleeding risk, a meta-analysis of 5 RCTs revealed a lower risk of GIB in patients taking P2Y 12 inhibitor monotherapy vs ASA monotherapy (OR 5 0.59, 0.39-0,89) (100). ## Future directions The greatest limitation to the panel's ability to provide unequivocal clinical recommendations was the certainty of evidence in the published literature. As highlighted throughout this clinical practice guideline, insufficient high-quality evidence exists in antithrombotic and antiplatelet drug users to evaluate strategies for the temporary interruption, drug reversal, and resumption against a comparator group with great certainty. In addition, we found too few studies focusing on advanced endoscopic procedures to inform our recommendations. The GRADE approach has clearly defined criteria for grading the certainty of evidence and the strength of recommendations. Accordingly, the certainty of much of the relevant evidence was downgraded mainly because of indirectness, risk of bias, and imprecision. For some clinical questions, we could not make a recommendation for or against the treatment strategy examined, given the very low certainty or absence of evidence comparing a treatment strategy that is now a common clinical practice (e.g., reversal of warfarin with vitamin K) with alternative treatment strategies. For all remaining clinical questions, the recommendations were conditional (rather than strong) because the certainty of the evidence was low or very low, and the criteria for paradigmatic situations as described in the "METHODS" section were not met. We suggest future studies focus on areas where insufficient evidence currently exists to inform clinical decisions. In particular, the potential benefit of PCC use for reversal of warfarin in the setting of acute GIB, the appropriate timing of resumption of P2Y 12 receptor inhibitors and anticoagulants (VKA and DOACs) after elective endoscopy, and whether it is necessary to interrupt P2Y 12 inhibitor antiplatelet monotherapy before elective endoscopy. There is also a lack of high certainty evidence informing optimal antithrombotic drug management before and after advanced endoscopic procedures. Future observational studies hoping to influence the management of antithrombotic agents in the periendoscopic period must standardize endoscopic techniques to eliminate confounders for GI bleeding and ensure adequate adjustment for confounders of both GI bleeding and thromboembolism. These studies should ensure the existence of an appropriate comparator group and report results in sufficient detail to allow for inclusion in future metaanalyses. Ideally, double-blinded RCTs with adequate allocation concealment should be undertaken to rigorously examine the questions of temporary interruption, reversal, and postprocedural resumption of antiplatelets and anticoagulants. Standardization of endoscopic techniques will increase the generalizability of RCT results. Multicenter studies are likely required, given the low event rate of postprocedural bleeding and thrombosis. Finally, there is a fundamental knowledge gap in the evaluation and characterization of GI endoscopic procedural bleeding risk groups. The current estimation of procedural bleeding risk is highly inconsistent, derived from studies with a serious risk of bias. A rigorous evaluation of procedural bleeding risk with the GRADE approach will clarify and improve the classification of endoscopic procedures and highlight knowledge gaps. [fig] Copyright © 2022: The American College of Gastroenterology and the Canadian Association of Gastroenterology. [/fig] [table] Table 1: Guideline statements, the strength of recommendation, and certainty of the evidence for the management of antithrombotic agents in the setting of acute GI bleed Management of antithrombotic agents in the setting of acute GI bleed Vitamin K antagonist reversal 1. For patients on warfarin who are hospitalized or under observation with acute GI bleeding, we suggest against FFP administration (conditional recommendation, very low certainty of evidence).2. For patients on warfarin who are hospitalized or under observation with acute GIB, we could not reach a recommendation for or against PCC administration.3. For patients on warfarin who are hospitalized or under observation with acute GIB, we suggest PCC administration compared with FFP administration (conditional recommendation, very low certainty of evidence).4. For patients on warfarin who are hospitalized or under observation with acute GIB (upper and/or lower), we suggest against the use of vitamin K (conditional recommendation, very low certainty of evidence). [/table] [table] Table 3: Empiric endoscopic procedural bleeding risk stratification Copyright © 2022 The American College of Gastroenterology and the Canadian Association of Gastroenterology. [/table] [table] Table 4: Empiric periprocedural thromboembolic risk stratification for patients receiving anticoagulant therapyThe sources used for the empiric classification of procedures included the International Society on Thrombosis and Haemostasis Guidance Statement, the BRIDGE trial, previously published guidelines, and expert opinion by the authors. VTE, venous thromboembolism. [/table]	None	None	We conducted systematic reviews of predefined clinical questions and used the Grading of Recommendations, Assessment, Development and Evaluations approach to develop recommendations for the periendoscopic management of anticoagulant and antiplatelet drugs during acute gastrointestinal (GI) bleeding and the elective endoscopic setting. The following recommendations target patients presenting with acute GI bleeding: For patients on warfarin, we suggest against giving fresh frozen plasma or vitamin K; if needed, we suggest prothrombin complex concentrate (PCC) compared with fresh frozen plasma administration; for patients on direct oral anticoagulants (DOACs), we suggest against PCC administration; if on dabigatran, we suggest against the administration of idarucizumab, and if on rivaroxaban or apixaban, we suggest against andexanet alfa administration; for patients on antiplatelet agents, we suggest against platelet transfusions; and for patients on cardiac acetylsalicylic acid (ASA) for secondary prevention, we suggest against holding it, but if the ASA has been interrupted, we suggest resumption on the day hemostasis is endoscopically confirmed. The following recommendations target patients in the elective (planned) endoscopy setting: For patients on warfarin, we suggest continuation as opposed to temporary interruption (1–7 days), but if it is held for procedures with high risk of GI bleeding, we suggest against bridging anticoagulation unless the patient has a mechanical heart valve; for patients on DOACs, we suggest temporarily interrupting rather than continuing these; for patients on dual antiplatelet therapy for secondary prevention, we suggest temporary interruption of the P2Y12 receptor inhibitor while continuing ASA; and if on cardiac ASA monotherapy for secondary prevention, we suggest against its interruption. Evidence was insufficient in the following settings to permit recommendations. With acute GI bleeding in patients on warfarin, we could not recommend for or against PCC administration when compared with placebo. In the elective periprocedural endoscopy setting, we could not recommend for or against temporary interruption of the P2Y12 receptor inhibitor for patients on a single P2Y12 inhibiting agent. We were also unable to make a recommendation regarding same-day resumption of the drug vs 1–7 days after the procedure among patients prescribed anticoagulants (warfarin or DOACs) or P2Y12 receptor inhibitor drugs because of insufficient evidence.
bd2e67da9800ce6d624cf1c58a9a9480dfe01ac4	pubmed	Brazilian practice guidelines for stroke rehabilitation: part II	Brazilian practice guidelines for stroke rehabilitation: part II # Introduction Stroke causes significant brain tissue damage and multiple neurological impairments, leading to a significant loss of function and residual disability. [bib_ref] Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives, Kuriakose [/bib_ref] The main goal of stroke rehabilitation is to organize and optimize the process of recovery, enabling a person to achieve their optimal physical, cognitive, communicative, emotional, and social levels of functioning through the integration of interdisciplinary rehabilitative techniques. [bib_ref] Stroke rehabilitation, Langhorne [/bib_ref] In stroke recovery, it is necessary to consider the greater improvement that occurs in the first three months. [bib_ref] The hemiplegic arm after stroke: measurement and recovery, Wade [/bib_ref] During this phase, variable spontaneous neurological improvement can be considered a confounder in the assessment of the rehabilitation intervention. [bib_ref] The hemiplegic arm after stroke: measurement and recovery, Wade [/bib_ref] However, progress in functional outcomes after three months seems to be largely dependent on learning adaptation strategies. [bib_ref] Impact of time on improvement of outcome after stroke, Kwakkel [/bib_ref] Improvement probably occurs through a complex combination of spontaneous recovery and learning-dependent processes, including restitution, substitution, and compensation. [bib_ref] Impact of time on improvement of outcome after stroke, Kwakkel [/bib_ref] Neurological repair probably occurs through brain reorganization, leading to true recovery associated with compensation and restitution in the later phases after stroke. [bib_ref] Understanding the pattern of functional recovery after stroke: facts and theories, Kwakkel [/bib_ref] Active, functional, and independent movement contribute to the brain reorganiza-tion after stroke and could be a key component in motor learning and rehabilitation. [bib_ref] Motor learning: its relevance to stroke recovery and neurorehabilitation, Krakauer [/bib_ref] [bib_ref] What is the evidence for physical therapy poststroke? A systematic review and..., Veerbeek [/bib_ref] The purpose of the Brazilian Practice Guidelines for Stroke Rehabilitation -Part II is to guide health professionals working in stroke rehabilitation with evidence from the most recent studies available. Brazilian versions of outcome measures used in stroke rehabilitation are presented in the ►Supplementary Material. The literature on interventions for each impairment and disability situation is presented, followed by practical recommendations. The classification of recommendation rating and level of evidence used in Part I was followed.The main challenge in developing this guideline was the heterogeneity and paucity of high-quality evidence to support intervention recommendations. Some meta-analyses of each intervention were based on low-or very low-quality evidence due to unclear or high risk of bias and the recruitment of small samples. [bib_ref] What is the evidence for physical therapy poststroke? A systematic review and..., Veerbeek [/bib_ref] Following the same methods used to write Part I, the members of the Scientific Department of Neurological Rehabilitation of the Brazilian Academy of Neurology participated in online discussion forums with predefined topics, followed by videoconference meetings in which controversies were discussed, leading to a consensus. For the preparation of the Brazilian Practice Guidelines for Stroke Rehabilitation, several national coauthors were asked to write the suggested topics following criteria defined by the guideline coordinators. The present work focuses on recent clinical trials, meta-analyses, and systematic reviews in the literature on stroke rehabilitation. ## Recommendation rating and level of evidence recommendations - Class I: There is evidence and/or consensus that the intervention is effective; - Class II: There is conflicting evidence and/or divergence of opinions about the effectiveness and usefulness of the intervention: -IIa: Although there is divergent evidence on the usefulness and effectiveness of the intervention, the recommendations are in favor of the intervention; -IIb: Utility and effectiveness are less established by the evidence or opinions; - Class III: There is evidence and/or consensus that the intervention is not useful or effective and may cause harm. Level of evidence Ã - A: Data are obtainded from multiple randomized clinical trials. - B: Data are obtained from a single randomized or nonrandomized study. - C: Consensus and expert opnions, case studies, or standart treatments. Ã Recommendations of systematic reviews and meta-analyses based on very low-to low-quality evidence were classified as level "B" of evidence. ## Disorders of communication: aphasia, dysarthria, and apraxia of speech The incidence of aphasia and dysarthria after a first stroke is of approximately 30% and 42% respectively. [bib_ref] Poststroke Aphasia Frequency, Recovery, and Outcomes: A Systematic Review and Meta-Analysis, Flowers [/bib_ref] Regarding the survivors six months poststroke, 35% remain aphasic and 57%, dysarthric. [bib_ref] Poststroke Aphasia Frequency, Recovery, and Outcomes: A Systematic Review and Meta-Analysis, Flowers [/bib_ref] The presence of apraxia of speech (AOS) alone is rare, co-occurring with aphasia in $ 30% of the cases. Aphasia is associated with a longer hospital stay and greater mortality and morbidity. Disorders of aphasia, AOS, and dysarthria negatively impact the ability to work, lead to social withdrawal, and increase the risk of developing anxiety and depression. Speech and language therapy is indicated for all patients with aphasia. A systematic review demonstrated that access to speech and language therapy benefits the functional use of language, language comprehension (listening or reading), and language production (speaking or writing) when compared with no access to therapy.Furthermore, functional communication was significantly better in people with aphasia submitted to therapy at a high intensity, high dose, or over a long period compared with those submitted to therapy at a lower intensity, lower dose, or over a shorter period.There is a consensus that intervention should start early.However, a recent prospective, randomized, singleblinded trial 11 aimed to determine whether intensive aphasia therapy, beginning within 14 days after stroke, improved communication recovery. The authors 11 found that early, intensive aphasia therapy did not improve communication recovery within 12 weeks poststroke compared with usual care. However, they 11 pointed out that most participants, regardless of group allocation, achieved significant clinical gains in language recovery. Regarding AOS, the articulatory-kinematic approach is the most used, studied, and recommended to improve speech sound accuracy. [bib_ref] Treatment for Acquired Apraxia of Speech: A Systematic Review of Intervention Research..., Ballard [/bib_ref] Speech therapy also positively affects the recovery of patients with dysarthria. 13 A metaanalysis 14 of patients with poststroke dysarthria showed that the alternating and sequential motion rate and maximum phonation time improved significantly after speech rehabilitation. The evidence that repetitive transcranial magnetic stimulation (rTMS) with transcranial direct current stimulation (tDCS) is effective in the treatment of aphasia is of low to moderate quality. [bib_ref] Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS):..., Lefaucheur [/bib_ref] [bib_ref] Transcranial direct current stimulation (tDCS) for improving aphasia after stroke: a systematic..., Elsner [/bib_ref] [bib_ref] An update on medications and noninvasive brain stimulation to augment language rehabilitation..., Saxena [/bib_ref] [bib_ref] Repetitive transcranial magnetic stimulation for management of poststroke impairments: An overview of..., Kim [/bib_ref] [bib_ref] Is There a Future for Noninvasive Brain Stimulation as a Therapeutic Tool?, Terranova [/bib_ref] Low frequency rTMS applied over the right inferior frontal gyrus is probably effective in promoting the recovery of non-fluent aphasics in the chronic stage of stroke, especially if used in combination with speech and language therapy. [bib_ref] Low-frequency rTMS of the unaffected hemisphere in stroke patients: A systematic review, Sebastianelli [/bib_ref] Anodal tDCS applied over the left inferior frontal gyrus is supported by evidence of moderate quality for its efficacy in the naming of nouns, but not verbs, in nonfluent aphasics in the chronic phases of stroke, with possible maintenance of gains during follow-up. [bib_ref] Low-frequency rTMS of the unaffected hemisphere in stroke patients: A systematic review, Sebastianelli [/bib_ref] Few studies on apraxia of speech and dysarthria have been conducted, and those available only involve small samples. The positive results reported in meta-analyses and systematic reviews do not necessarily reflect meaningful clinical benefits. [bib_ref] Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS):..., Lefaucheur [/bib_ref] Differences in the methodologies employed to analyze study data lead to different levels of evidence. [bib_ref] Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS):..., Lefaucheur [/bib_ref] Patient responses to stimuli vary greatly due to individual factors and different mechanisms of functional reorganization of the brain following stroke, which are poorly understood. [bib_ref] Is There a Future for Noninvasive Brain Stimulation as a Therapeutic Tool?, Terranova [/bib_ref] The strategy of applying inhibitory or excitatory stimuli to the left or right hemispheres may not be the optimal approach, and the best site and paradigm for stimulation must first be determined. [bib_ref] Transcranial direct current stimulation (tDCS) for improving aphasia after stroke: a systematic..., Elsner [/bib_ref] The evidence supporting the benefits of rTMS and tDCS is preliminary, and there is no consensus on the therapeutic use of these techniques in the clinical practice. [bib_ref] Transcranial direct current stimulation (tDCS) for improving aphasia after stroke: a systematic..., Elsner [/bib_ref] [bib_ref] An update on medications and noninvasive brain stimulation to augment language rehabilitation..., Saxena [/bib_ref] [bib_ref] Repetitive transcranial magnetic stimulation for management of poststroke impairments: An overview of..., Kim [/bib_ref] [bib_ref] Is There a Future for Noninvasive Brain Stimulation as a Therapeutic Tool?, Terranova [/bib_ref] Regarding the pharmacological approach, donepezil and memantine have been shown to improve several aspects of language; 21 the effects of galantamine, amphetamines, and levodopa remain inconclusive; bromocriptine demonstrated no benefits, 21 whereas piracetam promoted a transient limited effect. 22 ## Recommendations - Speech and language therapy should be started early for all poststroke patients with aphasia (Recommendation I-A); Arquivos de Neuro-Psiquiatria Vol. 80 No. 7/2022 © 2022. Academia Brasileira de Neurologia. All rights reserved. - The effectiveness of combined early and intensive aphasia therapy is uncertain (Recommendation IIb-A); - For AOS, an articulatory-kinematic approach is recommended (Recommendation IIa-A); - Speech therapy is indicated for dysarthria rehabilitation (Recommendation IIa-A); - The benefits of rTMS and tDCS in poststroke aphasia rehabilitation are uncertain (Recommendation IIb-A), as well as in AOS and dysarthria rehabilitation (Recommendation IIb-C); - Donepezil and memantine can be used for poststroke aphasia treatment (Recommendation IIa-A); - There are no recommendations for the use of piracetam, bromocriptine, galantamine, levodopa, or amphetamines (Recommendation III-A). ## Dysphagia Dysphagia occurs in 65% to 90% of stroke patients and is associated with aspiration pneumonia, dehydration, malnutrition, and increased mortality. [bib_ref] Dysphagia and Associated Pneumonia in Stroke Patients from Brazil: A Systematic Review, Pacheco-Castilho [/bib_ref] Although spontaneous recovery from dysphagia occurs in stroke patients, 11% to 50% will have permanent dysphagia up to 6 months after the stroke, increasing the risk of pneumonia 3-fold. In poststroke patients with laryngotracheal aspiration, pneumonia is eight times higher. [bib_ref] Dysphagia and Associated Pneumonia in Stroke Patients from Brazil: A Systematic Review, Pacheco-Castilho [/bib_ref] Dysphagia screening should be performed early, and bedside evaluation can provide valuable information. [bib_ref] Dysphagia screening: state of the art: invitational conference proceeding from the Stateof-the-Art..., Donovan [/bib_ref] However, bedside evaluation alone cannot detect aspiration without clinical signs. [bib_ref] Dysphagia in stroke patients, Singh [/bib_ref] If silent aspirations are suspected, videofluoroscopy and fiberoptic endoscopic evaluations are appropriate methods to evaluate the swallowing mechanism. [bib_ref] Clinical Application of Flexible Endoscopic Evaluation of Swallowing in Stroke, Pisegna [/bib_ref] [bib_ref] Temporal and Sequential Analysis of the Pharyngeal Phase of Swallowing in Poststroke..., Saconato [/bib_ref] Rehabilitation of dysphagia in stroke patients is based on the concept of neuroplasticity; it involves compensatory strategies and modification of the physiology of swallowing. Compensatory strategies include volume and texture modifications and postural techniques such as a chin tuck position. [bib_ref] Swallowing therapy for dysphagia in acute and subacute stroke, Bath [/bib_ref] Some maneuvers may serve as a compensatory strategy and function as rehabilitative exercises, such as the effortful swallow, supraglottic swallow, super-supraglottic swallow, and the Mendelsohn maneuver. [bib_ref] Swallowing therapy for dysphagia in acute and subacute stroke, Bath [/bib_ref] Other exercises, such as the Shaker exercise and Masako maneuver, may improve swallowing physiology. Tactile, thermal, or sour taste stimulation and noninvasive neurostimulation therapies are also used. [bib_ref] Swallowing therapy for dysphagia in acute and subacute stroke, Bath [/bib_ref] Swallowing therapies in survivors up to six months after stroke may reduce the length of hospital stay, dysphagia, chest infections, and swallowing ability. [bib_ref] Swallowing therapy for dysphagia in acute and subacute stroke, Bath [/bib_ref] However, they do not significantly affect mortality, dependency/disability, and case fatality outcomes. [bib_ref] Swallowing therapy for dysphagia in acute and subacute stroke, Bath [/bib_ref] A randomized trial 29 demonstrated significant recovery from dysphagia, prevention of aspiration pneumonia, and reduced time to return to oral feeding in participants who initiated swallowing therapy in the first 48 hours and during the first 3 days compared with a delayed dysphagia program in rehabilitation. Non-invasive neurostimulation therapies, such as rTMS, tDCS, and surface neuromuscular electrical stimulation pro-vide benefits regarding performance in heterogeneous swallowing tests. [bib_ref] The effects of surface neuromuscular electrical stimulation on poststroke dysphagia: a systemic..., Chen [/bib_ref] [bib_ref] Comparative Efficacy of Noninvasive Neurostimulation Therapies for Acute and Subacute Poststroke Dysphagia:..., Chiang [/bib_ref] However, the number and quality of the studies were relatively limited. Statistical heterogeneity was moderate, high, or not reported in some of the published meta-analyses 30,31 about the effects of these interventions in post-stroke dysphagia. Phase-3 clinical trials are required. There is no benefit with pharyngeal electrical stimuation. 32 ## Recommendations - Early swallowing therapies are recommended for recovery from dysphagia (Recommendation I-A); - Dysphagia screening should be performed early after stroke to prevent aspiration pneumonia, malnutrition, and dehydration (Recommendation I-B); ## Postural control and balance Changes in balance and postural control are caused by motor impairment and loss of sensory and spatial orientation of the body. They are common after stroke and negatively affect the quality of life, activities, and participation of individuals. [bib_ref] Motor strategies of postural control after hemispheric stroke, Tasseel-Ponche [/bib_ref] Trunk training, with support, on unstable surfaces, such as balls used in physical therapy sessions, air mattresses, pillows, and boards, appears to be superior to stable surfaces to improve static and dynamic balances.There is strong evidence of the benefits of trunk control training in sitting as well as mobile and static balances. [bib_ref] The effectiveness of trunk training on trunk control, sitting and standing balance..., Van Criekinge [/bib_ref] Two systematic reviews with meta-analyses showed that virtual reality on its own 36 and virtual reality associated with conventional physiotherapy 37 effectively improved poststroke balance. Despite limited evidence, telerehabilitation, combined with virtual reality, for balance training, can be an alternative to overcome difficulty in accessing a rehabilitation service.Hydrotherapy significantly improved postural balance, more so in chronic patients than in patients in the subacute phase. [bib_ref] Effectiveness of Hydrotherapy on Balance and Paretic Knee Strength in Patients With..., Chae [/bib_ref] Aerobic exercise on a cycle ergometer has no positive effect on balance. 40, However, the effects of treadmill gait training, with or without weight support, have been found to be positive. [bib_ref] The efficacy of treadmill training on balance dysfunction in individuals with chronic..., Tally [/bib_ref] Peripheral somatosensory stimulation was beneficial in controlling postural stability in individuals in the poststroke chronic phase as an adjuvant therapy. [bib_ref] Peripheral somatosensory stimulation and postural recovery after stroke -a systematic review, Schröder [/bib_ref] A meta-analysis [bib_ref] Effects of robotic gait training after stroke: A meta-analysis, Moucheboeuf [/bib_ref] showed that robot-assisted gait training improved balance when compared with the absence of this intervention, despite the limitations of the analyzed studies. The effects of mental imagery, rTMS, and tDCS are controversial due to the methodological variability in the studies. [bib_ref] Functional Balance and Postural Control Improvements in Patients With Stroke After Noninvasive..., Kang [/bib_ref] Functional task-training associated with musculoskeletal intervention and/or cardiopulmonary intervention and sensory interventions seem to be effective in improving balance and postural stability respectively. [bib_ref] Limited evidence of physical therapy on balance after stroke: A systematic review..., Hugues [/bib_ref] However, the heterogeneity of physical therapy and the weak methodological quality of studies limited the interpretation and the confidence in findings. [bib_ref] Limited evidence of physical therapy on balance after stroke: A systematic review..., Hugues [/bib_ref] The physical therapy techniques evaluated in this meta-analysis 47 included balance training, walking, transfers, getting up and down activities, reaching objects with upper limbs (ULs), active muscle strengthening, active-assisted and passive cardiopulmonary fitness, and sensory interventions such as thermal, tactile, visual, and vestibular stimulation. ## Ataxias The term ataxia refers to a disturbance in voluntary movement present in cases of injury or damage to the cerebellum, cerebellar peduncle, and cerebellar pathways of the brainstem. [bib_ref] Response to intensive upper extremity therapy by individuals with ataxia from stroke, Richards [/bib_ref] Ataxia, present in 2% to 3% of patients after stroke, is a loss of coordination, dysmetria, dysarthria, hypotonia, rebound phenomenon, and nystagmus. [bib_ref] A Comparative Study of Conventional Physiotherapy versus Robot-Assisted Gait Training Associated to..., Belas Dos Santos [/bib_ref] There are few intervention studies on ataxia in stroke patients. Case studies indicate that task training with specific goals can improve limb ataxia in poststroke individuals, and rTMS is still in the experimental phase. 50 ## Recommendations - Task training, with specific goals, can be used in poststroke ataxia (Recommendation IIb-C); - Repetitive transcranial magnetic stimulation is still in the experimental phase and should not be routinely used in the treatment of post-stroke ataxia (Recommendation III-C). ## Spasticity The prevalence of poststroke spasticity (PSS) ranges from 20% to 40%. [bib_ref] When does spasticity in the upper limb develop after a first stroke?..., Nam [/bib_ref] Loss of movement control, abnormal posture, increased muscle tone, painful spasms, and an overall decline in muscle function are the main symptoms. [bib_ref] When does spasticity in the upper limb develop after a first stroke?..., Nam [/bib_ref] Changes in the passive properties of muscles may lead to contractures. [bib_ref] When does spasticity in the upper limb develop after a first stroke?..., Nam [/bib_ref] The clinical assessment methods most commonly used include the Modified Ashworth Scale (MAS) and the Modified Tardieu Scale (MTS). [bib_ref] Their Clinical Relevance for Measuring Spasticity in Adult and Paediatric Neurological Populations, Ashworth [/bib_ref] A combination of rehabilitation techniques and pharmacological and non-pharmacological interventions produces better effects. [bib_ref] Botulinum Toxin Therapy Combined with Rehabilitation for Stroke: A Systematic Review of..., Hara [/bib_ref] Baclofen, tizanidine, and oral benzodiazepines, which are commonly used in daily practice, still lack good evidence for their use, with frequent adverse effects, especially in elderly patients. [bib_ref] Pharmacological interventions other than botulinum toxin for spasticity after stroke, Lindsay [/bib_ref] There is sufficient evidence to conclude that botulinum toxin is safe and effective in reducing UL and lower-limb spasticity after stroke. [bib_ref] Effectiveness of Botulinum Toxin Treatment for Upper Limb Spasticity Poststroke Over Different..., Andringa [/bib_ref] However, the effect on motor function remains unclear. [bib_ref] Botulinum Toxin Type A for the Treatment of Lower Limb Spasticity after..., Santamato [/bib_ref] A meta-analysis 57 showed improvement in impairment, but no significant effect on gait speed. A recent consensus of specialists 58 in the treatment of poststroke spasticity with botulinum toxin recommended an approach based on three key areas: individualized intervention, optimal injection technique and preparation of the toxin, and rehabilitation with adjuvant therapies concomitant with and after the injection of botulinum toxin. Severe forms of PSS can be treated with intrathecal baclofen. [bib_ref] Effect of Intrathecal Baclofen on Pain and Quality of Life in Poststroke..., Creamer [/bib_ref] Among the non-pharmacological approaches, kinesiotherapy 60 and functional bandaging (taping) 61 can be considered. Splints and orthoses have uncertain benefits. [bib_ref] Hand splinting for poststroke spasticity: a randomized controlled trial, Basaran [/bib_ref] Transcutaneous electrical nerve stimulation (TENS) and functional electrical stimulation (FES) reduce spasticity in the lower limbs. [bib_ref] Effect of Transcutaneous Electrical Nerve Stimulation on Spasticity in Adults With Stroke:..., Mahmood [/bib_ref] [bib_ref] Functional electrical stimulation early after stroke improves lower limb motor function and..., You [/bib_ref] Acupuncture and electroacupuncture combined with conventional routine care may be beneficial for PSS. 65 ## Recommendations - The application of botulinum toxin to target muscles is recommended for the treatment of spasticity (Recommendation I-A); - Transcutaneous electrical nerve stimulation is recommended to reduce muscle spasticity in the lower limbs (Recommendation I-A); - Functional electrical stimulation of spastic muscles can be considered (Recommendation IIa-A); - Treatment with intrathecal baclofen can be used in refractory cases (Recommendation IIa-A); - Acupuncture, electroacupuncture, and functional bandaging should be considered (Recommendation IIa-A); - Kinesiotherapy may be considered in the treatment of spasticity (Recommendation IIb-B); - Oral medications such as baclofen, tizanidine, and benzodiazepines may be used, always considering their adverse effects (Recommendation IIb-A); - The effects of botulinum toxin on function are uncertain (Recommendation IIb-A); - Splints and positioning orthoses have uncertain effects (Recommendation IIb-A). ## Upper limb The UL is affected in 80% and 40% of patients in the acute and chronic phases after stroke respectively. 66 Impairments of the UL chronically limit functional independence and satisfaction in 50% to 70% of stroke patients. Weakness, hypotonia, hypertonia, joint instability, and loss of motor control cause functional limitations in reaching, grasping, and manipulating objects. [bib_ref] Rehabilitation of Motor Function after Stroke: A Multiple Systematic Review Focused on..., Hatem [/bib_ref] Although extensively used in rehabilitation, there is limited evidence favoring the Bobath approach. [bib_ref] Effectiveness of the Bobath concept in the treatment of stroke: a systematic..., Díaz-Arribas [/bib_ref] Strength training can improve UL strength and function without increasing tone or pain. [bib_ref] Strength training improves upper-limb function in individuals with stroke: a meta-analysis, Harris [/bib_ref] Resistance training is superior to other therapies for muscular strength and motor function. [bib_ref] Resistance training in stroke rehabilitation: systematic review and meta-analysis, Veldema [/bib_ref] There is no evidence that stretching therapy improves UL motor impairment and disability. [bib_ref] Rehabilitation of Motor Function after Stroke: A Multiple Systematic Review Focused on..., Hatem [/bib_ref] Although a previous meta-analysis suggested that constraint-induced movement therapy (CIMT) might be superior to traditional rehabilitation, the most recent Cochrane review 70 indicated that CIMT was associated with limited improvement in motor impairment and function, but these benefits did not reduce disability. However, another metaanalysis 71 showed significant benefits of CIMT in patients with acute or subacute stroke. Biofeedback may have some beneficial impact, according to low-quality evidence. [bib_ref] Nature, timing, frequency and type of augmented feedback; does it influence motor..., Molier [/bib_ref] There is evidence of the effectiveness of mirror therapy in improving upper extremity motor function, motor impairment, activities of daily living, and pain, 73 in association with other conventional rehabilitation therapies for stroke patients. [bib_ref] Synergistic Effect of Combined Mirror Therapy on Upper Extremity in Patients With..., Luo [/bib_ref] Mental practice (MP) effectively reduces the limitations to UL activity after stroke, particularly in the first three months and in individuals with severe UL dysfunction. [bib_ref] Systematic Review and Meta-Analysis of the Effectiveness of Mental Practice for the..., Stockley [/bib_ref] Bilateral and unilateral UL training improved motor impairment and functional performance after stroke; however, bilateral training was superior in terms of improving motor impairment. [bib_ref] Comparison of bilateral and unilateral upper limb training in people with stroke:..., Chen [/bib_ref] Although some studies have shown positive effects with repetitive peripheral sensory stimulation (RPSS), [bib_ref] Repetitive Peripheral Sensory Stimulation and Upper Limb Performance in Stroke: A Systematic..., Conforto [/bib_ref] tDCS, [bib_ref] Different Therapeutic Effects of Transcranial Direct Current Stimulation on Upper and Lower..., Bai [/bib_ref] and rTMS, 79 these techniques are still under investigation. When initiated within two months of the stroke, FES is a promising therapy for UL recovery. [bib_ref] Effectiveness of upper limb functional electrical stimulation after stroke for the improvement..., Eraifej [/bib_ref] However, the very low quality of the evidence analyzed means that a clear conclusion about its effects cannot be established. Robot-assisted therapy promotes the use of the affected limb, intensifies rehabilitation through task repetition, and offers task-specific practice. [bib_ref] Upper extremity rehabilitation using fully immersive virtual reality games with a head..., Lee [/bib_ref] Virtual reality (VR) provides augmented feedback and preserves motivation. [bib_ref] Effectiveness of Virtual Reality-and Gaming-Based Interventions for Upper Extremity Rehabilitation Poststroke: A..., Karamians [/bib_ref] A common denominator of VR systems and robot-assisted therapy is playful intervention by means of serious games. [bib_ref] Development of a robotic upper limb assessment to configure a serious game, Dehem [/bib_ref] A serious game is defined as a game that has education or rehabilitation as its primary goal. [bib_ref] Adaptation in serious games for upper-limb rehabilitation: an approach to improve training..., Hocine [/bib_ref] These games combine entertainment, attentional engagement, and problem solving to challenge function and performance. [bib_ref] Adaptation in serious games for upper-limb rehabilitation: an approach to improve training..., Hocine [/bib_ref] After a case of stroke, VR for the UL appears to be more effective than the conventional methods, [bib_ref] Virtual reality for stroke rehabilitation, Laver [/bib_ref] and it may be beneficial when used as an adjunct to usual care. Upper-limb rehabilitation through serious games showed more improvement when compared with the conventional treatment, and long-term effect retention was maintained for UL function, but heterogeneity was high. [bib_ref] Serious games for upper limb rehabilitation after stroke: a meta-analysis, Doumas [/bib_ref] Robot-assisted therapy might be superior to conventional rehabilitation in improving severe UL motor impairment in stroke patients with hemiplegia and limited potential for spontaneous recovery. [bib_ref] Robot-Assisted Therapy for Upper Extremity Motor Impairment After Stroke: A Systematic Review..., Wu [/bib_ref] There is insufficient evidence to support the efficacy of methylphenidate, trazodone, levodopa, and nortriptyline in UL recovery after stroke. [bib_ref] Rehabilitation of Motor Function after Stroke: A Multiple Systematic Review Focused on..., Hatem [/bib_ref] Fluoxetine for six months did not improve functional outcomes and increased the risk of bone fractures.Although not specific to UL, a recent guideline presented a weak recommendation for cerebrolysin (30 mL intravenously for at least ten days) and citalopram (20 mg) to promote early motor neurorehabilitation after acute ischemic stroke. ## Mobility Limitations to mobility and activities related to gait are some of the most impacting sequelae of stroke. More than 20% of stroke survivors do not walk independently, and even if they achieve independence, most have difficulty ambulating in their communities. [bib_ref] Is accurate prediction of gait in nonambulatory stroke patients possible within 72..., Veerbeek [/bib_ref] An exercise program that combines cardiorespiratory training, to enhance cardiorespiratory fitness, and resistance training could promote greater walking speed, muscle strength, balance, and walking endurance. [bib_ref] Physical fitness training for stroke patients, Saunders [/bib_ref] Circuit class therapy (CCT) is superior to conventional therapy in improving mobility, independence, and gait speed in stroke patients. [bib_ref] Circuit class therapy for improving mobility after stroke, English [/bib_ref] The potential risk of falls should be considered. [bib_ref] Circuit class therapy for improving mobility after stroke, English [/bib_ref] Rhythmic auditory cueing enhances gait performance, dynamic postural stability, stride length, and cadence. [bib_ref] Effects of (music-based) rhythmic auditory cueing training on gait and posture post-stroke:..., Ghai [/bib_ref] Water-based exercises may improve muscle strength, balance, mobility, and aerobic capacity compared with land-based exercises.Improvement in the ability to walk independently with treadmill training (TT), with or without body weight support, was not superior when compared with no TT, but walking speed and walking endurance improved slightly in the short term. [bib_ref] Treadmill training and body weight support for walking after stroke, Mehrholz [/bib_ref] The effects were more significant, though not persistent, for those who were able to walk. [bib_ref] Treadmill training and body weight support for walking after stroke, Mehrholz [/bib_ref] Better recovery of walking speed and distance in ambulatory patients was observed with TT. [bib_ref] Treadmill walking improves walking speed and distance in ambulatory people after stroke..., Nascimento [/bib_ref] Gait in electromechanical-assisted training associated with physiotherapy after stroke promotes a greater chance of achieving independent walking than physiotherapy without these devices. [bib_ref] Electromechanical-assisted training for walking after stroke, Mehrholz [/bib_ref] Three months after stroke, participants who were not ambulatory seemed to benefit most from this type of intervention. [bib_ref] Electromechanical-Assisted Training for Walking After Stroke: A Major Update of the Evidence, Mehrholz [/bib_ref] Repetitive gait training within the first three months poststroke can lead to long-term functional improvements if provided with an end-effector robot. [bib_ref] Feasibility and effectiveness of repetitive gait training early after stroke: A systematic..., Schröder [/bib_ref] When compared with conventional therapy approaches, VR and interactive game training did not produce statistically significant changes in regarding improvements in gait speed or balance. [bib_ref] Virtual reality for stroke rehabilitation, Laver [/bib_ref] Compared with placebo or no intervention, there is no evidence of superiority in gait, motor function, and functional mobility after stroke from motor imagery. [bib_ref] Motor imagery for gait rehabilitation after stroke, Silva [/bib_ref] The Bobath approach was not superior in terms of regaining mobility, motor control of the lower limb and gait, balance, and activities of daily living of poststroke patients when compared with other interventions. [bib_ref] Effectiveness of the Bobath concept in the treatment of stroke: a systematic..., Díaz-Arribas [/bib_ref] No differences in motor function were observed between real acupuncture and sham acupuncture after stroke. [bib_ref] Acupuncture for stroke rehabilitation, Yang [/bib_ref] Stroke patients may require an assistive technology device to aid in mobility. These comprise orthoses, splints, wheelchairs, walkers, and crutches. Ankle-foot orthosis (AFO) is recommended to position the ankle during gait to prevent foot drop injury and to improve gait kinetics and kinematics of both the knee and ankle joints in poststroke gait. [bib_ref] A systematic review and meta-analysis of the effect of an ankle-foot orthosis..., Tyson [/bib_ref] There are two AFO models: fixed AFOs are recommended for patients who demonstrate great ankle instability during gait, and articulated AFOs are indicated for patients with greater stability of the ankle joint. [bib_ref] Effect of ankle-foot orthosis on functional mobility and dynamic balance of patients..., De Paula [/bib_ref] [bib_ref] The effects of ankle-foot orthoses on walking speed in patients with stroke:..., Shahabi [/bib_ref] The AFO can improve ankle and knee kinematics, kinetics, and the energy cost of walking in stroke survivors. [bib_ref] Effect of ankle-foot orthosis on functional mobility and dynamic balance of patients..., De Paula [/bib_ref] However, no convincing evidence has been observed regarding walking speed. [bib_ref] The effects of ankle-foot orthoses on walking speed in patients with stroke:..., Shahabi [/bib_ref] A decrease in energy expenditure during gait with AFO was also observed. [bib_ref] Effect of types of ankle-foot orthoses on energy expenditure metrics during walking..., Daryabor [/bib_ref] Ankle joint stabilization improves with FES of the foot dorsiflexors. [bib_ref] A Clinical Practice Guideline for the Use of Ankle-Foot Orthoses and Functional..., Johnston [/bib_ref] It consists of a structure with different presentations in which plantar sensors are connected to superficial electrodes that promote the contraction of the tibial and dorsiflexor muscles, preventing foot drop during the swing phase of gait. 107 A meta-analysis 108 concluded that there was evidence that AFO and FES can increase gait speed, mobility, dynamic balance, quality of life, endurance, and muscle activation poststroke. Another meta-analysis 109 of low-quality evidence showed that FES applied to the paretic peroneal nerve, when combined with physiotherapy, can improve ankle dorsiflexion, balance, and functional mobility. The benefits of walking with a cane poststroke are uncertain. A comparative study of the effect of a simple cane and a four-point cane in individuals three months after a stroke showed that the use of a cane improves gait symmetry, which is indicated for patients at the beginning of gait training. [bib_ref] Immediate effects of cane use on gait symmetry in individuals with subacute..., Beauchamp [/bib_ref] However, despite the methodological limitations of the studies, a systematic review 111 showed no improvement in gait parameters concerning speed, step length, cadence, and symmetry after stroke with a single support cane. There was a slight reduction in speed with a four-point cane compared with the gait without a mobility device. [bib_ref] Which type of cane is the most efficient, based on oxygen consumption..., Jeong [/bib_ref] Walkers can help gait in patients with balance deficits, but weakness in the UL or the inability to use the hand to grasp the walker is a limitation to their use. When comparing the use of a simple cane with a four-point cane and walkers, it was observed that the energy spent in gait in individuals who used a walker was higher.Mobility devices such as wheelchairs, walking sticks, and bath chairs are associated with greater independence after a stroke. 113 ## Recommendations - An exercise program, including cardiorespiratory and resistance training, should be used to improve gait after stroke (Recommendation I-A); - Circuit class training is recommended for walking and balance recovery poststroke (Recommendation I-A); - Functional electrical stimulation can be useful in improving ankle dorsiflexion, balance, and functional mobility (Recommendation IIa-B); - It is reasonable to use AFO in gait rehabilitation after stroke (Recommendation IIa-A); - Gait performance, dynamic postural stability, stride length, and cadence can be improved with rhythmic auditory cueing (Recommendation IIa-A); - Water-based exercises can be recommended for gait rehabilitation after stroke (Recommendation IIa-B); - Treadmill training, with or without body weight support, can improve speed and walking endurance poststroke, and is reasonable to use (Recommendation IIa-B); - Electromechanical-assisted gait added to physiotherapy can be beneficial for gait recovery, mainly in the first three months poststroke, and for participants who are not able to walk. ## Cognition Poststroke cognitive deficits occur early and are quite frequent, as they appear within the first 3 months in up to 55% of patients when at least 1 cognitive domain is considered. [bib_ref] Dementia and cognitive impairment three months after stroke, Madureira [/bib_ref] Poststroke dementia occurs when there is cognitive decline immediately after or within the first six months after vascular ictus, with no evidence of improvement in this period. [bib_ref] The Vascular Impairment of Cognition Classification Consensus Study. Alzheimers Dement, Skrobot [/bib_ref] Since an informal clinical evaluation may underdiagnose cognitive decline, the use of test that have already been validated is recommended. [bib_ref] National Institute of Neurological Disorders and Stroke-Canadian Stroke Network vascular cognitive impairment..., Hachinski [/bib_ref] No superiority was observed among the tests that assess cognition. [bib_ref] Test accuracy of cognitive screening tests for diagnosis of dementia and multidomain..., Lees [/bib_ref] Reducing the levels of systolic blood pressure is effective in decreasing the incidence of poststroke cognitive deficit. [bib_ref] Thijs LSystolic Hypertension in Europe Trial Investigators. Risk and benefit of treatment..., Celis [/bib_ref] The use of statins shows conflicting results.Donepezil and galantamine may be useful to improve poststroke cognition, but the benefits of memantine and rivastigmine are not well established.Evidence 121 suggests that physical activity is an intervention with a protective role that may improve poststroke cognition. In addition, it is a low-cost strategy with a positive impact on motor function, quality of life, and cardiopulmonary condition.Cognitive rehabilitation has shown benefits, improving poststroke memory and attention, but with limited conclusions regarding its efficacy due to the quality of the studies published. [bib_ref] CMTask Force on Cognitive Rehabilitation European Federation of Neurological Societies. EFNS guidelines..., Cappa [/bib_ref] The association between cognitive and physical rehabilitation seems to provide greater benefits than isolated therapies. [bib_ref] Effects of combined intervention of physical exercise and cognitive training on cognitive..., Bo [/bib_ref] Studies 125 with VR are isolated, but show promising results. A meta-analysis 126 of four systematic reviews on poststroke cognitive impairments showed that acupuncture is safe and improves cognitive function without serious adverse events in stroke patients. Repetitive transcranial magnetic stimulation and tDCS are still in an exploratory stage. [bib_ref] The Effect of Non-Invasive Brain Stimulation (NIBS) on Attention and Memory Function..., Hara [/bib_ref] There is no evidence to ## Unilateral spatial neglect The non-recognition of space, usually on one side of the body, or of any stimulus applied to it, is called hemineglect syndrome or unilateral spatial neglect (USN), [bib_ref] Definition: Spatial neglect, Cubelli [/bib_ref] and it designates a consistent, exaggerated spatial asymmetry in processing information in bodily and/or extrabodily space due to an acquired cerebral lesion, which cannot be explained by primary motor or sensory deficits. The processing of neglected information can occur implicitly, without reaching consciousness, and can influence task performance. [bib_ref] Definition: Spatial neglect, Cubelli [/bib_ref] Unilateral space neglect occurs in $ 50% of individuals after right-hemisphere stroke, and it may persist in 75%, with some symptoms, in the chronic phase. [bib_ref] Hemispatial neglect, Parton [/bib_ref] Patients with neglect are often unaware of or fail to acknowledge items on their contralesional side and attend instead to items on the same side as their brain damage-their ipsilesional side. [bib_ref] Hemispatial neglect, Parton [/bib_ref] Unilateral space neglect causes prolonged hospitalization, impaired functional recovery, and reduced quality of life. [bib_ref] Unilateral spatial neglect in the acute phase of ischemic stroke can predict..., Luvizutto [/bib_ref] Several rehabilitation methods have been developed to improve spatial neglect in the last few decades. These can be classified according to their theoretical basis: 132 1) enhancing awareness of neglect behavior through a top-down mechanism; 2) low-level bottom-up sensory stimulation; and 3) neuromodulation. Top-down treatments consist of training the gaze direction using cues from the patient's left side. Videos to show the patient their omissions during recorded functional tasks and mental images can also be used. However, these methods are limited because they require attention skills, which can be hampered by the lack of awareness of spatial neglect behaviors, such as anosognosia. [bib_ref] Top-down and bottom-up approaches for the treatment of unilateral spatial neglect in..., Dintén-Fernández [/bib_ref] Bottom-up treatments, including prismatic adaptation, visual scanning training, optokinetic stimulation, VR, limb activation, neck vibration combined with prism adaptation, voluntary trunk rotation, and vestibular rehabilitation improve immediate and long-term performance in USN. [bib_ref] Top-down and bottom-up approaches for the treatment of unilateral spatial neglect in..., Dintén-Fernández [/bib_ref] [bib_ref] Virtual reality treatment and assessments for post-stroke unilateral spatial neglect: A systematic..., Ogourtsova [/bib_ref] Moderate-quality evidence showed that rTMS was more efficient than sham for USN after stroke. [bib_ref] Noninvasive Brain Stimulations for Unilateral Spatial Neglect after Stroke: A Systematic Review..., Kashiwagi [/bib_ref] Repetitive transcranial magnetic stimulation in the posterior parietal cortex, and theta-burst stimulation, improved USN after stroke. [bib_ref] The effect of theta-burst stimulation on unilateral spatial neglect following stroke: a..., Cotoi [/bib_ref] Very low-quality evidence suggested that tDCS has a beneficial effect in improving USN after stroke. 136 ## Recommendations - Repeated "top-down" and "bottom-up" interventions can be considered, such as prismatic adaptation, visual scanning training, optokinetic stimulation, VR, limb activation, motor imagery, voluntary trunk rotation, vestibular rehabilitation, and vibration of the neck combined with prismatic adaptation to improve USN after stroke (Recommendation IIa-A); - The benefits of tDCS and rTMS to reduce USN after stroke are uncertain (Recommendation IIb-A). ## Sensory impairment (hearing, vision, and touch) Sensory impairment after stroke, including hearing, vision, touch, and proprioception, is directly linked to activity limitations and participation restrictions. [bib_ref] Sensory loss in hospital-admitted people with stroke: characteristics, associated factors, and relationship..., Tyson [/bib_ref] However, they can improve with therapeutic intervention, particularly multimodal interventions. [bib_ref] A review of the evidence underpinning the use of visual and auditory..., Parker [/bib_ref] Hearing loss of a vascular cause is usually associated with cerebellar infarction in the territory of the anterior inferior cerebellar artery. [bib_ref] Recent Advances in Cerebellar Ischemic Stroke Syndromes Causing Vertigo and Hearing Loss, Kim [/bib_ref] The incidence of hearing loss in stroke patients is twice as high as that of non-stroke individuals, and it can limit participation in rehabilitation programs. [bib_ref] Risk of sudden sensorineural hearing loss in stroke patients: A 5-year nationwide..., Kuo [/bib_ref] Approximately 20% of stroke survivors report severe difficulties with speech recognition in the presence of background noise, despite normal audiometry.Hearing loss is usually treated with a personal frequency-modulated (FM) system with meaningful benefits. 142 A prospective, nonrandomized, controlled study in stroke patients showed clinical improvements in the speech reception threshold with the use of a personal FM system. [bib_ref] Long-term use benefits of personal frequency-modulated systems for speech in noise perception..., Koohi [/bib_ref] Visual impairment after stroke has a prevalence of 73% in the acute stroke population. [bib_ref] High incidence and prevalence of visual problems after acute stroke: An epidemiology..., Rowe [/bib_ref] The four most impaired visual functions are reduced central vision, loss of the peripheral visual field, eye movement disorders, and visual perception disorders. [bib_ref] Vision In Stroke cohort: Profile overview of visual impairment, Group [/bib_ref] For the treatment of visual loss, prism lenses, unilateral eye occlusion, adapted lighting, picture amplification, environment modification, orthoptic exercises, Fresnel prism, verbal, written, and head posture advice have been employed. [bib_ref] Interventions for visual field defects in people with stroke, Pollock [/bib_ref] The evidence for all these interventions is weak, and there is a lack of evidence relating to their effect on functional ability in activities of daily living. [bib_ref] Interventions for visual field defects in people with stroke, Pollock [/bib_ref] One in two individuals who had a stroke had reduced sensation, impacting both the ability to function independently and the overall quality of life. [bib_ref] Effects of Somatosensory Impairment on Participation After Stroke, Carey [/bib_ref] In acute ischemic stroke, almost 60% of patients showed somatosensory impairment in at least one subitem in the acute stage, but there is considerable recovery over time. Reduced sensation is associated with reduced motor function in terms of quality of movement control, and lesser rehabilitation outcomes. [bib_ref] Somatosensory Deficits After Ischemic Stroke, Kessner [/bib_ref] Sensory rehabilitation, which triggers the activation of the cutaneous nerves, can be performed with somatosensory afferents, such as thermal, pressure, peripheral nerve, transcutaneous electrical nerve, and vibration stimulations. [bib_ref] A sensorimotor stimulation program for rehabilitation of chronic stroke patients, De Diego [/bib_ref] Additionally, a sensory retraining approach based on graded re-education using learning principles and augmenting sensory input, such as proprioception, tactile recognition, desensitization, stereognosis, location, and discrimination is another option for sensory stimulation. Additionally, with haptic-based augmented reality, feedback devices that augment targeted sensory afferents can be used. [bib_ref] A sensorimotor stimulation program for rehabilitation of chronic stroke patients, De Diego [/bib_ref] Systematic reviews and meta-analyses have shown that a varied range of intervention methods intended for retraining leg somatosensory function after stroke effectively improves somatosensory impairment and balance, but not gait. [bib_ref] Sensory retraining of the leg after stroke: systematic review and meta-analysis, Chia [/bib_ref] A systematic review showed that somatosensory retraining may assist people in regaining somatosensory discrimination skills in the arm after stroke. 151 ## Recommendations - Frequency-modulated systems are recommended for hearing loss after stroke (Recommendation I-B); - Leg somatosensory retraining can be used to improve balance after stroke (Recommendation IIa-A); - Arm somatosensory retraining can improve somatosensory discrimination skills after stroke (Recommendation IIa-A); - Prism lenses, unilateral eye occlusion, adapted lighting, picture amplification, environment modification, orthoptic exercises, Fresnel prism, verbal, written, and head posture advice may be used for visual impairment after stroke (Recommendation IIb-C). ## Rehabilitation continuity: home rehabilitation, return to leisure, work, and driving Home rehabilitation (HR) should be part of the ongoing rehabilitation planning, according to a meta-analysis. [bib_ref] Systematic Review and Meta-Analysis of Home-Based Rehabilitation on Improving Physical Function Among..., Chi [/bib_ref] Well-established and early HR resulted in a better quality of life. [bib_ref] Systematic Review and Meta-Analysis of Home-Based Rehabilitation on Improving Physical Function Among..., Chi [/bib_ref] Resistive reach and grip exercises in the home environment showed positive results in the activity level of the ULs. [bib_ref] Effects of functional and analytical strength training on upper-extremity activity after stroke:..., Graef [/bib_ref] Home mirror therapy associated with repetition training and activities of daily living can result in better responses in motor activity and in the sit-and-stand test. [bib_ref] Effects of Home-Based Versus Clinic-Based Rehabilitation Combining Mirror Therapy and Task-Specific Training..., Hsieh [/bib_ref] Visuomotor feedback training at home was an effective method to improve USN. [bib_ref] Efficacy of home-based visuomotor feedback training in stroke patients with chronic hemispatial..., Rossit [/bib_ref] In poststroke home treatment, VR was beneficial for UL mobility. [bib_ref] Home-based Upper Extremity Stroke Therapy Using a Multiuser Virtual Reality Environment: A..., Thielbar [/bib_ref] Home rehabilitation with glove therapy and fingertip sensors with visual feedback on a screen according to the movements performed improved hand movement compared with conventional treatment in HR. [bib_ref] Home-based hand rehabilitation after chronic stroke: Randomized, controlled single-blind trial comparing the..., Zondervan [/bib_ref] Home caregivers promoted positive results for poststroke physical function and depressive symptoms.Stroke patients have been shown to have difficulties participating in leisure and recreational activities. [bib_ref] Systematic Review and Meta-Analysis of Home-Based Rehabilitation on Improving Physical Function Among..., Chi [/bib_ref] Recreational activity programs improved physical and mental function. [bib_ref] Predictors of return to work after stroke: a prospective, observational cohort study..., Nascimento [/bib_ref] Less than 50% of poststroke patients can return to work 6 months post-stroke and 50% have deficiencies in performing work activities 5 years after the event. [bib_ref] The effect of a workplace intervention programme on return to work after..., Ntsiea [/bib_ref] Intervention in the work environment promoted a higher percentage of return to work. [bib_ref] The effect of a workplace intervention programme on return to work after..., Ntsiea [/bib_ref] Occupational rehabilitation interventions have shown positive effects on accommodation to the environment and job satisfaction. [bib_ref] The ReWork-Stroke rehabilitation programme described by use of the TIDieR checklist, Johansson [/bib_ref] After a stroke, drivers may have compromised reflexes, leading to risks behind the wheel, with a consequent increase in the chances of collisions, excessive speed, and invasion of the opposite lane. [bib_ref] Rehabilitation for improving automobile driving after stroke, George [/bib_ref] Although the effects of rehabilitation on poststroke return to steering are uncertain, the use of a rotary knob in steering in a specific position and driving simulators can be used as tools for a return to driving activity after stroke. [bib_ref] Muscle activation of drivers with hemiplegia caused by stroke while driving using..., Jung [/bib_ref] ## Recommendations ## Medication adherence Medication adherence is defined as "the extent to which a person's behavior when using medications corresponds with the agreed recommendations from a health care provider".Five dimensions and two factors influence adherence behavior. The five dimensions are the patient, the health system, socioeconomic status, therapy, and health status. The factors are classified as intentional, such as skipping a dose of the drug when considering that the symptoms are under control, and unintentional, such as skipping a dose due to forgetfulness.Limitations to the adherence to medications affect $ 50% of poststroke individuals.Patients with atrial fibrillation and greater adherence to oral anticoagulants have a lower risk of stroke, transient ischemic attack, and mortality.Better adherence to statins and antihypertensives is also associated with a lower risk of stroke. [bib_ref] Adherence to Antihypertensive Medications and Stroke Risk: A Dose-Response Meta-Analysis, Xu [/bib_ref] On the other hand, non-adherence is associated with a greater chance of recurrence, mortality, long-term disability, and dementia. [bib_ref] Long-term mortality after first-ever and recurrent stroke in young adults, Aarnio [/bib_ref] Better medication adherence is associated with better knowledge of medications and the need to use them. [bib_ref] Mobile phone text messaging to improve medication adherence in secondary prevention of..., Adler [/bib_ref] Although promising, the use of automated telecommunication interventions, including text messages and interactive voice response, showed conflicting results in two metaanalyses 168,169 that analyzed medication adherence for secondary prevention of cardiovascular disease. Intervention with telephone support, conducted mainly by nurses, can be effective. [bib_ref] Telemedical strategies for the improvement of secondary prevention in patients with cerebrovascular..., Kraft [/bib_ref] Medication adherence improved after self-management interventions to better control risk factors in poststroke individuals. [bib_ref] A Systematic Review of Randomized Controlled Trials of Medication Adherence Interventions in..., Wessol [/bib_ref] Interventions based on cognitive and behavioral orientation, such as simplifying the act of taking medications, environment reminders, and information to improve drug treatment beliefs, improved medication adherence after stroke. 170 ## Recommendations - Interventions based on cognitive and behavioral orientation should be conducted to improve medication adherence (Recommendation I-A); ## Palliative care Neurological palliative care (PC) has become increasingly important and relevant in studies worldwide. Considering that it is comprehensive, multidisciplinary care, it makes perfect sense to apply it to patients with neurological diseases, especially those affected by stroke, to alleviate and prevent the suffering of people with serious, life-threatening diseases.Palliative care should be initiated early in stroke patients, not only when the patient is close to death. [bib_ref] American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, and..., Holloway [/bib_ref] neurology or Intensive Care Unit (ICU) team and by a PC service at the time of diagnosis. [bib_ref] Neuropalliative care: Priorities to move the field forward, Creutzfeldt [/bib_ref] There are three possible models for the integration of neurological care and PC. [bib_ref] Neuropalliative care: Priorities to move the field forward, Creutzfeldt [/bib_ref] The first one is the consultative model, through an exceptional evaluation via consultation with the PC team. The second one is the integrated model, in which the teams work together simultaneously. The third one is primary neuropalliative care, in which the neurologist is trained to provide primary PC and determine when there is a need for referral to a specialized team. In the last model, neurological PC provides greater involvement, as the neurologist who follows the patient since the diagnosis has a stronger connection and more data to predict and define a therapeutic plan. [bib_ref] Neuropalliative care: Priorities to move the field forward, Creutzfeldt [/bib_ref] The main contributions of the neurologist in primary PC, which can be useful for every professional involved in the care of the patient, are recognizing the PC needs associated with each neurological disease, identifying and treating pain, providing basic psychosocial and spiritual support, acquiring communication skills (including empathic listening), evaluating the prognosis, supporting patients and families regarding tragic choices, being aware of last-resort PC options, and acknowledging and managing the caregiver's distress and needs. [bib_ref] American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, and..., Holloway [/bib_ref] Neurologists should also know how to identify an indication for specialized (or secondary) PC, which includes management of refractory and complex physical symptoms, management of complex psychological and spiritual suffering, assistance in conflict resolution in relation to the objective and treatment options, transfer to hospice, and end-oflife management. 173 ## Recommendations - Palliative care is recommended for people with stroke in cases of reduced quality of life and reduced life expectancy (Recommendation I-C); - Palliative care should be provided by neurologists, the ICU team, and the PC Service at the time of diagnosis (Recommendation I-B); - Formal assessment of PC should be recommended in endof-life situations, in the presence of refractory pain, dyspnea, agitation, mood disorders, long-term feeding assistance, ventilation, palliative extubation, and assistance in resolving conflicts between family members and health teams (Recommendation I-B). ## Cerebrovascular events related to sars-cov-2 infection Infection by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has been heavily associated with short-and medium-term neurological complications. [bib_ref] Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus..., Harapan [/bib_ref] These conditions increase the risk of headache, encephalopathy, epileptic seizures, delirium, and cerebrovascular events such as ischemia, intracranial hemorrhage, central venous thrombosis, and subarachnoid hemorrhage. [bib_ref] Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus..., Harapan [/bib_ref] The incidence of cerebrovascular disease in patients with active SARS-Cov-2 infection ranges from 2.3% to 6%, and it is higher among patients with more severe infection. [bib_ref] Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus..., Harapan [/bib_ref] One study 174 reported that central venous thrombosis occurred in 0.3% of cases, and infection increased the frequency of involvement of multiple cerebral arterial territories, with more extensive lesions and subsequent greater neurological severity. At the same time, younger people were more affected than controls. [bib_ref] Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus..., Harapan [/bib_ref] The coronavirus disease 2019 (COVID-19) pandemic has radically changed processes, patient access, and stroke care. However, the nature and quality of stroke care across the entire service line have proven benefits in long-term results. [bib_ref] Canadian Stroke Best Practices Advisory Council. Canadian Stroke Best Practice Guidance During..., Smith [/bib_ref] Standards and scope in the care of stroke patients must be maintained; otherwise, the recurrence rate of stroke and ongoing disabilities in general will increase and generate a new burden on an already overloaded service network. Overall, measures to preserve the best stroke management practices must be implemented in the context of the pandemic across the health system. Alternative care models such as telerehabilitation may provide greater access to care for stroke patients during the COVID-19 pandemic. [bib_ref] Canadian Stroke Best Practices Advisory Council. Canadian Stroke Best Practice Guidance During..., Smith [/bib_ref] However, the literature is still scarce, and robust evidence on stroke rehabilitation related to SARS-CoV-2 infection is lacking. ## Recommendations - Rehabilitation strategies must comprise a multidisciplinary approach focusing on neurological impairments and disabilities after stroke that is related to SARS-CoV-2 infection (Recommendation IIb-C); - Access to specialized centers such as stroke units, outpatient care, early support on discharge, and community stroke rehabilitation might be considered for stroke related to SARS-CoV-2 (Recommendation IIb-C). ## Future of stroke rehabilitation The flourishing of rehabilitation science has broadened knowledge about the heterogeneity of plasticity and recovery mechanisms in different individuals and poststroke phases. [bib_ref] Plasticity during stroke recovery: from synapse to behaviour, Murphy [/bib_ref] To develop clinically-relevant strategies, solid bridges need to be built between studies in animals, proofof-concept studies, randomized clinical trials in different phases, pragmatic studies, good-quality meta-analyses, and the practical needs of the patients, their families, professionals, and health services. In recent years, studies such as EXCITE, FLAME, FOCUS, and AVERT (for a review, please check the study by Cramer 177 ), among others, have shown that it is possible to test rehabilitation interventions and understand that patient characteristics are crucial for choosing therapies with a greater likelihood of success. "Precision rehabilitation" with realistic and individualized goals can thus be implemented. With this approach, it becomes crucial to define "the right therapy for the right patient at the right time". Consensus on outcomes to be used in rehabilitation research, advances in neurophysiology techniques, structural and functional neuroimaging, genetics, data science, and artificial intelligence (AI), recognition of the importance of interdisciplinary work, patient opinions or preferences regarding the goals of the rehabilitation process, as well as the involvement of patients in this process, have contributed to increasing innovations. [bib_ref] Impact of Telerehabilitation for Stroke-Related Deficits, Knepley [/bib_ref] [bib_ref] National Institutes of Health StrokeNet Telerehab Investigators. Efficacy of Home-Based Telerehabilitation vs..., Cramer [/bib_ref] Among the techniques that may be included in poststroke rehabilitation in the future, for example, through the enhancement of adaptive mechanisms of plasticity, are the use of drugs, non-invasive brain-computer interface (NIBCI), and behavioral interventions. [bib_ref] A clinical evaluation on the spatial patterns of non-invasive motor imagery-based brain-computer..., Ang [/bib_ref] Social isolation during the COVID-19 pandemic underscored the need to develop telerehabilitation tools that use strategies such as videoconferencing to supervise rehabilitation activities. A study 179 compared this intervention with the same rehabilitation protocol applied in an out-ofhome environment and observed an improvement in the levels of disability, balance, and stress of the caregiver without distinctions among groups. Telerehabilitation may be effective for motor rehabilitation and is less costly than conventional therapy. [bib_ref] Impact of Telerehabilitation for Stroke-Related Deficits, Knepley [/bib_ref] Technological advances may increase the effectiveness of different telerehabilitation techniques and leverage other promising perspectives such as NIBCI, 180 wearable sensors, 181 devices for communication in critically-ill patients, 182 feedback and motivation systems, [bib_ref] Effect of a mixed realitybased intervention on arm, hand, and finger function..., Colomer [/bib_ref] and interactive robots, 184 among others. Despite many exciting possibilities, there is still a gap between research and the daily practice. For the design, testing, and implementation of useful strategies in the practice, it is essential that networks bring together researchers and rehabilitation professionals so that multicenter studies can be performed by considering the needs and opportunities in local, regional, or national cost-effectiveness contexts. Interventions that work in other countries may not work well in Brazil, and vice versa. Facilitators and barriers to rehabilitation can be very different in a large urban center and a small town in the heart of the Amazon. Access to rehabilitation after stroke in different Brazilian regions has been evaluated by the Access to Rehabilitation after Stroke (AReA) study.Therapies based on new technologies do not always result in clinical benefits and are sometimes accompanied by costs that make them unaffordable for many. Therefore, it is crucial to choose evidence-based rehabilitation interventions suited for our reality. By doing so, we will be able to drastically impact the quality of life of millions of people with stroke. ## Suggested sites for patients and caregivers # Conclusions The field of rehabilitation is open to incorporating new interventions to enhance the practice and the care after stroke. There have been significant breakthroughs in the last two decades through randomized controlled trials on stroke rehabilitation. High-level evidence supports the following recommendations: early speech, language, and swallowing therapy; specific training exercises for balance; botulinum toxin to reduce spasticity; mirror therapy; mental practice; unilateral and bilateral training; strengthening of upper limb improvement; cardiorespiratory and resistance training for gait recovery; physical activity as an adjunctive treatment to cognitive decline; and home planned rehabilitation after stroke. Future research is needed to establish the role of new technologies, such as neuromodulation, robotics, VR, and telerehabilitation as a routine in the clinical practice. # Authors' contributions [fig] •: Surface neuromuscular electrical stimulation, rTMS, and tDCS are under investigation, but evidence about their clinical effectiveness is not well established (Recommendation IIb-A); Videofluoroscopy and fiberoptic endoscopic evaluations can be performed if aspiration is suspected without clinical symptoms or signs (Recommendation IIa-B); Pharyngeal electrical stimulation is not recommended to improve dysphagia after stroke (Recommendation III-A). [/fig] [table] - 46: Arquivos de Neuro-Psiquiatria Vol. 80 No. 7/2022 © 2022. Academia Brasileira de Neurologia. All rights reserved. [/table]	None	http://www.thieme-connect.de/products/ejournals/pdf/10.1055/s-0042-1757692.pdf	Abstract The Brazilian Practice Guidelines for Stroke Rehabilitation – Part II, developed by the Scientific Department of Neurological Rehabilitation of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia, in Portuguese), focuses on specific rehabilitation techniques to aid recovery from impairment and disability after stroke. As in Part I, Part II is also based on recently available evidence from randomized controlled trials, systematic reviews, meta-analyses, and other guidelines. Part II covers disorders of communication, dysphagia, postural control and balance, ataxias, spasticity, upper limb rehabilitation, gait, cognition, unilateral spatial neglect, sensory impairments, home rehabilitation, medication adherence, palliative care, cerebrovascular events related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the future of stroke rehabilitation, and stroke websites to support patients and caregivers. Our goal is to provide health professionals with more recent knowledge and recommendations for better rehabilitation care after stroke.
484e8e687aa9770436319fc7a068b09fc04f13fe	pubmed	KASL clinical practice guidelines: Management of Hepatitis C	KASL clinical practice guidelines: Management of Hepatitis C AimsPractice Guidelines for Management of Hepatitis C were first established in 2004. Since then, many study results have been published concerned with epidemiology, clinical outcomes and related factors, concept of response-guided therapy, therapeutic strategy, and results. Moreover, as direct acting antivirals (DAA) have been recently developed and adapted to practice, treatment of hepatitis C is rapidly evolving. Therefore, the Korean Association for the Study of the Liver (KASL) revised the guidelines based on a systematic approach that reflects evidence-based medicine and expert opinions.The clinical practice guidelines for the management of hepatitis C have been revised to be useful for treatment, research, and education. These recommendations are not absolute standards of care, and adoption of the guidelines in clinical practice may differ for individual patients. ## Levels of evidence and grades of recommendations The quality of evidence was classified according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system [fig_ref] Table 1: Grading of Recommendations, Assessment, Development, and Evaluation [/fig_ref]. [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] Based on the types of studies, randomized, control studies were approached from a high level of evidence, while observational studies were approached from a low level of evidence. The level of evidence was adjusted by accounting for the factors influencing the quality of the studies. Through follow-up studies, the level of evidence was defined as follows: A, indicating the highest level of evidence with the smallest possibility of any changes in the conclusion; B, indicating a moderate level of potential changes; and C, indicating the lowest level of evidence with the greatest possibility of any changes. The strength of a recommendation was also classified according to the GRADE system. Each study was classified as strong recommendation [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] or weak recommendation [bib_ref] Current status of hepatitis C virus infection in Korea, Suh [/bib_ref] under overall consideration of quality of evidence, the balance between the desirable and undesirable effect of an intervention, and socioeconomic aspects including cost or availability. A strong recommendation indicated that the interventions could be applied in most patients with high degree of certainty and that there was a greater possibility of desirable effects, high-quality evidence, and presumed patient-important outcomes, cost-effectiveness, preference, and compliance. A weak recommendation indicated a suggestion made with less certainty but that could be considered favorable for many patients, based on the level of evidence, cost, or preferences of the patients or medical practitioners. ## List of key questions The revision committee considered the following clinical questions as the key components to be covered in these guidelines. [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref]. What is the epidemiology and natural history of hepatitis C in South Korea? 2. How should the diagnosis and evaluation of severity of chronic hepatitis C be made? 3. What is the goal of treatment and who are the targets for the antiviral treatment of hepatitis C? 4. How is the treatment response defined, and what are predictors of the response? 5. How are patients with chronic HCV genotype 1 and 4 infections treated? 6. How are patients with chronic HCV genotype type 2, 3, and 6 infections treated? 7. How are patients with acute hepatitis C treated? 8. How are the adverse effects of antiviral drugs managed and how the patients monitored during and after antiviral treatment? 9. How are patients with special conditions (cirrhosis, liver ## Criteria ## Quality of evidence high (a) Further research is very unlikely to change our confidence in the estimate of effect. ## Moderate (b) Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. ## Low (c) Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any change of estimate is uncertain. # Strength of recommendation Strong [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost. Weak [bib_ref] Current status of hepatitis C virus infection in Korea, Suh [/bib_ref] Variability in preference and values, or more uncertainty. Recommendation is made with less certainty, higher cost or resource consumption. Of the quality levels of evidence, we excluded "very low quality " in our guideline for convenience, which was originally included in the GRADE system. ## Prevalence rate of adult health check examinees The HCV prevalence rate in adult health check examinees was reported as 1.7% when tested by 1 st -generation enzyme immunoassay (EIA) in early 1990s, just following the discovery of HCV. [bib_ref] Prevalence of hepatitis C virus antibody among Korean adults, Kim [/bib_ref] The estimated age-standardized prevalence of anti-HCV in the adult (≥40 years of age) health check examinees was reported as 1.29% (95% confidence interval 1.12-1. [bib_ref] Global epidemiology of hepatitis B and hepatitis C in people who inject..., Nelson [/bib_ref] and was about 193,000 persons in a collective study including health checkup examinees from Seoul, Ulsan, Jeollanam-do, and Daegu between 1995 and 2000. [bib_ref] PCR prevalence and risk factors of hepatitis C virus infection in the..., Jeong [/bib_ref] [bib_ref] Geographic characteristics of positivity of anti-HCV and Chonnam province: survey data of..., Na [/bib_ref] [bib_ref] A study on markers of viral hepatitis in adults living in Daegu..., Park [/bib_ref] [bib_ref] A study on positive rate of HBsAg, HBsAb and anti-HCV in Korean..., Seo [/bib_ref] [bib_ref] Epidemiology of hepatitis C virus in Korea, Shin [/bib_ref] In 2009, the anti-HCV prevalence rate in health examinations of 291,314 adults ≥20 years of age from 29 health examination Prevalence of anti-HCV in blood donors, pregnant women, and children The anti-HCV prevalence rate in 2,040,151 blood donors in 1997 in South Korea was 0.34% as tested by 3 rd -generation EIA. [bib_ref] Experience of anti-HCV antibody immunoblot test in Korean blood donors, Oh [/bib_ref] From 2005 to 2009, the anti-HCV prevalence in 11,064,532 blood donors was 0.16%, and the HCV RNA-positive rate was 8.4 (0.0084%) of 100,000 donors, among whom 81% were young people aged 10-30 years. [bib_ref] Prevalence of hepatitis C virus infections and distribution of hepatitis C virus..., Oh [/bib_ref] In South Korea, the risk of blood transfusion-related HCV infection decreased from 1 in 81,431 in 2000/2001 to 1 in 2,984,415 after implementation of nucleic acid test for HCV screening of donated blood beginning in February, 2005. [bib_ref] Residual risk of transfusiontransmitted infection with human immunodeficiency virus, hepatitis C virus,..., Kim [/bib_ref] The anti-HCV prevalence rates in pregnant women were reported as 0.49-1.7%, [bib_ref] Transmission of hepatitis C virus from mothers to infants: its frequency and..., Moriya [/bib_ref] [bib_ref] Prospective reevaluation of risk factors in mother-to-child transmission of hepatitis C virus:..., Okamoto [/bib_ref] and a domestic report investigating over 5,000 pregnant women reported rates of 0.42-0.44%. [bib_ref] Hepatitis C virus infection in pregnancy, Kim [/bib_ref] [bib_ref] Prevalence of HCV infection in pregnant woman and vertical transmission, Kang [/bib_ref] Among anti-HCV-positive pregnant women, 57-60% were positive for HCV RNA. [bib_ref] Hepatitis C virus infection in pregnancy, Kim [/bib_ref] [bib_ref] Prevalence of HCV infection in pregnant woman and vertical transmission, Kang [/bib_ref] Domestic studies on HCV prevalence rate in children and adolescents are insufficient. A 0.82% anti-HCV-positive rate tested by 3rd generation EIA in 2,080 children between 6 and 11 years of age living in Seoul was reported. [bib_ref] The prevalence of anti-HCV positivity in healthy Korean children, Lee [/bib_ref] However, there have been no other reports or studies on children and adolescents, hindering the accurate assessment of HCV prevalence rate in the pediatric population of South Korea. ## Prevalence of anti-hcv in high-risk group High-risk groups for HCV infection include people with a history of intravenous drug use (IVDU), patients receiving hemodialysis, and those with HIV infection, hemophilia, and leprosy. However, the HCV prevalence rate in these groups has been reported mostly before 2000, with little data since then. Domestic anti-HCV prevalence rate in the IVDU group was reported as 48.4-79.2%. [bib_ref] Prevalence of hepatitis C, B and human immunodeficiency virus among drug users..., Kim [/bib_ref] [bib_ref] Seropositivity of anti-HCV in intravenous drug abusers, Lee [/bib_ref] [bib_ref] High prevalence of HBV and HCV infection among intravenous drug users in..., Yun [/bib_ref] [bib_ref] Prevalence and associated clinical characteristics of hepatitis B, C, and HIV infections..., Min [/bib_ref] Among anti-HCV-positive persons, [bib_ref] Steatosis accelerates the progression of liver damage of chronic hepatitis C patients..., Adinolfi [/bib_ref].1% were HCV RNA-positive. [bib_ref] Prevalence and associated clinical characteristics of hepatitis B, C, and HIV infections..., Min [/bib_ref] Meanwhile, in case of sharing cocaine suction pipe, the anti-HCV prevalence rate was similar to IVDU group. [bib_ref] High prevalence of hepatitis C virus infection among noninjecting drug users: association..., Macias [/bib_ref] Anti-HCV prevalence rate was 5.9-14.7% [bib_ref] Prevalence and risk factors of hepatitis C virus infectioin in chronic hemodialysis..., Kim [/bib_ref] [bib_ref] Prevalence of anti-HCV in hemodialysis patients in Taegu and Kyeongbuk, Shin [/bib_ref] in previous studies that included more than 200 patients with chronic kidney diseases and the rate significantly correlated with duration of hemodialysis. Coinfection rate of HCV was high in those infected with HIV; about 25% of westerners and 5.0-6.3% of HIV-infected individuals in South Korea were coinfected with HCV. [bib_ref] Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a..., Sherman [/bib_ref] [bib_ref] Seroprevalence of sexually transmitted viruses in Korean populations including HIV-seropositive individuals, Kim [/bib_ref] [bib_ref] Trends of mortality and cause of death among HIV-infected patients in Korea, Lee [/bib_ref] Anti-HCV prevalence rate in 104 hemophilia patients tested by 3rd-generation EIA of was 42.3% in 2002 and the risk of infection correlated with age and severity of hemophilia. [bib_ref] Viral hepatitis and change of lymphocyte subpopulation in hemophiliacs in Chonnam Kwangju..., Kim [/bib_ref] In their 2012 annual report, the Korea Hemophilia Foundation (KHF) reported that 430 of 2,148 (20.0%) hemophilia patients were anti-HCVpositive and 118 of 2,148 (5.5%) were HCV RNA-positive.Leprosy patients can be considered a high-risk group of HCV infection due to their skin lesions and long-term cohabitation in limited areas. The prevalence rate of 96 leprosy patients tested by 2 nd -generation EIA was 67.7% in 1997 and 82% of these individuals were immunoblot-positive. [bib_ref] The prevalence of hepatitis C virus infection in leprous patients, Choi [/bib_ref] ## Incidence rate of hcv infection Studies on HCV incidence rate are rare, since only 20-30% of those with acute HCV infection develop symptoms. HCV incidence rates are decreasing in Western countries.In the US the incidence rate decreased from 7.4 of 100,000 people from 1982-1989 to 0.7 of 100,000 people from 1994-2006, [bib_ref] Incidence and transmission patterns of acute hepatitis C in the United States, Williams [/bib_ref] and in Italy, a decreased from 2.02 of 100,000 people in 1996 to 0.55 of 100,000 people in 2006 was reported. [bib_ref] Boccia A. Hepatitis C virus infections trends in Italy, Torre [/bib_ref] The HCV infection incidence rate in South Korean blood donors was reported as 13.8 of 100,000 according to a survey conducted on those who donated blood at least twice from 1994-1996. [bib_ref] Study on the seroincidence of hepatitic C virus infection among blood donors..., Oh [/bib_ref] The recent HCV infection incidence rates among blood donors who donated at least twice in 2 years between 2000 and 2010 were estimated 6. ## Prevention ## Route of transmission HCV transmission occurs by parenteral exposure. The main routes of transmission include transfusion of contaminated blood or blood products, organ transplantation, IVDU, unsafe injection or medical procedures, stabs by contaminated syringe or needle, sexual contact with HCV infected person, or perinatal transmission from infected mother to newborns. Transmission via transfusion was a main route of infection until 1991, but the possibility has become extremely low since a screening test was introduced for blood donors. [bib_ref] A new strategy for estimating risks of transfusion-transmitted viral infections based on..., Busch [/bib_ref] [bib_ref] Impact of individual-donation nucleic acid testing on risk of human immunodeficiency virus,..., Vermeulen [/bib_ref] [bib_ref] A multi-Chinese blood center study testing serologic-negative donor samples for hepatitis C..., Shan [/bib_ref] The most important route of recent HCV transmission is the use of illicit drugs in developed countries such as the US or Europe; HCV prevalence rate is low, [bib_ref] Public health issues of hepatitis C virus infection, Papatheodoridis [/bib_ref] whereas anti-HCV prevalence in the IVDU group was reported as high as 50-90%. [bib_ref] Global epidemiology of hepatitis B and hepatitis C in people who inject..., Nelson [/bib_ref] Meanwhile, unsafe injection with multiple-use medication vials or reused syringes, or unsanitary medical procedures including surgery, endoscopy, and dental treatment without proper disinfection are reported as the main causes of HCV transmission in developing countries. [bib_ref] Unsafe injections in low-income country health settings: need for injection safety promotion..., Kermode [/bib_ref] [bib_ref] The German Hep-Net acute hepatitis C cohort: impact of viral and host..., Deterding [/bib_ref] [bib_ref] Multiple clusters of hepatitis virus infections associated with anesthesia for outpatient endoscopy..., Gutelius [/bib_ref] In addition, meta-analyses have reported that risk factors of HCV transmission include piercing, acupuncture, or tattooing without proper disinfection. [bib_ref] Body piercing as a risk factor for viral hepatitis: an integrative research..., Hayes [/bib_ref] [bib_ref] Is acupuncture a risk factor for hepatitis? Systematic review of epidemiological studies, Ernst [/bib_ref] [bib_ref] Tattooing and the risk of transmission of hepatitis C: a systematic review..., Jafari [/bib_ref] The HCV infection risk by a small dose of percutaneous exposure, such as needle sticks, is 1.8% (0-7%) [bib_ref] Epidemiology of hepatitis C, Alter [/bib_ref] [bib_ref] Occupational transmission of hepatitis C in healthcare workers and factors associated with..., Tomkins [/bib_ref] [bib_ref] Risk of hepatitis C seroconversion after occupational exposures in health care workers...., Puro [/bib_ref] [bib_ref] Hepatitis C virus infection in healthcare workers: risk of exposure and infection, Lanphear [/bib_ref] in other countries and 0.92% in South Korea. [bib_ref] Transmission of hepatitis C virus by occupational percutaneous injuries in South Korea, Ryoo [/bib_ref] Heterosexual persons with chronic HCV infection in long-term monogamous relationships with a partner had little evidence for sexual transmission of HCV. However, the risk becomes higher with multiple sex partners, and unsafe sex including anal sex, sex accompanying wounds, sex carrying other sexually transmitted diseases like HIV, or in homosexuals. [bib_ref] Is sexual contact a major mode of hepatitis C virus transmission?, Tohme [/bib_ref] [bib_ref] Incidence of acute hepatitis C virus infection among men who have sex..., Yaphe [/bib_ref] The percentage of perinatal transmission was reported as 1-6.2%. [bib_ref] Hepatitis C virus in pregnancy, Prasad [/bib_ref] [bib_ref] Maternal-infant transmission of hepatitis C virus infection, Roberts [/bib_ref] It was reported as 1.7% when the mothers were positive for anti-HCV regardless of HCV RNA-positivity, and as 4.3%(3.9-7.1%) in case of HCV RNA-positive mothers. [bib_ref] Maternal-infant transmission of hepatitis C virus infection, Roberts [/bib_ref] [bib_ref] Perinatal transmission of hepatitis C virus infection, Indolfi [/bib_ref] The risk of perinatal transmission increased in female infants, HIV-positive mothers, and mothers with high blood HCV RNA levels.Cesarean section is reportedly not a preventative method for HCV transmission,and transmission via nursing was very low. Thus, it is not necessary to limit breast-feeding unless nipples are injured or are bleeding.Reports of horizontal transmission between siblings or family members of HCV infected person are based on a low level of evidence. [bib_ref] Intrafamilial transmission of hepatitis C virus, Indolfi [/bib_ref] A comparative study 69 of 1,173 HCV patients and 534 control group in five university hospitals between 2007 and 2011 in South Korea reported several independent risk factors of infection including illicit use of drug, needle stick injury, transfusion before 1995, tattoo, and age. 69 ## Counselling for prevention Since an effective vaccine has not been developed, the main strategy of prevention is to educate people on the risk factors for HCV infection and to keep the strict standard for sanitation in every place performing the percutaneous procedures. HCV infected persons should be counseled not to donate blood, organs, tissues, or semen, and not to share any instrument penetrating skin. They should individually use instruments including toothbrushes, oral hygiene devices, razors, or nail clippers so his/her blood are not exposed to other people. Finger stabbing needles commonly used for Korean home remedy should not be shared. IVDU should be persuaded to stop drug abuse and they should not reuse syringes, needles, injection solution, cotton swab, or alcohol sponges. They must be reminded that other people can be infected via recklessly disposed needles. Since risk of infection among monogamous couples is very low, use of barrier protections among these couples are not necessarily recommended. Nevertheless, if the partner of the infected individual request or for the infected person with multiple sex partners, it is recommended to use condoms. Routine screening for HCV is not recommended for all pregnant women. However, for those with a risk factor, prenatal testing for HCV is needed. HCV infection does not mean a restriction of breast-feeding or a recommendation of specific delivery, such as Cesarean section. Health care facilities should be careful to block HCV transmission. Proper disinfection, cleaning, and management of materials and instruments are essential in medical procedures and invasive procedures including tattooing, piercing, or acupuncture. [Recommendations] 1. HCV infected persons should not donate blood, organs, tissues, or semen (A1). HCV infected persons should avoid to share toothbrushes, oral hygiene devices, razors, nail clippers, or any instrument penetrating skin, so as not to expose his/her blood to other people (C1). 2. Intravenous drug abusers should be counseled to stop illicit drug abuse (A1). They should be educated about routes of infection and tested regularly for HCV infection (B1). 3. Proper disinfection, cleaning, and management of materials and instruments are essential in medical procedures and invasive procedures including tattooing, piercing, or acupuncture (B1). 4. Since risk of infection among monogamous sexual partners is very low, use of barrier protection is not advised in these couples (B1). However, for those with multiple sex partners, it is recommended to use condoms (B1). ## For pregnant women, if a risk factor for hcv infection is detected or hcv infection is suspected otherwise, prenatal testing for hcv infection is recommended (b1). HCV infection does not mean a restriction of breastfeeding or a recommendation of specific delivery, such as Cesarean section (B2). ## Natural history ## Acute hcv infection After 1-3 weeks of HCV infection, HCV RNA becomes detectable in blood and rapidly increases. [bib_ref] A longterm study of hepatitis C virus replication in non-A, non-B hepatitis, Farci [/bib_ref] [bib_ref] Natural history of acute and chronic hepatitis C, Maasoumy [/bib_ref] Serum alanine transaminase (ALT) level increases due to hepatocyte damage after 4-12 weeks of the infection. Most infection is asymptomatic (70-80%) but symptoms including flu-like symptoms, fatigue, vomiting, nausea, right upper quadrant pain, muscle pain, or pruritus may develop within 2-12 weeks. About 20% of acute infection accompanies jaundice with serum bilirubin level below 3-8 mg/dL, and acute liver failure occurs rarely in <1% of cases. Acute hepatitis progressed to chronic infection in 54-85% of patients and 20-50% of patients recovered spontaneously within 3-4 months. [bib_ref] Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis, Corey [/bib_ref] [bib_ref] Acute hepatitis C: current status and remaining challenges, Santantonio [/bib_ref] [bib_ref] Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on..., Alter [/bib_ref] Spontaneous recovery rate is different depending on route of infection; spontaneous recovery rate in post-transfusion cases was 12%, while in the cases not related to transfusion it was 29-52%. [bib_ref] Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on..., Alter [/bib_ref] [bib_ref] Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance, Gerlach [/bib_ref] [bib_ref] Long-term follow-up of non-A, non-B (type C) post-transfusion hepatitis, Tremolada [/bib_ref] Factors related to spontaneous recovery are hepatitis accompanying jaundice, female, low viral load, and genotype 3. 75-77 A Korean study reported that among 18 acute hepatitis C patients (17 patients showed symptoms), 12 patients spontaneously recovered and 6 patients progressed to chronic hepatitis. [bib_ref] Spontaneous viral clearance in patients with acute hepatitis C can be predicted..., Hofer [/bib_ref] Another study including 47 patients of acute hepatitis C enrolled in seven Korean institutions showed that mean age of 45.8 years, 21 of 47 (44.7%) patients recovered spontaneously, and 16 patients received antiviral therapy. All 12 patients who were treated and followed-up patients achieved a sustained virological response (SVR). Ten patients who did not receive antiviral therapy progressed to chronic hepatitis. [bib_ref] Natural history of acute symptomatic hepatitis C in Korea, Kim [/bib_ref] A single nucleotide polymorphism (SNP) of the interleukin 28B (IL 28B) gene is strongly related to spontaneous recovery from acute hepatitis C infection. [bib_ref] Acute hepatitis C in Korea: different modes of infection, high rate of..., Kim [/bib_ref] [bib_ref] Genetic variation in IL28B and spontaneous clearance of hepatitis C virus, Thomas [/bib_ref] [bib_ref] A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis..., Tillmann [/bib_ref] IL28B is located on chromosome 19 and expresses interferon-lamda-3. A study reported a spontaneous recovery rate of 53% in case with genotype CC of IL28B SNP rs12979860 and of 28% in genotype CT or TT (Odds ratio (OR)=0.33, P<10 -12 ). [bib_ref] IL28B genetic variants and gender are associated with spontaneous clearance of hepatitis..., Rao [/bib_ref] However, future studies are needed since there have been no Korean studies of IL28B SNP in acute HCV infection. Factors affecting disease progression include duration of infection, age at the time of infection (≥40 years of age), male, alcohol intake, coinfection with other viruses (HBV, HIV), insulin resistance, obesity, immune-depressed patients, organ transplantees, elevation of ALT, or genetic factors such as IL28B. [bib_ref] Natural history of acute and chronic hepatitis C, Maasoumy [/bib_ref] Excessive alcohol intake by chronic hepatitis C patients is strongly related to occurrence of cirrhosis, and increases risk of HCC. [bib_ref] Natural history of liver fibrosis progression in patients with chronic hepatitis C...., Poynard [/bib_ref] [bib_ref] Rate of natural disease progression in patients with chronic hepatitis C, Zarski [/bib_ref] [bib_ref] The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in..., Harris [/bib_ref] [bib_ref] Impact of alcohol on the histological and clinical progression of hepatitis C..., Wiley [/bib_ref] [bib_ref] Progression of type C chronic hepatitis to liver cirrhosis and hepatocellular carcinoma--its..., Noda [/bib_ref] Fatty liver, insulin resistance, and obesity increase risks of hepatic fibrosis and HCC development in chronic hepatitis C patients. [bib_ref] Contribution of obesity to hepatitis C-related fibrosis progression, Ortiz [/bib_ref] [bib_ref] Obesity is an independent risk factor for hepatocellular carcinoma development in chronic..., Ohki [/bib_ref] [bib_ref] Steatosis accelerates the progression of liver damage of chronic hepatitis C patients..., Adinolfi [/bib_ref] [bib_ref] Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with..., Ohata [/bib_ref] Coinfection of HIV or HBV in chronic HCV infection causes faster progression of liver diseases and increases the risk of HCC compared to HCV single infection. [bib_ref] Rates and risk factors of liver fibrosis progression in patients with chronic..., Poynard [/bib_ref] [bib_ref] Significance of prior hepatitis B virus infection in the development of hepatocellular..., Imazeki [/bib_ref] [bib_ref] Independent and additive effect modification of hepatitis C and B viruses infection..., Tsai [/bib_ref] In addition, coinfection of hepatitis A virus (HAV) in chronic hepatitis C increases the risk of hepatic failure. [bib_ref] Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic..., Vento [/bib_ref] Pathologic stage of hepatic fibrosis at the time of chronic hepatitis C diagnosis is the most important predictor for progression to cirrhosis (refer to the Diagnosis section of this manuscript). 86,100 Stage 1 hepatic fibrosis has a 10-30% incidence rate of cirrhosis over a period of 15 years, while most cases of stage 3 hepatic fibrosis are expected to progress to cirrhosis within 15 years. Therefore, patients diagnosed as having hepatic fibrosis over stage 2 must be considered for active antiviral treatment. ## Chronic hcv infection [Recommendations] 6. Continuous management and surveillance for development of cirrhosis and HCC is necessary in chronic hepatitis C patients (A1). 7. Chronic hepatitis C patients are recommended abstinence from alcohol or moderation in drinking, and to maintain suitable body weight through physical exercise and dietary control, since disease progression is related to alcohol, obesity, or insulin resistance (B1). needed to confirm HCV infection. Physical examination and history taking should be done to understand the routes of transmission and block further reinfection. HCV genotyping is essential for treatment and radiologic examination, liver biopsy, or noninvasive evaluation of hepatic fibrosis can be done to determine necessity of treatment, and to assess liver disease severity. Interpretation of serological and virological test results is summarized in . ## Patients with chronic hcv infection without antibodies against hav and hbv should be vaccinated for hav and hbv (c1 ## Diagnosis ## Serologic assays ## Anti-hcv Detection of anti-HCV in serum or plasma is used for screening of a high risk group and for diagnosis of acute or chronic hepatitis C. [bib_ref] Molecular diagnosis of viral hepatitis, Pawlotsky [/bib_ref] The 3 rd generation EIA uses recombinant antigens including core, NS3, NS4, and NS5 of HCV protein, and its sensitivity and specificity are 97.2-99% and 99.8-100%, respectively, when tested in immune-competent individuals. [bib_ref] Sensitivity and specificity of third-generation hepatitis C virus antibody detection assays: an..., Colin [/bib_ref] [bib_ref] Use and interpretation of virological tests for hepatitis C, Pawlotsky [/bib_ref] If signal/cutoff (S/ CO) ratios of 3 rd generation EIA exceed 3.8, a positive result will be apparent in 95% of recombinant immunoblot assay (RIBA). [bib_ref] What strategy should be used for diagnosis of hepatitis C virus infection..., Pawlotsky [/bib_ref] [bib_ref] NAT of the United States and Canadian blood supply, Stramer [/bib_ref] [bib_ref] Guidelines for laboratory testing and result reporting of antibody to hepatitis C..., Alter [/bib_ref] However, a cutoff level of S/CO ratios can be different according to the types of equipment, so that high S/CO ratios do not always mean true positive. [bib_ref] Role of signal-to-cutoff ratios in hepatitis C virus antibody detection, Moretti [/bib_ref] Recently, use of enhanced chemiluminescent immunoassay (CLIA) or electrochemiluminescence immunoassay (ECLIA) is increasing since those assays detect antigen-antibody reaction more sensitively compared to 3 rd generation EIA. Meanwhile, there is point-of-care tests using saliva or fingerstick blood producing rapid results within 20 minutes. [bib_ref] Evaluation of a new, rapid test for detecting HCV infection, suitable for..., Lee [/bib_ref] Average time between infection and seroconversion of anti-HCV is 8-9 weeks and anti-HCV is detectable in >97% of patients with HCV infection within 6 months. [bib_ref] The natural history of community-acquired hepatitis C in the United States, Alter [/bib_ref] [bib_ref] Diagnosis, management, and treatment of hepatitis C: an update, Ghany [/bib_ref] Anti-HCV is not a neutralizing antibody and persists indefinitely in chronic hepatitis C patients or even after recovery. Therefore, the differentiation of current infection from the past infection after recovery is impossible using anti-HCV positivity. Negative result for anti-HCV in combination with a positive result for HCV RNA may represent early state of acute infection, chronic infection in the setting of severe immunosuppressed condition, such as patients on hemodialysis, HIV coinfection, solid organ transplantation recipients, hypo-/ a-gammaglobulinemia, and patients with HCV-associated essential mixed cryoglobulinemia. [bib_ref] Hepatitis C virus infection, Lauer [/bib_ref] [bib_ref] Sensitivity and specificity of third-generation hepatitis C virus antibody detection assays: an..., Colin [/bib_ref] [bib_ref] Screening for hepatitis C virus in human immunodeficiency virusinfected individuals, Thio [/bib_ref] In these patients, HCV RNA testing is necessary for diagnosis of HCV infection. On the other hand, false-positive result for anti-HCV with negative result for HCV RNA can occur in patients with autoimmune diseases. [bib_ref] Hepatitis C virus (HCV) and autoimmune liver diseases, Meyer Zum Buschenfelde [/bib_ref] Recombinant immunoblot assay (RIBA) RIBA detects 4 HCV-specific antibodies on nitrocellulose strips. [bib_ref] Diagnosis, management, and treatment of hepatitis C: an update, Ghany [/bib_ref] Borderline positive results of anti-HCV using EIA or CLIA test can be confirmed with RIBA, but RIBA has low sensitivity despite high specificity. [bib_ref] Guidelines for laboratory testing and result reporting of antibody to hepatitis C..., Alter [/bib_ref] [bib_ref] Low-positive anti-hepatitis C virus enzyme immunoassay results: an important predictor of low..., Dufour [/bib_ref] Recently, clinical role of RIBA has disappeared because validated HCV RNA assays are sequentially conducted in patients showing positive result for anti-HCV to confirm HCV infection. ## Virological assays HCV RNA assays HCV RNA assays are classified as quantitative and qualitative assays. Since the detection cutoff of qualitative assays is 50 IU/mL and more sensitive than previous generation quantitative assays, HCV RNA qualitative assays had been used as a diagnostic confirmation of HCV infection and HCV RNA quantification is used for pretreatment assessment and monitoring of virological response during and after antiviral therapy. [bib_ref] Molecular diagnosis of viral hepatitis, Pawlotsky [/bib_ref] [bib_ref] Guidelines for laboratory testing and result reporting of antibody to hepatitis C..., Alter [/bib_ref] [bib_ref] Molecular diagnostics of hepatitis C virus infection: a systematic review, Scott [/bib_ref] However, recently available quantitative HCV RNA assays are using real-time polymerase chain reaction (PCR) and transcription-mediated amplification (TMA), and are very sensitive with lower detection limit of 12-15 IU/mL, while they have a broad measuring range with upper limit of 7-8 log IU/mL with 98-99% of diagnostic specificity independent of HCV genotype. 104,119-124 Therefore, quantitative HCV RNA tests are now widely used both for diagnosis and evaluation of treatment response. [bib_ref] Multi-center evaluation of the Abbott RealTime HCV assay for monitoring patients undergoing..., Vermehren [/bib_ref] In 1997, the World Health Organization established an international standard for HCV RNA quantification unit, IU, rather than HCV copy numbers. [bib_ref] Standardization of hepatitis C virus RNA quantification, Pawlotsky [/bib_ref] [bib_ref] Establishment of the first international standard for nucleic acid amplification technology (NAT)..., Saldanha [/bib_ref] However, since different laboratories can vary in viral quantification results, [bib_ref] Hepatitis C virus: virology, diagnosis and management of antiviral therapy, Chevaliez [/bib_ref] it is recommended to use the same laboratory test before, during, and after-treatment for monitoring, if possible. [bib_ref] Diagnosis, management, and treatment of hepatitis C: an update, Ghany [/bib_ref] Blood HCV RNA is detectable as early as 2 weeks after infection, [bib_ref] Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on..., Alter [/bib_ref] rapidly increases to reach a plateau, and decreases along with ALT after ALT attains a maximum level. [bib_ref] Immunology of hepatitis B virus and hepatitis C virus infection, Rehermann [/bib_ref] HCV RNA levels maintain a steady state in patients with chronic hepatitis C. [bib_ref] Immunology of hepatitis B virus and hepatitis C virus infection, Rehermann [/bib_ref] [bib_ref] Stealth and cunning: hepatitis B and hepatitis C viruses, Wieland [/bib_ref] HCV RNA levels do not significantly correlated with the severity of hepatic inflammation or fibrosis, and show little changes during chronic infection state without antiviral treatment. [bib_ref] Fluctuations in viral load (HCV RNA) are relatively insignificant in untreated patients..., Nguyen [/bib_ref] [bib_ref] Use of diagnostic testing for managing hepatitis C virus infection, Ferreira-Gonzalez [/bib_ref] Genotyping assays HCV genotyping is useful for epidemiologic studies as well as for predicting treatment response. Therefore, HCV genotype should be assessed before treatment for determining the optimal therapeutic duration and dose of ribavirin. [bib_ref] Serological determination of hepatitis C virus genotype: comparison with a standardized genotyping..., Pawlotsky [/bib_ref] HCV is classified into six major genotypes (1-6) and is subdivided into subtypes identified by lower-case letters, such as 1a or 1b. Differences of 31-33% at the nucleotide level among each genotype, compared with 20-25% among each subtype.HCV genotype does not change within a same person unless otherwise reinfected. Determining HCV genotypes and subtypes can be performed by using direct sequence analysis, reverse hybridization, or restriction fragment mass polymorphism (RFMP). [bib_ref] Diagnosis and management of chronic viral hepatitis: antigens, antibodies and viral genomes, Chevaliez [/bib_ref] Most genotyping assays analyze 5'-untranslated region (UTR) and HCV core regions where nucleotide sequences are highly conserved. [bib_ref] Variation of the hepatitis C virus 5' non-coding region: implications for secondary..., Smith [/bib_ref] With analysis of 5'-UTR region, HCV genotyping errors occur at a rate of <3%, but HCV subtyping errors may occur in 10-25%; especially, this assay does not accurately discriminate between subtype 1a and 1b. [bib_ref] Development and clinical evaluation of a microarray for hepatitis C virus genotyping, Park [/bib_ref] [bib_ref] Hepatitis C virus genotyping: interrogation of the 5' untranslated region cannot accurately..., Chen [/bib_ref] [bib_ref] Hepatitis C virus (HCV) genotype 1 subtype identification in new HCV drug..., Chevaliez [/bib_ref] Subtyping is not necessary in antiviral therapy using interferon alpha and ribavirin combination, but in the treatment including DAAs, subtypes may need to be confirmed since DAAs act differently according to genotype 1a and 1b. [bib_ref] Hepatitis C virus (HCV) genotype 1 subtype identification in new HCV drug..., Chevaliez [/bib_ref] Genotyping is not possible in <5% of the patients. This results from low HCV levels, problems with the PCR amplification process, or high nucleotide variability of HCV genome itself. [bib_ref] Determination of hepatitis C virus genotype by direct sequence analysis of products..., Germer [/bib_ref] HCV drug-resistance mutation tests HCV drug-resistance test has not been performed clinically, unlike cases with hepatitis B virus infection. As various DAAs are being used with improvement of outcomes of treatment, drug resistance tests for these drugs may be needed in the future. 142 ## Screening test for hcv infection Routine screening for HCV infection is recommended in populations at risk, such as those with a history of blood transfusions or organ transplantation prior to 1992; persons who have injected illicit drug; persons with HIV infection, hemophilia, or Hansen's disease; persons who have been on hemodialysis; children born to mothers infected with HCV; and health care providers after a needle stick injury or mucosal exposure to HCV positive blood [fig_ref] http [/fig_ref]. [bib_ref] Diagnosis, management, and treatment of hepatitis C: an update, Ghany [/bib_ref] In 2012, the US Centers for Disease Control and Prevention expanded the screening population to the birth cohort born between 1945-1965 and recommended to screen for HCV once in a lifetime, considering cost effectiveness. [bib_ref] Hepatitis C virus testing of persons born during 1945-1965: recommendations from the..., Smith [/bib_ref] [bib_ref] Screening for hepatitis C virus infection in adults: U.S. preventive services task..., Moyer [/bib_ref] [bib_ref] The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary..., Rein [/bib_ref] A Japanese study revealed that the strategy of hepatitis C screening appears cost-effective in the general population as well as in the high-risk group, [bib_ref] Cost-effectiveness of the national screening program for hepatitis C virus in the..., Nakamura [/bib_ref] but an European study showed that the screening test for general population is cost-effective only in HCV prevalent areas. [bib_ref] Long-term effectiveness and cost-effectiveness of screening for hepatitis C virus infection, Sroczynski [/bib_ref] Therefore, since the epidemiologic characteristics and health care system differ between nations, to adapt the optimal screening strategy in Korea, further research on its cost effectiveness is urgently needed. ## Diagnosis in case of accidental exposure The average incidence of anti-HCV seroconversion in healthcare providers af ter accidental percutaneous exposure from HCV-infected blood was reported to be 1.8% (0-7%) in other countries [bib_ref] Risk of hepatitis C seroconversion after occupational exposures in health care workers...., Puro [/bib_ref] [bib_ref] Hepatitis C virus infection in healthcare workers: risk of exposure and infection, Lanphear [/bib_ref] [bib_ref] The epidemiology of acute and chronic hepatitis C, Alter [/bib_ref] [bib_ref] Hepatitis C virus infection in medical personnel after needlestick accident, Mitsui [/bib_ref] [bib_ref] Induction of hepatitis C virus (HCV)-specific T cells by needle stick injury..., Kubitschke [/bib_ref] and 0.92% in South Korea. [bib_ref] Transmission of hepatitis C virus by occupational percutaneous injuries in South Korea, Ryoo [/bib_ref] When a person is exposed to HCV-positive source, baseline testing for ant-HCV and serum ALT level should be performed. If anti-HCV is negative, HCV RNA assay should be performed 4-6 weeks after exposure for early diagnosis. Even if baseline tests for HCV infection were all negative, follow-up testing for anti-HCV and serum ALT level should be performed 4-6 months after the exposure.If anti-HCV is positive, a confirmative test is needed. ## Assessment of liver disease severity To decide the treatment for HCV infected patients, the severity of the liver disease must be evaluated through liver biopsy and/or noninvasive tests. It is important to confirm whether the patient has liver cirrhosis or not before treatment since existence of liver cirrhosis can make difference in the treatment response, its prognosis, and necessity of surveillance for HCC. ## Liver biopsy Liver biopsy is assessed for grade and stage of the hepatic injury. [bib_ref] Diagnosis, management, and treatment of hepatitis C: an update, Ghany [/bib_ref] [bib_ref] The liver biopsy in chronic hepatitis C: a view from the other..., Kleiner [/bib_ref] The Metavir 154 and Ishak 155 scoring systems are most widely used, and the scoring system proposed by the South Korean Study Group for the Pathology of Digestive Diseases is used in South Korea [fig_ref] Table 4: Comparison of scoring systems for histological stage114 [/fig_ref]. [bib_ref] Histological grading and staging of chronic hepatitis: standardized guideline proposed by the..., Park [/bib_ref] Although liver biopsy is not mandatory prior to treatment, it can help to determine when to start treatment and to provide information regarding the treatment response and prognosis. Considering the natural history of the disease, the cost of treatment and its possible adverse effects, treatment can be postponed if liver histopathology shows minimal to moderate fibrosis state <2 (Metavir stage 2 or periportal fibrosis of the South Korean Study Group for the Pathology of Digestive Diseases, F2). [bib_ref] Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on..., Alter [/bib_ref] [bib_ref] Assessment of fibrosis progression in untreated Irish women with chronic hepatitis C..., Levine [/bib_ref] [bib_ref] Natural history of hepatitis C, Thomas [/bib_ref] In this case, a liver biopsy should be repeated at 4-5 years later to reassess the necessity of treatment according to the progression speed of liver disease. [bib_ref] Watchful waiting with periodic liver biopsy versus immediate empirical therapy for histologically..., Wong [/bib_ref] About 5-30% of patients with genotype 1 with consistently normal serum ALT may have severe fibrosis [bib_ref] Prospective study on anti-hepatitis C viruspositive patients with persistently normal serum alanine..., Martinot-Peignoux [/bib_ref] [bib_ref] Chronic hepatitis C in patients with persistently normal alanine transaminase levels, Shiffman [/bib_ref] [bib_ref] Fibrosis progression in initially mild chronic hepatitis C, Boccato [/bib_ref] [bib_ref] Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels, Persico [/bib_ref] and liver biopsy would be useful to determine treatment initiation in this group. [bib_ref] Natural history of liver fibrosis progression in patients with chronic hepatitis C...., Poynard [/bib_ref] [bib_ref] The long-term pathological evolution of chronic hepatitis C, Yano [/bib_ref] [bib_ref] Hepatitis activity index is a key factor in determining the natural history..., Fontaine [/bib_ref] Even though hepatic steatosis [bib_ref] The liver biopsy in chronic hepatitis C: a view from the other..., Kleiner [/bib_ref] [bib_ref] Steatosis affects chronic hepatitis C progression in a genotype specific way, Rubbia-Brandt [/bib_ref] [bib_ref] Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis..., Poynard [/bib_ref] and liver iron load overload 168 might impede treatment response, presence of these findings is not the contraindication of treatment. [bib_ref] Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral..., Westin [/bib_ref] [bib_ref] The impact of steatosis on disease progression and early and sustained treatment..., Patton [/bib_ref] [bib_ref] Iron reduction before and during interferon therapy of chronic hepatitis C: results..., Fontana [/bib_ref] If the liver biopsy is not conducted and treatment is not undertaken, continuous monitoring is needed. Liver biopsy and start of treatment should be considered when there is elevation of serum ALT level and evidence of liver disease progression. 114 ## Noninvasive tests for evaluation of liver fibrosis Even though liver biopsy has been widely accepted as a gold standard test for evaluation of liver fibrosis, [bib_ref] Role of liver biopsy in the management of chronic liver disease: selective..., Reiss [/bib_ref] [bib_ref] Do we still need a liver biopsy? Are the serum fibrosis tests..., Crockett [/bib_ref] it can cause serious complications [bib_ref] The role of liver biopsy in chronic hepatitis C, Dienstag [/bib_ref] [bib_ref] Practices of liver biopsy in France: results of a prospective nationwide survey...., Cadranel [/bib_ref] and sampling errors, [bib_ref] Sampling error and intraobserver variation in liver biopsy in patients with chronic..., Regev [/bib_ref] and it requires histopathologic specialist for accurate interpretation and also medical costs. Therefore, various blood marker panels have been developed including aspartate aminotransferase (AST)-platelet ratio index (APRI) and AST/ALT ratio (AAR), and Forns' index that use combination of AST, ALT, prothrombin time, platelet, and cholesterol; FibroTest, Hepascore, FibroMeter that use indirect fibrosis markers, such as α-2 macroglobulin and haptoglobin; FibroSpect II and Enhanced Liver Fibrosis test that use direct fibrosis markers, such as hyaluronic acid and tissue inhibitor of matrix metalloproteinase-1. [bib_ref] Noninvasive measures of liver fibrosis, Rockey [/bib_ref] [bib_ref] Biomarkers of liver injury for hepatitis clinical trials: a metaanalysis of longitudinal..., Poynard [/bib_ref] [bib_ref] Value of two noninvasive methods to detect progression of fibrosis among HCV..., Colletta [/bib_ref] [bib_ref] Enhanced Liver Fibrosis (ELF) test accurately identifies liver fibrosis in patients with..., Parkes [/bib_ref] [bib_ref] AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection, Sheth [/bib_ref] [bib_ref] Identification of chronic hepatitis C patients without hepatic fibrosis by a simple..., Forns [/bib_ref] [bib_ref] Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of..., Shaheen [/bib_ref] [bib_ref] Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest,..., Poynard [/bib_ref] [bib_ref] Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C..., Adams [/bib_ref] [bib_ref] Improved diagnostic accuracy of blood tests for severe fibrosis and cirrhosis in..., Boursier [/bib_ref] [bib_ref] An independent and prospective comparison of two commercial fibrosis marker panels (HCV..., Patel [/bib_ref] APRI is calculated by the formula (AST/upper limit of normal for AST) × 100/platelet count (×10 9 /L). The APRI is shown to be accurate in predicting both significant fibrosis (Ishak score ≥3) defined as APRI >1.5 (AUROC=0.8) and cirrhosis defined as APRI>2 (AUROC=0.89). [bib_ref] A simple noninvasive index can predict both significant fibrosis and cirrhosis in..., Wai [/bib_ref] A normal value of AAR is <0.8, but it increases along with hepatic fibrosis progression, so that AAR value >1.0 has a 73.7-100% positive predictive value in diagnosis. [bib_ref] AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection, Sheth [/bib_ref] [bib_ref] Aspartate aminotransferase: alanine aminotransferase ratio in chronic hepatitis C infection: is it..., Park [/bib_ref] [bib_ref] Validity and clinical utility of the aspartate aminotransferasealanine aminotransferase ratio in assessing..., Giannini [/bib_ref] Liver stiffness measurement using transient elastography can be used to assess hepatic fibrosis, [bib_ref] Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the..., Castera [/bib_ref] [bib_ref] Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients..., Castera [/bib_ref] [bib_ref] Clinical applications of transient elastography, Jung [/bib_ref] [bib_ref] Clinical application of liver stiffness measurement using transient elastography in chronic liver..., Kim [/bib_ref] although it is not approved by the Food and Drug Administration as of 2013. Transient elastography cannot totally replace liver biopsy, because it often cannot produce reliable measurements in obese patients, and tends to give falsely high results in cases of acute hepatitis with severe inflammation and necrosis with mild fibrosis. [bib_ref] Acute viral hepatitis increases liver stiffness values measured by transient elastography, Arena [/bib_ref] [bib_ref] Transient elastography is unreliable for detection of cirrhosis in patients with acute..., Sagir [/bib_ref] In case of chronic hepatitis C, cutoff values determining significant fibrosis (≥F2) vary from study-to-study, ranging from 7.1 to 8.8 kPa, with an AUROC of 0.79-0. The AUROC of transient elastography for diagnosis of liver cirrhosis ranged from 0.95-0.97, with cutoff value of 12.5-14.6 kPa (77-78% positive predictive value, 95-97% negative predictive value). [bib_ref] Noninvasive measures of liver fibrosis, Rockey [/bib_ref] [bib_ref] Diagnostic accuracy of the aspartate aminotransferase-to-platelet ratio index for the prediction of..., Shaheen [/bib_ref] [bib_ref] Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the..., Castera [/bib_ref] [bib_ref] Non-invasive evaluation of liver fibrosis using transient elastography, Castera [/bib_ref] [bib_ref] Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with..., Ziol [/bib_ref] [bib_ref] Performance of transient elastography for the staging of liver fibrosis: a meta-analysis, Friedrich-Rust [/bib_ref] [bib_ref] SAFE biopsy: a validated method for large-scale staging of liver fibrosis in..., Sebastiani [/bib_ref] [bib_ref] Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic..., Degos [/bib_ref] Other newly developed noninvasive tests include acoustic radiation force impulse (ARFI) imaging, real time elastography, magnetic resonance (MR) elastography, diffusion-weighted MR image, and MR spectroscopy. However, validations of their effectiveness are still needed. [bib_ref] Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications, Talwalkar [/bib_ref] [bib_ref] MR elastography for noninvasive assessment of hepatic fibrosis: Reproducibility of the examination..., Lee [/bib_ref] [Recommendations] 9. Anti-HCV should be tested in patients suspected of having acute or chronic HCV infection (A2). [bib_ref] Epidemiology of hepatitis C virus in Korea, Shin [/bib_ref]. HCV RNA should be tested in patients with a positive anti-HCV test for the purpose of confirmative diagnosis (A1). ## Even with negative anti-hcv, hcv rna testing is required when acute hcv infection is suspected or in the presence of unexplained liver disease in immunosuppressed patients (b1). 12. HCV RNA quantitative assay and genotyping should be performed prior to antiviral treatment (A1). 13. As soon as being exposed to infected blood or body fluid, testing of anti-HCV and serum ALT level should be performed. If the test result of anti-HCV is negative, HCV RNA assay is to be conducted 4-6 weeks after the exposure for early diagnosis. Even if baseline tests were all negative, follow-up testing for anti-HCV and serum ALT level should be done 4-6 months after the exposure (B2). 14. Assessment of liver disease severity is essential prior to antiviral treatment (B1). [bib_ref] Transmission of hepatitis C virus from mothers to infants: its frequency and..., Moriya [/bib_ref]. Liver biopsy (B2) and/or noninvasive test for assessment of hepatic fibrosis (C2) can be done to make treatment decision and to predict prognosis. ## Treatment goals The goals of hepatitis C treatment are to eradicate HCV and to prevent complications and mortality from liver cirrhosis and HCC. It is difficult to evaluate the treatment goal in a short period of time due to slow evolution of chronic hepatitis C over several decades. Therefore, the short-term goal of hepatitis C treatment is to achieve an SVR defined as undetectable serum HCV RNA by a sensitive assay with a lower limit of detection <50 IU/mL at 24 weeks after the end of treatment. Since HCV does not reappear in 99% of the patients who achieve SVR, [bib_ref] Reduction therapy of alanine aminotransferase levels prevent HCC development in patients with..., Rino [/bib_ref] [bib_ref] HCV carriers with persistently normal aminotransferase levels, Puoti [/bib_ref] SVR is considered as actual eradication of HCV. In >90% of patients who achieve SVR, histological hepatic fibrosis improves or at least does not get worse, [bib_ref] Histologic improvement of fibrosis in patients with hepatitis C who have sustained..., Shiratori [/bib_ref] [bib_ref] Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients..., Poynard [/bib_ref] complications of cirrhosis significantly decrease, [bib_ref] Long-term follow-up of the hepatitis C HENCORE cohort: response to therapy and..., Pradat [/bib_ref] occurrence of hepatocellular carcinoma decreases, [bib_ref] Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development..., Shiratori [/bib_ref] [bib_ref] Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of..., Ogawa [/bib_ref] and survival rate improves. [bib_ref] Impact of viral eradication on mortality related to hepatitis C: a modeling..., Deuffic-Burban [/bib_ref] [bib_ref] Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related..., Bruno [/bib_ref] [Recommendations] [bib_ref] Prospective reevaluation of risk factors in mother-to-child transmission of hepatitis C virus:..., Okamoto [/bib_ref]. The goals of hepatitis C treatment are to eradicate HCV and to prevent complications and mortality from liver cirrhosis and hepatocellular carcinoma. (A1). 17. A short-term goal of hepatitis C treatment is to achieve an SVR defined as an undetectable serum HCV RNA by a sensitive assay with a lower limit of detection <50 IU/mL at 24 weeks after the end of treatment (A1). ## Indications for treatment All hepatitis C patients who have no contraindications to treatment can be considered for antiviral treatment. However, treatment would be applicable in cases where benefits of treatment overweigh the risks of treatment. Generally, treatment is recommended for patients with significant hepatic fibrosis (≥ stage F2), and initiation of treatment for those with advanced http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2014.20.2.89 fibrosis (stage F3-4) is required as soon as possible. In case of mild hepatic fibrosis, treatment can be delayed after considering patient age, willingness for treatment, or perspectives of new drugs. Absolute contraindications to the combination therapy of peginterferon alpha and ribavirin are summarized in [fig_ref] Table 5: Contraindications to treatment with peginterferon alpha and ribavirin 114 Uncontrolled psychiatric illness... [/fig_ref]. Treatment should be individualized considering benefits and risks in cases of decompensated cirrhosis, liver transplant recipients, current users of illicit drugs or alcohol, chronic renal diseases, coinfection with HIV, and no or mild fibrosis on liver biopsy [fig_ref] Table 6: Persons for whom therapy should be individualized 114 Acute hepatitis C No... [/fig_ref]. The criteria of contraindications or individualization may change, since DAAs that are more efficient with fewer adverse effects are expected to be adapted to practice in the future. A persistently normal ALT is defined as ALT value <40 IU/mL on two to three occasions separated by at least a month over a period of 6 months. Patients with persistently normal ALT have milder fibrosis compared to patients with abnormal ALT on average, 215,216 but about 5-30% of patients with persistently normal ALT have advanced fibrosis and cirrhosis. 217-219 A Korean study reported that some untreated patients with persistently normal ALT had progressive liver disease, and the risk of progressive liver disease was higher in patients with ALT value >23 IU/mL. [bib_ref] Disease progression in chronic hepatitis C patients with normal alanine aminotransferase levels, Sinn [/bib_ref] Therefore, it is necessary to redefine the normal range of ALT and to treat patients with advanced fibrosis more actively, regardless ALT value. The SVR rate of normal ALT groups is similar to that of abnormal ALT groups. [bib_ref] Treatment of chronic hepatitis C patients with persistently normal alanine aminotransferase levels..., Arora [/bib_ref] [bib_ref] Sustained virological response rates and health-related quality of life after interferon and..., Bini [/bib_ref] The elderly (>65 years of age) often have advanced liver diseases with higher necessity of treatment, 223 but the SVR rates are lower and the adverse effects are more frequent. [bib_ref] Efficacy and safety of pegylated interferon combined with ribavirin for the treatment..., Huang [/bib_ref] [bib_ref] Treatment response and tolerability of pegylated Interferon-alpha plus ribavirin combination therapy in..., Kim [/bib_ref] However, treatment of elderly hepatitis C patients can decrease the incidence rate of HCC and increase the survival rate. [bib_ref] Necessities of interferon therapy in elderly patients with chronic hepatitis C, Ikeda [/bib_ref] [bib_ref] Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C, Arase [/bib_ref] A recent study reported that the SVR rate in patients >60 years of age is similar to that of patients in 50-59 years of age. [bib_ref] Efficacy of peg-interferon-alpha-2a plus ribavirin for patients aged 60 years and older..., Sinn [/bib_ref] [bib_ref] Elderly age is not a negative predictive factor for virological response to..., Frei [/bib_ref] Little data are available concerning treatment in those >70 years of age. The decision of treatment in the elderly follows general rules. ## [recommendations] 18. All HCV-infected patients with no contraindications to treatment are considered as targets of treatment (A2). 19. Treatment should be individualized under overall consideration of the severity of liver diseases, chance of treatment success, risks of severe adverse effects, status of accompanying diseases, and patient willingness for treatment (B1). ## Definition of treatment response The combination therapy of peginterferon alpha and ribavirin has considerable cost and adverse effects. Meanwhile, the likelihood of SVR gets higher as the time of HCV RNA disappearance during the therapy is shorter. [bib_ref] Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled..., Mangia [/bib_ref] Response-guided therapy is a strategy to modify the duration of treatment based on the time of HCV RNA disappearance by measuring serum HCV RNA at weeks 4, 12, and 24 of treatment. A rapid virological response (RVR) is defined as undetectable HCV RNA by a sensitive assay with lower limit of detection <50 IU/mL at week 4 of treatment. The SVR rate is expected to be 87.5-100% in HCV genotype 1 patients with a RVR and to be 33.3-63.8% in those without a RVR. [bib_ref] Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon..., Jensen [/bib_ref] [bib_ref] Predictive value of rapid virological response and early virological response on sustained..., Yu [/bib_ref] [bib_ref] Rapid virological response and treatment duration for chronic hepatitis C genotype 1..., Yu [/bib_ref] The SVR rate is expected to be 85-86.5% in HCV genotype 2 and 3 patients with a RVR, and 54-58.3% in those without a RVR. [bib_ref] Predictive value of rapid virological response and early virological response on sustained..., Yu [/bib_ref] An early virological response (EVR) is defined as undetectable HCV RNA using a sensitive assay with a lower limit of detection <50 IU/mL, or ≥2 log reduction of HCV RNA compared with the baseline level. The SVR rate is as low as 3% in HCV genotype 1 patients without an EVR. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients..., Davis [/bib_ref] [bib_ref] Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon..., Ferenci [/bib_ref] Therefore, medical costs and adverse effects can be reduced by discontinuing therapy in cases without an EVR. An EVR is classified as a complete EVR (cEVR) defined as undetectable HCV RNA and a partial EVR (pEVR) defined as an EVR with detectable HCV RNA at week 12. A delayed virological response (DVR) is defined as a pEVR that eventually resulted in undetectable HCV RNA at week 24. 238,239 A null response is defined as <2 log reduction of HCV RNA level from baseline at week 12 of therapy, whereas partial nonresponse is defined as ≥2 log reduction of HCV RNA level from baseline but detectable HCV RNA at week 12 and 24. An end-of-treatment response (ETR) is defined as undetectable HCV RNA at the end of treatment using a sensitive assay with a lower limit of detection <50 IU/mL. SVR is defined as undetectable HCV RNA by a sensitive assay with a lower limit of detection <50 IU/mL at 24 weeks after the cessation of treatment. A SVR evaluated at 12 weeks (SVR12) after the end of treatment is reported to be almost identical to a SVR at 24 weeks after the cessation of treatment, [bib_ref] Earlier sustained virologic response end points for regulatory approval and dose selection..., Chen [/bib_ref] and recent clinical trials for new drugs tend to evaluate therapeutic efficacy by a SVR12. Viral breakthrough refers to the reappearance of HCV RNA during the treatment after virological response, and relapse is defined as the reappearance of HCV RNA after treatment is discontinued [fig_ref] http [/fig_ref]. [Recommendations] [bib_ref] The prevalence of anti-HCV positivity in healthy Korean children, Lee [/bib_ref]. HCV RNA in blood should be measured at weeks 4, 12, and 24 of treatment depending on HCV genotype to 21. HCV RNA should be measured at the end of treatment and 24 weeks after the cessation of treatment to evaluate therapeutic effects and to identify the achievement of SVR (A1). ## Predictors of treatment responses Predicting the likelihood of SVR is helpful for each patient's decision to initiate therapy [fig_ref] Table 8: Predictors of SVR [/fig_ref]. Strongest pretreatment predictors for SVR include HCV genotype, [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study..., Hadziyannis [/bib_ref] degree of hepatic fibrosis, [bib_ref] Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of..., Thompson [/bib_ref] and IL28B polymorphism. [bib_ref] Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of..., Thompson [/bib_ref] [bib_ref] Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance, Ge [/bib_ref] The SVR rates are 40-60% in HCV genotype 1 patients whereas they are about 70-80% in HCV genotype 2 and 3 patients. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Efficacy and tolerability of peginterferon alpha plus ribavirin in the routine daily..., Park [/bib_ref] Patients with F0-F2 fibrosis have 2.7-times higher SVR rates compared to those with F3-F4 fibrosis. [bib_ref] Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of..., Thompson [/bib_ref] The SVR rates are higher by 2.4-2.7 times in patients with a viral load <400,000-800,000 IU/mL compared to those with a viral load exceeding 800,000 IU/mL. [bib_ref] Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon..., Jensen [/bib_ref] [bib_ref] Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of..., Thompson [/bib_ref] [bib_ref] Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with..., Von Wagner [/bib_ref] The SVR rates decrease with conditions including old age (>40 years of age), [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] African-Americans, [bib_ref] Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in..., Muir [/bib_ref] body weight over 70 kg, [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients..., Davis [/bib_ref] [bib_ref] Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon..., Ferenci [/bib_ref] [bib_ref] Extended treatment duration for hepatitis C virus type 1: comparing 48 versus..., Berg [/bib_ref] [bib_ref] Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C..., Pearlman [/bib_ref] [bib_ref] Earlier sustained virologic response end points for regulatory approval and dose selection..., Chen [/bib_ref] and insulin resistance. [bib_ref] Insulin resistance predicts response to peginterferon-alpha/ribavirin combination therapy in chronic hepatitis C..., Dai [/bib_ref] [bib_ref] Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic..., Romero-Gomez [/bib_ref] Recent studies have revealed that host IL28B polymorphism is a strong predictor for SVR. [bib_ref] Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of..., Thompson [/bib_ref] [bib_ref] Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance, Ge [/bib_ref] [bib_ref] An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2..., Mangia [/bib_ref] SVR rates vary depending on SNP of IL28B; in other words, C or T allele of the rs12979869 locus. The SVR rates of HCV genotype 1 Caucasian patients are 69%, 33%, and 27% in CC homozygote, CT heterozygote, and TT homozygote, respectively. The SVR rates of HCV genotype 1 African-American patients are 48%, 15%, and 13%, respectively. [bib_ref] Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of..., Thompson [/bib_ref] [bib_ref] An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2..., Mangia [/bib_ref] The SVR rates of HCV genotype 1 Korean patients are 73-88% in CC homozygote and 0-40% in CT heterozygote. [bib_ref] Polymorphism near the IL28B gene in Korean hepatitis C virus-infected patients treated..., Lyoo [/bib_ref] [bib_ref] Role of interleukin 28B-related gene polymorphisms in chronic hepatitis C and the..., Jung [/bib_ref] [bib_ref] Efficacy of peginterferon and ribavirin is associated with the IL28B gene in..., Jeong [/bib_ref] IL28B polymorphism is variable depending on race. CC homozygote population in Korea accounts for 88-89%, 251-253 compared to 17% in African-Americans and 37% in Caucacinas 243 . Further study is needed to evaluate the usefulness of pretreatment determination of IL28B polymorphism in Korea, where about 90% of the population has the CC homozygote, although many institutions in western countries determine IL28B polymorphisms to predict SVR prior to the initiation of treatment. Polymorphism of the rs8099917 locus near IL28B also affects SVR, and a SVR rate is higher in the TT or TG genotype than in the GG genotype. [bib_ref] Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy..., Tanaka [/bib_ref] RVR is the strongest on-treatment predictor for SVR, [bib_ref] Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon..., Jensen [/bib_ref] [bib_ref] Predictive value of rapid virological response and early virological response on sustained..., Yu [/bib_ref] and the likelihood of a SVR increases by 9-times with a RVR. [bib_ref] Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of..., Thompson [/bib_ref] Meanwhile, an EVR is a strong negative predictor for a SVR and the SVR rate is very low (3%) without an EVR. [bib_ref] Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients..., Davis [/bib_ref] In addition, SVR increases when medication adherence exceeds 80%, 255 so efforts to assess and maintain the medication adherence can increase the SVR rate. ## Treatment of chronic hepatitis c Treatment of hepatitis C is rapidly evolving. SVR rates have increased from about 10% with conventional interferon monotherapy for 6 months, to about 54-56% with combination therapy of peginterferon alpha and ribavirin, and further to 75% with triple therapy in which boceprevir or telaprevir is added to the peginterferon alpha and ribavirin combination therapy. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Diagnosis, management, and treatment of hepatitis C, Strader [/bib_ref] [bib_ref] Boceprevir for untreated chronic HCV genotype 1 infection, Poordad [/bib_ref] [bib_ref] Telaprevir for previously untreated chronic hepatitis C virus infection, Jacobson [/bib_ref] [bib_ref] Response-guided telaprevir combination treatment for hepatitis C virus infection, Sherman [/bib_ref] In South Korea, the dual combination therapy of peginterferon alpha and ribavirin has been the standard therapy in 2013, since DAA is still not approved for practice. Response-guided therapy is used to reduce adverse effects and to increase therapeutic effects. It is expected that drugs including DAAs with a strong antiviral effect and relatively few adverse effects will be introduced soon in South Korea. DAA acts on a specific step of viral life cycle. DAAs including NS3/4A protease inhibitors, NS5A inhibitors, and NS5B polymerase inhibitors and host-targeting antiviral agents, such as the cyclophyllin A inhibitor and miR-122, are under development. It is expected that triple or quadruple therapy in which one or two DAAs plus peginterferon alpha and ribavirin, or interferon-free therapy with combination of oral agents would be available soon. [bib_ref] Current and future therapies for hepatitis C virus infection, Liang [/bib_ref] [bib_ref] New direct-acting antiviral agents for the treatment of hepatitis C virus infection..., Welsch [/bib_ref] Nearly 90% of a SVR rate and shortening of treatment duration with those new therapeutic strategies have been reported, 262,263 although more evidence is needed. However, the high cost of the drugs, drug resistance, drug interactions, and new adverse effects must be considered. ## Treatment of genotypes 1 and 4 chronic hepatitis c ## Optimal treatment of genotypes 1 and 4 The standard of care for HCV genotypes 1 and 4 infected patients in 2013 in South Korea is combination therapy of peginterferon alpha and ribavirin for 48 weeks. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study..., Hadziyannis [/bib_ref] Currently, two types of peginterferon alpha are approved for the treatment of chronic hepatitis C: peginterferon alpha-2a (pegasys; Hoffman-La Roche, USA) and peginterferon alpha-2b (peg-Intron; MSD, USA). Peginterferon alpha is a polyethylene glycol (PEG)-modified inter- [bib_ref] Efficacy of peginterferon and ribavirin combination therapy of chronic hepatitis C: a..., Park [/bib_ref] This is related to the higher frequency of favorable IL28B genotypes in Koreans than in Whites or Blacks. [bib_ref] Genetic variation in IL28B and spontaneous clearance of hepatitis C virus, Thomas [/bib_ref] [bib_ref] Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance, Ge [/bib_ref] [bib_ref] Role of interleukin 28B-related gene polymorphisms in chronic hepatitis C and the..., Jung [/bib_ref] [bib_ref] Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy..., Tanaka [/bib_ref] [bib_ref] IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin..., Suppiah [/bib_ref] [bib_ref] Association of a single nucleotide polymorphism near the interleukin-28B gene with response..., Sinn [/bib_ref] Standard of care for HCV genotype 4 infected patients is the combination therapy of peginterferon alpha and ribavirin for 48 weeks, the same as the standard of care for HCV genotype 1. SVR rate was reported as 72%. [bib_ref] Meta-analysis: a randomized trial of peginterferon plus ribavirin for the initial treatment..., Khuroo [/bib_ref] There are no reports on therapeutic outcome for chronic HCV genotype 4 in South Korea. ## Response-guided therapy in genotypes 1 and 4 Several studies have investigated whether treatment duration could be shortened from 48 to 24 weeks when a RVR is achieved using combination therapy of peginterferon alpha and ribavirin for HCV genotype 1 patients. SVR rates of 24-and 48-week treatment groups were 77.2-100% and 85-92.4%, respectively, 230,231,273-276 which were not statistically significant. However, the upper limit of lower level of HCV RNA concentration was inconsistent, ranging from 400,000 to 800,000 IU/mL and the number of recruited patients was not large enough in those studies. Recently, two meta-analyses of randomized controlled studies including the patients with a RVR showed that a lower rate of SVR and higher recurrence rate were observed in the 24-week treatment group when compared with that in the 48-week treatment group. However, in pooled analysis in patients with low baseline HCV viral load (<400,000 IU/mL) SVR rates were not statistically different between the 24-and 48-week treatment groups. [bib_ref] Shortened treatment duration in treatment-naive genotype 1 HCV patients with rapid virological..., Moreno [/bib_ref] [bib_ref] Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of..., Martino [/bib_ref] The results support the conclusion, patients with genotype 1 who achieve a RVR and low baseline viral load (<400,000 IU/mL) may have their duration of therapy shortened to 24 weeks if there are no negative predictors of response, such as advanced liver fibrosis, cirrhosis, obesity, or insulin resistance. [bib_ref] Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled..., Mangia [/bib_ref] Meanwhile, in patients with genotype 4 with a RVR, the 24-week treatment group had a similar SVR rate to that of the 48-week treatment group, regardless of baseline viral load. [bib_ref] Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1..., Ferenci [/bib_ref] [bib_ref] Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis..., Kamal [/bib_ref] Treatment should be stopped in patients who do not achieve an EVR, as a SVR rate in these patients with standard treatment duration is <3%, and in patients with pEVR and detectable HCV RNA at week 24, as a SVR rate is 2-4%. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients..., Davis [/bib_ref] [bib_ref] Prediction of treatment outcome in patients with chronic hepatitis C: significance of..., Berg [/bib_ref] Meanwhile, an additional 10-20% increase in SVR rate was reported in an extended treatment to 72 weeks when patients achieved a pEVR with negative HCV RNA at week 24. [bib_ref] Extended treatment duration for hepatitis C virus type 1: comparing 48 versus..., Berg [/bib_ref] [bib_ref] Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C..., Pearlman [/bib_ref] [bib_ref] Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of..., Martino [/bib_ref] [bib_ref] Randomized trial of peginterferon alfa-2b and ribavirin for 48 or 72 weeks..., Buti [/bib_ref] However, extension of duration of treatment should be carefully determined after considering many aspects of patients, such as adverse effects or compliance. In case of a cEVR without RVR, SVR rate was reported as 62-70%, [bib_ref] Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled..., Mangia [/bib_ref] [bib_ref] Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon..., Ferenci [/bib_ref] [bib_ref] Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C..., Pearlman [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1..., Ferenci [/bib_ref] and extension of the treatment duration did not increase the SVR rate. [bib_ref] Extended treatment duration for hepatitis C virus type 1: comparing 48 versus..., Berg [/bib_ref] [bib_ref] Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of..., Martino [/bib_ref] Retreatment of HCV genotype 1 and 4 patients who fail to respond to previous treatment Patients who have failed prior treatment can be classified as relapsers and non-responders. Retreatment with peginterferon alpha and ribavirin can be considered for relapsers who have previously been treated with conventional interferon alpha with or without ribavirin, or peginterferon alpha monotherapy, since SVR rates are reported as 31-47%. [bib_ref] Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed..., Sherman [/bib_ref] [bib_ref] A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment..., Jacobson [/bib_ref] However, as for relapsers after peginterferon alpha and ribavirin therapy, a SVR rate after re-treatment with the same regimen was reported as only 23%, and retreatment should be carefully determined after discussion with the patient. [bib_ref] Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed..., Poynard [/bib_ref] In non-responders to conventional interferon alpha with or without ribavirin, retreatment with peginterferon alpha and ribavirin should be carefully determined considering that the SVR rate is very low (8-24%) in these patients. [bib_ref] Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed..., Sherman [/bib_ref] [bib_ref] A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment..., Jacobson [/bib_ref] [bib_ref] Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed..., Poynard [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have..., Shiffman [/bib_ref] [bib_ref] Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients, Taliani [/bib_ref] Retreatment with same regimen in non-responders to peginterferon alpha and ribavirin is not recommended, since SVR rates are only 4-8%. The retreatment should be postponed until DAAs are available. During retreatment, SVR rates of patients with a cEVR is 35.1-49%, with a pEVR is 3.5-12%, and those without an EVR is http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2014.20.2.89 0-1%. Therefore, cEVR can be a useful marker in determining cessation of the retreatment. [bib_ref] Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed..., Poynard [/bib_ref] [bib_ref] Re-treatment of patients with chronic hepatitis C who do not respond to..., Jensen [/bib_ref] [bib_ref] Predicting early and sustained virological responses in prior nonresponders to pegylated interferon..., Marcellin [/bib_ref] A maintenance therapy with a low dose of peginterferon alpha is not recommended because it cannot reduce long-term complications in patients with advanced liver fibrosis or cirrhosis. [bib_ref] Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have..., Shiffman [/bib_ref] [bib_ref] Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic..., Bruix [/bib_ref] New therapies including DAAs in genotypes 1 and 4 ## Triple therapy including boceprevir or telaprevir The standard therapy in Europe and the US during 2011-2013 was a triple therapy combining peginterferon alpha, ribavirin, and oral protease inhibitor, such as boceprevir or telaprevir. However, these two protease inhibitors have not yet been approved in South Korea. In two phase III clinical trials using boceprevir [bib_ref] Boceprevir for untreated chronic HCV genotype 1 infection, Poordad [/bib_ref] [bib_ref] Boceprevir for previously treated chronic HCV genotype 1 infection, Bacon [/bib_ref] and three phase III clinical trials using telaprevir, [bib_ref] Telaprevir for previously untreated chronic hepatitis C virus infection, Jacobson [/bib_ref] [bib_ref] Response-guided telaprevir combination treatment for hepatitis C virus infection, Sherman [/bib_ref] [bib_ref] Telaprevir for retreatment of HCV infection, Zeuzem [/bib_ref] SVR rates were reported as 63-75%, 69-88%, and 29-33% in treatment-naïve patients, relapsers, and non-responders to peginterferon alpha and ribavirin, respectively. There were additional improvement in SVR by 25-30% in naïve patients and 25-60% in treatment experienced patients compared to combination therapy with peginterferon alpha and ribavirin. However, more adverse effects were reported in triple therapy including boceprevir or telaprevir compared to the dual combination therapy. [bib_ref] Boceprevir for untreated chronic HCV genotype 1 infection, Poordad [/bib_ref] [bib_ref] Response-guided telaprevir combination treatment for hepatitis C virus infection, Sherman [/bib_ref] [bib_ref] Boceprevir for previously treated chronic HCV genotype 1 infection, Bacon [/bib_ref] [bib_ref] Telaprevir for retreatment of HCV infection, Zeuzem [/bib_ref] In the boceprevir trials, dysgeusia, anemia, and neutropenia were more common, while in the telaprevir trials, rashes, anemia, and anorectal symptoms (discomfort and pruritus) were more common. In addition, drug resistance should be considered because of the reduced drug compliance due to the discomfort and inconvenience in taking numerous drugs three times a day. Drug-drug interaction should also be considered, since boceprevir and telaprevir are metabolized in cytochrome P450 system (CYP2C, CYP3A4, and CYP1A) causing interaction with many other drugs. Information of drug interactions is provided in various websites (e.g., www/hepdruginteractions.org). Another issue of increasing concern is differentiating patients who require immediate treatment with the triple therapy from those who can wait until drugs with improved adverse effects or lower prices are available, because the triple therapy imposes considerable expense. ## Present situation for other newly developed drugs Peginterferon lamda acts on receptors that are different from those of peginterferon alpha. The receptors of interferon lamda are found mainly on hepatocytes. A clinical trial reported a higher RVR rate and significantly lower occurrence of adverse effects including hematologic side effects, flu-like symptoms, and muscular pain compared to peginterferon alpha.New DAAs being evaluated in clinical trials include NS3/4A protease inhibitors (asunaprevir, faldaprevir, ABT-450, etc.), NS5A polymerase inhibitors (daclatasvir, etc.), NS5B polymerase inhibitors (sofosbuvir, deleobuvir, ABT-333, etc.), and host-acting antiviral agents include cyclophilin A inhibitor, miR-122 inhibitor (miravirsen). [bib_ref] Treatment of chronic hepatitis C patients with persistently normal alanine aminotransferase levels..., Arora [/bib_ref] [bib_ref] Current and future therapies for hepatitis C virus infection, Liang [/bib_ref] [bib_ref] New direct-acting antiviral agents for the treatment of hepatitis C virus infection..., Welsch [/bib_ref] [bib_ref] Exploratory study of oral combination antiviral therapy for hepatitis C, Poordad [/bib_ref] [bib_ref] Sofosbuvir for previously untreated chronic hepatitis C infection, Lawitz [/bib_ref] [bib_ref] Preliminary study of two antiviral agents for hepatitis C genotype 1, Lok [/bib_ref] [bib_ref] Treatment of HCV infection by targeting microRNA, Janssen [/bib_ref] [bib_ref] Clinical relevance of HCV antiviral drug resistance, Welsch [/bib_ref] These drugs can be simply administrated orally (except miravirsen, which is injected) with fewer adverse effects and stronger antiviral effects. A SVR12 rate (SVR rate at 12 weeks after the cessation of treatment) was 90% in a phase III clinical trial with sofosbuvir plus peginterferon alpha and ribavirin in 327 treatment naïve patients with chronic HCV (including 17% of cirrhosis patients) genotype 1, 4, 5, and 6 (seven patients of type 5 and 6). [bib_ref] Sofosbuvir for previously untreated chronic hepatitis C infection, Lawitz [/bib_ref] Many clinical trials with interferon-free, DAA combination regimens have been done or are ongoing. These have reported different therapeutic outcomes depending on the combination of drugs and subtypes (1a vs. 1b) of HCV. [bib_ref] New direct-acting antiviral agents for the treatment of hepatitis C virus infection..., Welsch [/bib_ref] [bib_ref] Exploratory study of oral combination antiviral therapy for hepatitis C, Poordad [/bib_ref] [bib_ref] Preliminary study of two antiviral agents for hepatitis C genotype 1, Lok [/bib_ref] [bib_ref] Clinical relevance of HCV antiviral drug resistance, Welsch [/bib_ref] [bib_ref] Faldaprevir and deleobuvir for HCV genotype 1 infection, Zeuzem [/bib_ref] Therefore, a therapeutic strategy with more effective combination regimen, less adverse effect, and reduced drug resistance is expected to become available. ## 2) in patients with a rvr and low baseline hcv viral load (<400,000 iu/ml), and without any negative predictors for svr (advanced liver fibrosis, cirrhosis, obesity or insulin resistance), shortening of treatment duration to 24 week s c an be considered (b1). 3) in patients of genotype 4 with a rvr, 24-week ## Retreatment of hcv genotypes 1 and 4 patients who failed to respond to previous treatment 1) retreatment with peginterferon alpha plus ribavirin can be considered for relapsers or non-responders that were previously treated with conventional interferon with or without ribavirin, or peginterferon monotherapy (b2). patients who failed to achieve a svr after peginterferon alpha and ribavirin combination therapy are not recommended to be retreated by the same regimen (a2). 2) a low-dose maintenance therapy with peginterferon alpha is not recommended for patients who have failed a combination therapy with peginterferon alpha and ribavirin (a1). Triple therapy with peginterferon alpha and ribavirin plus either boceprevir or telaprevir is recommended for treatment naïve or experienced HCV genotype 1 patients (A1). It is desirable that more effective regimens including DAAs are adapted to Korean patients after further studies. ## Treatment of genotypes 2 and 3 chronic hepatitis c ## Optimal treatment of genotypes 2 and 3 The first-line treatment of HCV genotypes 2 and 3 patients is combination therapy of any one of two peginterferon alpha and ribavirin for 24 weeks. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study..., Hadziyannis [/bib_ref] [bib_ref] Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients:..., Jacobson [/bib_ref] [bib_ref] Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously..., Zeuzem [/bib_ref] [bib_ref] A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in..., Ferenci [/bib_ref] Peginterferon alpha-2a should be injected 180 μg subcutaneously once a week, regardless of body weight, whereas peginterferon alpha-2b is to be injected 1.5 μg/kg subcutaneously once a week. Ribavirin is to be given at a flat dose of 800 mg daily, regardless of the type of peginterferon alpha used. There is insufficient evidence to show whether a weight-based dose of ribavirin is more effective in achieving a SVR for HCV genotype 2 and 3 patients. [bib_ref] Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study..., Hadziyannis [/bib_ref] [bib_ref] Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients:..., Jacobson [/bib_ref] The SVR rate of Korean patients with HCV genotype 2 treated with the first-line therapy exceeded 80%. [bib_ref] Efficacy and tolerability of peginterferon alpha plus ribavirin in the routine daily..., Park [/bib_ref] [bib_ref] Efficacy and tolerability of pegylated interferon-alpha2a plus ribavirin versus pegylated interferon-alpha2b plus..., Lee [/bib_ref] Although a SVR rate of HCV genotype 3 in Korean patients is hardly been reported, reports from other ethnicities show a lower SVR rate in HCV genotype 3 patients by 10-20% than that of genotype 2. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study..., Hadziyannis [/bib_ref] [bib_ref] Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with..., Von Wagner [/bib_ref] [bib_ref] Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of..., Martino [/bib_ref] [bib_ref] Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients:..., Jacobson [/bib_ref] [bib_ref] A randomized, prospective trial of ribavirin 400 mg/day versus 800 mg/day in..., Ferenci [/bib_ref] [bib_ref] Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype..., Mangia [/bib_ref] [bib_ref] Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients..., Dalgard [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype..., Shiffman [/bib_ref] ## Response-guided therapy in genotype 2 and 3 patients Although several studies investigated whether the treatment duration could be shortened according to the on-treatment virological response, [bib_ref] Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with..., Von Wagner [/bib_ref] [bib_ref] Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype..., Mangia [/bib_ref] [bib_ref] Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients..., Dalgard [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype..., Shiffman [/bib_ref] [bib_ref] A randomised study of peginterferon and ribavirin for 16 versus 24 weeks..., Yu [/bib_ref] [bib_ref] Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week..., Diago [/bib_ref] [bib_ref] Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin..., Lagging [/bib_ref] [bib_ref] Comparison of peg-interferon alfa-2a and ribavirin for 12 or 24 weeks in..., Mecenate [/bib_ref] the results of these studies should not be compared directly since factors affecting SVR rates, such as duration of the shorted treatment, dose of ribavirin, proportion of patients with a RVR, are heterogeneous. A study comparing 16-week therapy with 24-week therapy each including about 350 patients reported a lower SVR rate of 65% in the 16-week treatment group compared to 82% in the 24-week treatment group. [bib_ref] Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype..., Shiffman [/bib_ref] However, shortening of the treatment duration was not performed according to the on-treatment response, RVR, but was randomly assigned in this study. Meanwhile, in HCV genotype 3 patients, the same study reported a SVR rate of 61% in the 16-week treatment group and 71% in the 24-week treatment group that was not statistically significantly different. Another study compared 16-week and 24-week treatment groups of 200 HCV genotype 2 patients for each group, and reported a SVR rate of 81% in the 16-week group and 92% in the 24-week group, with no statistically significant difference. [bib_ref] Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week..., Diago [/bib_ref] However, the 16-week treatment group had a relapse rate of 17%, which was significantly higher than that of the 5% rate of the 24-week treatment group. In addition, this study used weight-based dose of ribavirin from 1,000 to 1,200 mg in combination with peginterferon alpha and resulted in a higher relapse rate, despite an equivalent SVR rate, as that of the 24-week therapy. As for the factors predicting relapse after treatment other than the duration of the therapy, existence of cirrhosis, baseline high viral load, body weight, gender, and old age have been suggested. [bib_ref] Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with..., Von Wagner [/bib_ref] [bib_ref] Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week..., Diago [/bib_ref] [bib_ref] Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin..., Lagging [/bib_ref] However, studies contradicting these results also exist, and further evidences are required. [bib_ref] Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype..., Mangia [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype..., Shiffman [/bib_ref] In conclusion, patients with genotype 2 and 3 who achieve RVR may have their duration of therapy shortened to [bib_ref] Prospective reevaluation of risk factors in mother-to-child transmission of hepatitis C virus:..., Okamoto [/bib_ref] fibrosis, cirrhosis, and high baseline viral load, at the expense of a higher chance of post-treatment relapse. If negative predictors of response exist, such as advanced liver fibrosis or cirrhosis, there is a lack of evidence supporting equal efficacy of shortened therapy. Meanwhile, studies testing the efficacy of extended duration of treatment up to 48 weeks in patients with negative predictors for response, such as lack of RVR, high baseline HCV RNA level, or accompanying advanced liver fibrosis or cirrhosis. A study on 1,311 HCV genotype 2 or 3 patients with negative predictors for SVR reported no benefit of extended treatment duration to 48 weeks on achieving SVR. 242 ## Retreatment of hcv genotype 2 and 3 patients who fail to respond to previous treatment Retreament with peginterferon alpha and ribavirin combination therapy may be given to HCV genotype 2 or 3 patients that were previously treated with conventional interferon with or without ribavirin, or peginterferon alpha without ribavirin, and failed to achieve SVR. [bib_ref] Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed..., Sherman [/bib_ref] [bib_ref] A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment..., Jacobson [/bib_ref] [bib_ref] Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed..., Poynard [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have..., Shiffman [/bib_ref] [bib_ref] Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients, Taliani [/bib_ref] [bib_ref] Retreatment of hepatitis C patients with pegylated interferon combined with ribavirin in..., Goncales [/bib_ref] [bib_ref] Relapse to prior therapy is the most important factor for the retreatment..., Sagir [/bib_ref] [bib_ref] Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C, Krawitt [/bib_ref] The SVR rate after retreatment with peginterferon alpha and ribavirin combination therapy in relapsers is reported to be 54.8-67.0%, whereas the SVR rate of nonresponders after retreatment is 39.3-53.0%. [bib_ref] Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed..., Sherman [/bib_ref] [bib_ref] A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment..., Jacobson [/bib_ref] There is insufficient evidence for adequate duration of retreatment in HCV genotype 2 and 3 patients, and previous studies on retreatment arbitrarily applied treatment duration of either 24 weeks or 48 weeks. [bib_ref] Peginterferon alfa-2a (40KD) plus ribavirin in chronic hepatitis C patients who failed..., Sherman [/bib_ref] [bib_ref] A randomized trial of pegylated interferon alpha-2b plus ribavirin in the retreatment..., Jacobson [/bib_ref] [bib_ref] Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed..., Poynard [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have..., Shiffman [/bib_ref] [bib_ref] Retreatment of hepatitis C patients with pegylated interferon combined with ribavirin in..., Goncales [/bib_ref] [bib_ref] Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C, Krawitt [/bib_ref] A study including relapsers after 24-week of peginterferon alpha and ribavirin therapy who were retreated with the same regimen for the extended period of 48 weeks (n=92) reported a SVR rate of 57%. [bib_ref] Peginterferon alfa-2b and ribavirin: effective in patients with hepatitis C who failed..., Poynard [/bib_ref] Therefore, for those who fail to achieve a SVR after peginterferon alpha and ribavirin treatment, there is still not enough evidence for the retreatment using the same regimen and it is not recommended, especially in non-responders. ## New therapies in genotypes 2 and 3 Although a relatively high SVR rate can be achieved by 24-week combination therapy with peginterferon alpha and ribavirin in HCV genotype 2 and 3 patients, new therapeutic strategies may be required for patients that fail to achieve a SVR, and those who cannot tolerate interferon-based treatment. A phase III clinical trial investigating the efficacy of 12-week treatment of ribavirin Week 0 Week 4 Week 12 Week 24 Week 48 Week and sofosbuvir combination therapy on 70 treatment naïve HCV genotype 2 or 3 patients reported a SVR12 rate of 97%. [bib_ref] Sofosbuvir for previously untreated chronic hepatitis C infection, Lawitz [/bib_ref] In addition, a SVR12 rate of 94% was achieved after 16 weeks of sofosbuvir and ribavirin combination therapy in 32 treatment experienced chronic HCV genotype 2 patients. [bib_ref] Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment..., Jacobson [/bib_ref] Therefore, interferon-free DAA combination regimens are effective in both treatment failure and interferon intolerant patients, and are expected to become available in Korea. ## [recommendations] 24. Optimal treatment of genotypes 2 and 3 [fig_ref] Figure 3: Treatment algorithm for patients with genotype 2, 3 chronic HCV infection [/fig_ref] ## 1) treatment with one of two peginterferon alpha molecules in combination with ribavirin should be planned for 24 weeks (a1). 2) the dose for peginterferon alpha-2a is 180 μg subcutaneously once a week and peginterferon alpha-2b is 1.5 μg/kg per week (a1). daily administration of 800 mg of ribavirin should be done, regardless of body weight (a2). 3) in patients with an rvr and without any negative predictors for svr, shortening of treatment duration to 16 weeks can be considered (b2). However, shortening of treatment duration should be done in caution, since this can result in higher relapse rate (A2). ## Retreatment of hcv genotype 2 and 3 patients who fail to respond to previous treatment. 1) retreatment with peginterferon alpha plus ribavirin can be considered for relapsers or non-responders that were previously treated with conventional interferon with or without ribavirin, or peginterferon alpha monotherapy (b2). 2) non-responders to a full course of treatment with peginterferon alpha plus ribavirin are not recommended to be retreated by the same regimen (b2). ## Treatment of genotype 6 chronic hepa-titis c HCV genotype 6 is limited mostly to Southeast Asia, Southern China, Hong Kong, and Macau. It comprises about 1% of total chronic HCV patients in South Korea. [bib_ref] Chronic hepatitis C: genotypes 4 to 9, Nguyen [/bib_ref] SVR rate of chronic HCV genotype 6 treated with combination of peginterferon alpha and ribavirin is 70.0-85.7%, which is comparable with that of HCV genotype 3 and higher than that of HCV genotype 1. [bib_ref] Response to combined interferon and ribavirin is better in patients infected with..., Yuen [/bib_ref] [bib_ref] Chronic hepatitis C genotype 6 responds better to pegylated interferon and ribavirin..., Tsang [/bib_ref] [bib_ref] Response to pegylated interferon and ribavirin in Asian American patients with chronic..., Nguyen [/bib_ref] A study comparing the efficacy of fixed dose ribavirin and weight based ribavirin for HCV genotype 6 patients is not available. All studies of peginterferon alpha based treatment for HC V genot ype 6 have adapted weight based doses of ribavirin. [bib_ref] Chronic hepatitis C genotype 6 responds better to pegylated interferon and ribavirin..., Tsang [/bib_ref] [bib_ref] Response to pegylated interferon and ribavirin in Asian American patients with chronic..., Nguyen [/bib_ref] [bib_ref] Chronic hepatitis C virus genotype 6 infection: response to pegylated interferon and..., Fung [/bib_ref] [bib_ref] Higher rate of sustained virologic response in chronic hepatitis C genotype 6..., Nguyen [/bib_ref] [bib_ref] Randomized controlled trial of pegylated interferon-alfa 2a and ribavirin in treatment-naive chronic..., Lam [/bib_ref] [bib_ref] A randomized trial of 48 versus 24 weeks of combination pegylated interferon..., Thuy [/bib_ref] Two randomized control studies on combination therapy of peginterferon alpha and ribavirin reported no statistical difference in SVR between 24-week and 48-week treatment. [bib_ref] Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis, Corey [/bib_ref] [bib_ref] Acute hepatitis C in Korea: different modes of infection, high rate of..., Kim [/bib_ref] [bib_ref] Randomized controlled trial of pegylated interferon-alfa 2a and ribavirin in treatment-naive chronic..., Lam [/bib_ref] [bib_ref] A randomized trial of 48 versus 24 weeks of combination pegylated interferon..., Thuy [/bib_ref] [bib_ref] When and how to treat acute hepatitis C?, Licata [/bib_ref] [bib_ref] Acute hepatitis C in a contemporary US cohort: modes of acquisition and..., Wang [/bib_ref] [bib_ref] Rate of sustained virologic response in relation to baseline hepatitis C virus..., Mcgovern [/bib_ref] No study has been conducted about retreatment for HCV genotype 6 patients who failed previous treatment. [Recommendations] ## Optimal treatment of genotype 6 1) treatment with one of two peginterferon alpha molecules in combination with ribavirin should be planned for 24 weeks (a1). 2) the dose for peginterferon alpha-2a is 180 μg subcutaneously once a week and for peginterferon alpha-2b is 1.5 μg/kg per week(a1). ribavirin is to ## Treatment of acute hepatitis c Spontaneous recovery rate of acute hepatitis C varies from 20-50%. [bib_ref] Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis, Corey [/bib_ref] [bib_ref] Acute hepatitis C in Korea: different modes of infection, high rate of..., Kim [/bib_ref] [bib_ref] When and how to treat acute hepatitis C?, Licata [/bib_ref] [bib_ref] Acute hepatitis C in a contemporary US cohort: modes of acquisition and..., Wang [/bib_ref] [bib_ref] Rate of sustained virologic response in relation to baseline hepatitis C virus..., Mcgovern [/bib_ref] Treatment can be initiated immediately after the diagnosis of acute hepatitis C. However, evidence supports a therapeutic strategy of delaying treatment for 8-12 weeks to allow spontaneous remission. [bib_ref] Early treatment improves outcomes in acute hepatitis C virus infection: a meta-analysis, Corey [/bib_ref] [bib_ref] Peginterferon alfa-2b therapy in acute hepatitis C: Impact of onset of therapy..., Kamal [/bib_ref] [bib_ref] Immediate vs. delayed treatment in patients with acute hepatitis C based on..., Deuffic-Burban [/bib_ref] According to a randomized control study comparing an immediate treatment with a delayed treatment for 12 weeks, the SVR rate of the delayed treatment is not inferior to the immediate treatment considering spontaneous recovery rate and treatment-induced SVR. [bib_ref] Delayed versus immediate treatment for patients with acute hepatitis C: a randomised..., Deterding [/bib_ref] Anti-HCV antibody starts to appear at the time of highest ALT and of decreasing point of blood HCV RNA, which is about 8-12 weeks after the infection when most patients may not show any specific symptoms. [bib_ref] Immunology of hepatitis B virus and hepatitis C virus infection, Rehermann [/bib_ref] Therefore, testing for serum HCV RNA is useful for diagnosis and treatment when acute hepatitis C is suspected but showing a negative result for anti-HCV. SVR rate is as high as 80-90% when acute hepatitis C is treated by conventional interferon alpha or by peginterferon alpha monotherapy for 24 weeks. [bib_ref] Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial, Nomura [/bib_ref] [bib_ref] Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C..., Kamal [/bib_ref] [bib_ref] Barriers to interferon-alpha therapy are higher in intravenous drug users than in..., Broers [/bib_ref] [bib_ref] Efficacy of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with..., Santantonio [/bib_ref] [bib_ref] Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the..., Wiegand [/bib_ref] [bib_ref] Duration of peginterferon therapy in acute hepatitis C: a randomized trial, Kamal [/bib_ref] Peginterferon alpha-2b and ribavirin combination therapy did not increase an SVR rate compared to that of peginterferon alpha-2b monotherapy. [bib_ref] Delayed versus immediate treatment for patients with acute hepatitis C: a randomised..., Deterding [/bib_ref] [bib_ref] Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C..., Kamal [/bib_ref] No clear additional benefits of combining ribavirin with interferon alpha or peg-interferon alpha are apparent to date. The optimal treatment duration for acute hepatitis C is not definitely established. A randomized control study (n=34 in each group) reported no significant difference between SVR rates (82.4% in the 12-week treatment group and 91.2% in the 24-week treatment group) regardless of HCV genotypes. [bib_ref] Duration of peginterferon therapy in acute hepatitis C: a randomized trial, Kamal [/bib_ref] However, studies reporting good therapeutic outcomes of acute hepatitis C have tended to adopt a 24-week treatment, this length of treatment is recommended until contrar y evidence is presented. [bib_ref] Short-term interferon-alfa therapy for acute hepatitis C: a randomized controlled trial, Nomura [/bib_ref] [bib_ref] Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the..., Wiegand [/bib_ref] [bib_ref] Duration of peginterferon therapy in acute hepatitis C: a randomized trial, Kamal [/bib_ref] [Recommendations] [bib_ref] Prevalence of anti-HCV in hemodialysis patients in Taegu and Kyeongbuk, Shin [/bib_ref]. Antiviral therapy is to be considered for treatment of acute hepatitis C (A1). 28. Initiation of treatment can be postponed for 8-12 weeks after onset of acute hepatitis C to allow spontaneous recovery (B2). ## Peginterferon alpha monotherapy is preferentially considered in treatment of acute hepatitis c (b1), and duration of treatment is to be 24 weeks (b2). ## Management of adverse effects of an-tiviral treatment for hepatitis c ## Monitoring adverse effects of antiviral treatment During combination therapy of peginterferon alpha and ribavirin, many patients experience adverse effects; 10-20% of patients discontinue the treatment and 20-30% of patients experience dose reduction. [bib_ref] Side effects of therapy of hepatitis C and their management, Fried [/bib_ref] [bib_ref] Side effects of therapy for chronic hepatitis C, Russo [/bib_ref] Patients who received ≥ 80% of both their planned peginterferon alpha and ribavirin doses for ≥ 80% of the expected duration show an SVR rate of 63%, which was significantly higher than that (52%) of the patients who received reduced dose (<80%) of one or both drugs. [bib_ref] Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic..., Mchutchison [/bib_ref] Therefore, meticulous monitoring and management of adverse effects can improve therapeutic outcome by preventing from drug discontinuation or dose reduction. ## Adverse effects of antiviral therapy and its management More than 20% of patients treated with the peginterferon alpha and ribavirin combination therapy experience headache, fever, myalgia, muscular rigidity, arthralgia, nausea, anorexia, weight loss, diarrhea, hair loss, skin rash, pruritus, inflammation on sites of injection, dyspnea, fatigue, insomnia, irritability, or depression [fig_ref] http [/fig_ref]. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study..., Hadziyannis [/bib_ref] [bib_ref] Treating viral hepatitis C: efficacy, side effects, and complications, Manns [/bib_ref] However, severity or frequency of these adverse effects may vary, since these adverse reactions have been reported from patients chosen for clinical trials. [bib_ref] Treating viral hepatitis C: efficacy, side effects, and complications, Manns [/bib_ref] Adverse effects after peginterferon alpha injection can be classified as flu-like symptoms, myelosuppression, neuropsychological problems, and autoimmune dysfunction. Flu-like symptoms including fever, fatigue, myalgia, or nausea occur in about 37% of the patients, [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study..., Hadziyannis [/bib_ref] but these symptoms can be alleviated by administration of analgesics and usually lessened 4-6 weeks after the treatment. [bib_ref] Treating viral hepatitis C: efficacy, side effects, and complications, Manns [/bib_ref] Myelosuppression causes neutropenia and thrombocytopenia, the main causes of dose reduction, and often set the therapeutic limit in cirrhosis. Dose of peginterferon alpha should be reduced or skipped in case of severe adverse effects. Especially, when absolute neutrophil count decreases to under 750/mm 3 or platelet count decreases to <50,000/mm 3 , dose reduction should be considered; when absolute neutrophil count decreases under 500/mm 3 or platelet count decreases under 25,000/mm 3 , drug discontinuation should be considered. Later, re-administration of the drugs can be considered following adequate recovery of absolute neutrophil count and platelet count; for example, 50% of the previous dose can be administered when absolute neutrophil count recovers up to1,000/mm 3 or over, and platelet count up to 75,000/mm 3 or over, with continuous monitoring of those cell counts. Although evidences for the role of granulocyte colony stimulating factor (G-CSF) on lowering infection rate and on improving SVR are not enough, use of G-CSF can be considered in some patients with cirrhosis. [bib_ref] A national French survey on the use of growth factors as adjuvant..., Thevenot [/bib_ref] Meanwhile, treatment is to be halted in case of acute deterioration of hepatitis with elevation of ALT to over 10 times of upper-normal level or severe bacterial infection, such as sepsis. Even though thrombopoietin receptor agonist can raise platelet count in cirrhosis prior to treatment, [bib_ref] Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C, Mchutchison [/bib_ref] use of this drug should be done very carefully, since evidence for improved SVR rate by this drug remain insufficient, whereas the risk of thrombosis can cause portal vein thrombosis. [bib_ref] Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia, Afdhal [/bib_ref] Neuropsychological problems including insomnia, difficulty in concentrating, memory impairment, irritability, or apathy can be caused by peginterferon alpha. Especially, severe depression can provoke a suicide attempt, which requires careful observation during antiviral treatment. [bib_ref] Suicide associated with alfa-interferon therapy for chronic viral hepatitis, Janssen [/bib_ref] Past history of depression should be checked for, since presence of uncontrolled depression is a contraindication to the treatment. Depression occurs in about 28% of patients during the treatment, [bib_ref] Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis, Udina [/bib_ref] and antidepressants like serotonin uptake inhibitors can be used to maintain the treatment. [bib_ref] Paroxetine for the prevention of depression induced by high-dose interferon alfa, Musselman [/bib_ref] Preventive administration of antidepressants can reduce occurrence of depression during the treatment but cannot increase SVR rate. [bib_ref] Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis, Udina [/bib_ref] [bib_ref] Paroxetine for the prevention of depression induced by high-dose interferon alfa, Musselman [/bib_ref] Thyroid complications can occur in about 15-20% of patients, due to immunomodulatory function of peginterferon alpha, [bib_ref] Treating viral hepatitis C: efficacy, side effects, and complications, Manns [/bib_ref] [bib_ref] Interferon alpha treatment and thyroid dysfunction, Tomer [/bib_ref] which may be from autoimmune or non-autoimmune causes; autoimmune thyroid diseases are classified as Graves' disease, Hashimoto's disease, and auto-antibody generation against thyroid gland 345 and non-autoimmune thyroid disease results from thyroid damage by HCV itself. [bib_ref] Interferon alpha treatment and thyroid dysfunction, Tomer [/bib_ref] [bib_ref] The clinical and physiological spectrum of interferon-alpha induced thyroiditis: toward a new..., Mandac [/bib_ref] [bib_ref] Thyroid autoimmune disorders in patients with chronic hepatitis C before and during..., Marazuela [/bib_ref] Hashimoto's disease is the most common and starts with hyperthyroidism and may progress to hypothyroidism. Thyroid function may not be recovered even after the cessation of treatment. [bib_ref] Development of thyroid disease during therapy of chronic viral hepatitis with interferon..., Lisker-Melman [/bib_ref] [bib_ref] Long-term outcome of interferon-alpha-induced thyroid autoimmunity and prognostic influence of thyroid autoantibody..., Carella [/bib_ref] Discontinuation of treatment should be considered in case of severe hyperthyroidism during interferon administration, while treatment can be maintained with careful observation if hyperthyroidism is not severe. [bib_ref] Thyrotoxicosis induced by alpha-interferon therapy in chronic viral hepatitis, Wong [/bib_ref] In case of hypothyroidism at the beginning, interferon therapy can be maintained by administrating thyroxine. [bib_ref] Interferon alpha treatment and thyroid dysfunction, Tomer [/bib_ref] Meanwhile, thyroid gland dysfunction can occur even after the end of treatment [bib_ref] Treating viral hepatitis C: efficacy, side effects, and complications, Manns [/bib_ref] and it is desirable to check thyroid stimulating hormone (TSH) and free thyroxine levels at 2-4-month intervals during treatment and regularly for 1 year after the termination of treatment. Various kinds of autoimmune diseases, such as systemic lupus erythematosus, type 1 diabetes mellitus, asthma, interstitial pulmonary fibrosis, or thyroid diseases, can be induced by interferon therapy. [bib_ref] Interferon therapy in chronic viral hepatitis; an autoimmunity dilemma, Gutkowski [/bib_ref] Therefore, baseline evaluation of these diseases is necessary prior to the initiation of treatment, although existence of these diseases is not an absolute contraindication to the http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2014.20.2.89 treatment especially when these diseases are well controlled. [bib_ref] Treating viral hepatitis C: efficacy, side effects, and complications, Manns [/bib_ref] [bib_ref] Interferon alpha treatment and thyroid dysfunction, Tomer [/bib_ref] Other adverse effects related to peginterferon alpha, such as visual field defect, retinal hemorrhage and edema, hearing defect, tinnitus, vomiting, nausea, pruritus, weight loss or hair loss, improve after termination of treatment. [bib_ref] Treating viral hepatitis C: efficacy, side effects, and complications, Manns [/bib_ref] Frequency of retinal defect is reported as about 3.8-30.9% [bib_ref] Interferon-induced retinopathy and its risk in patients with diabetes and hypertension undergoing..., Panetta [/bib_ref] [bib_ref] A prospective study of change in visual function in patients treated with..., Malik [/bib_ref] [bib_ref] Intraocular complications of IFN-alpha and ribavirin therapy in patients with chronic viral..., Sene [/bib_ref] [bib_ref] Pegylated interferon-associated retinopathy is frequent in hepatitis C virus patients with hypertension..., Vujosevic [/bib_ref] with variable clinical course from severe visual field defect to no symptoms, and it is desirable to check the retina prior to the treatment in cases with risk factors such as old age, hypertension, or diabetes 356-358 even though pretreatment and regular follow-up evaluation of retina remains debatable. Hearing loss occurs in <1% of patients and it cannot be recovered completely even after the termination of treatment. [bib_ref] Sudden hearing loss in patients with chronic hepatitis C treated with pegylated..., Formann [/bib_ref] A common adverse effect of ribavirin is hemolytic anemia due to dose-dependent direct toxicity of ribavirin to erythrocytes and it may be a barrier to successful treatment. [bib_ref] Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C..., De Franceschi [/bib_ref] Anemia due to ribavirin can deteriorate ischemic heart or pulmonary diseases in patients with existing cardiac or pulmonary diseases. [bib_ref] Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C..., De Franceschi [/bib_ref] Immediate dose reduction by 200 mg should be considered when hemoglobin level decreases to under 10 g/dL and drug discontinuation should be considered in case of anemia with under 8.5 g/dL hemoglobin, but re-administration of the reduced dose is possible when anemia improves. Recombinant erythropoietin can be used in case of severe anemia, not to stop ribavirin or to prevent dose reduction, although the evidence of erythropoietin raising SVR rate is lacking. [bib_ref] A national French survey on the use of growth factors as adjuvant..., Thevenot [/bib_ref] [bib_ref] Epoetin alfa maintains ribavirin dose in HCVinfected patients: a prospective, double-blind, randomized..., Afdhal [/bib_ref] Meanwhile, it is apprehended that ribavirin causes congenital deformity during pregnancy, therefore thorough contraception is essential during treatment and for 6 months after treatment for both male and female patients. [bib_ref] Embryotoxic, teratogenic, and metabolic effects of ribavirin in mice, Kochhar [/bib_ref] Other adverse effects related to ribavirin include fatigue, pruritus, rashes, sinusitis, and gout. Educating patients on treatment related adverse effects and their management helps to maintain the therapy. Detection of the adverse reactions during the first 2-4 weeks of the treatment is important and monitoring at 4-12 week intervals thereafter is required even if the patients seem to tolerate the antiviral therapy well. [Recommendations] [bib_ref] Trends of mortality and cause of death among HIV-infected patients in Korea, Lee [/bib_ref]. A pretreatment evaluation of depression, cardiac and pulmonary diseases, hypertension, diabetes mellitus, thyroid diseases, or anemia is needed to monitor adverse effects of treatment (B1). ## Monitoring of adverse effects at 2-4 week interval after the initiation of the treatment and thereafter at 4-12 week intervals during the treatment (C1). 32. When absolute neutrophil count decreases to <750/ mm 3 or platelet count decreases to <50,000/mm 3 , dose reduction of peginterferon alpha should be considered; when absolute neutrophil count decreases to <500/mm 3 or platelet count decreases to <25,000/mm 3 , discontinuation of peginterferon alpha should be considered. Later, re-administration of peginterferon alpha with reduced dose can be considered following adequate recovery of absolute neutrophil count and platelet count and continuous monitoring of those counts is needed (C2). ## Dose reduction of ribavirin should be considered when anemia with hemoglobin level <10 g/dl occurs and discontinuation of ribavirin should be considered in case of hemoglobin level <8.5 g/dl. later, when anemia improves, re-administration of ribavirin with reduced d o se i s p o s si ble a n d co nti n u o u s m o n ito ri n g o f hemoglobin level is needed (c2). 34. monitoring of tsh and free thyroxine levels at 2-4-month intervals is recommended to investigate the occurrence of thyroid abnormality (c1). 35. a ppropriate management is needed w hen depression develops during the antiviral treatment and antiviral treatment should be halted in case of severe depression (c1). ## Monitoring after the end of treatment Continuous observation of undetectable HCV RNA after reaching SVR can be regarded as complete eradication of HCV. Re-infection of HCV is possible even after reaching SVR, mainly involving IVDU. [bib_ref] Infrequent reinfection after successful treatment for hepatitis C virus infection in injection..., Backmund [/bib_ref] [bib_ref] Follow-up studies of treatment for hepatitis C virus infection among injection drug..., Dalgard [/bib_ref] [bib_ref] A prospective study to examine persistent HCV reinfection in injection drug users..., Currie [/bib_ref] [bib_ref] Reinfection with hepatitis C virus following sustained virological response in injection drug..., Grebely [/bib_ref] Therefore, follow-up is needed to check re-infection or relapse of HCV after reaching SVR. A risk of HCC remained even after reaching SVR in case of accompanying cirrhosis or advanced hepatic fibrosis prior to the treatment. [bib_ref] Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related..., Bruno [/bib_ref] In these patients, monitoring for HCC according to the surveillance strategy and management of general complications of cirrhosis are needed. If SVR is not achieved, the incidence of HCC and progress of the disease is significantly higher compared to the cases with SVR, [bib_ref] Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related..., Bruno [/bib_ref] [bib_ref] A sustained virologic response reduces risk of all-cause mortality in patients with..., Backus [/bib_ref] and continuous management of chronic hepatitis is necessary in cases without SVR. [bib_ref] Boccia A. Hepatitis C virus infections trends in Italy, Torre [/bib_ref]. Continuous observation of undetectable HCV RNA after reaching SVR can be regarded as a complete eradication of HCV (C1). 37. A risk of hepatocellular carcinoma or complication of chronic liver disease still exist even after achieving SVR in patients with cirrhosis or advanced hepatic fibrosis, and continuous management and surveillance following the strategies for chronic liver diseaseare needed (B1). 38. If SVR is not achieved, continuous management of chronic liver disease is necessary (B1). ## Treatment of special populations Considering that clinical trials on patients in specific medical conditions have many limitations, antiviral treatment in these populations should be individualized. ## Cirrhosis ## Treatment of patients with compensated cirrhosis Compensated cirrhosis has a high probability of progression to decompensated cirrhosis or development of HCC. Thus, antiviral treatment is strongly recommended unless there are absolute contraindications. The acquisition of SVR in patients with cirrhosis or advanced hepatic fibrosis leads to the reduction of liver diseaserelated mortality and incidence of HCC. [bib_ref] Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development..., Shiratori [/bib_ref] [bib_ref] Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related..., Bruno [/bib_ref] [bib_ref] Longterm effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular..., Hung [/bib_ref] [bib_ref] Sustained virologic response and clinical outcomes in patients with chronic hepatitis C..., Veldt [/bib_ref] However, SVR rate of a combination therapy with peginterferon alpha plus ribavirin is significantly lower in patients with cirrhosis or advanced hepatic fibrosis compared to those patients with mild fibrosis. A Korean study reported SVR rates of 20.8% in genotype 1 HCV infected patients and 52.6% in genotype 2 HCV infected patients with Child-Turcotte-Pugh (CTP) class A cirrhosis. [bib_ref] Peginterferon alpha and ribavirin combination therapy in patients with hepatitis C virus-related..., Kim [/bib_ref] Also, meticulous monitoring and management of complications are necessary, since cirrhotic patients are usually elderly and treatment-related complications occur more frequently. Cirrhotic patients have low neutrophil and platelet counts due to portal hypertension and splenomegaly, so hematological problems including anemia, neutropenia, or thrombocytopenia often occur during treatment. Therefore, growth factors such as recombinant erythropoietin or G-CSF could be helpful overcoming these complications. [bib_ref] Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon..., Schmid [/bib_ref] Triple therapy using boceprevir or telaprevir has tended to produce a higher SVR rate than that of the standard combination therapy and a 48-week triple therapy resulted in higher SVR rate than that of 'response-guided therapy' in genotype 1 HCV-infected compensated cirrhotic patients. [bib_ref] Telaprevir for previously untreated chronic hepatitis C virus infection, Jacobson [/bib_ref] [bib_ref] Telaprevir for retreatment of HCV infection, Zeuzem [/bib_ref] [bib_ref] Efficacy and safety of boceprevir plus peginterferon-ribavirin in patients with HCV G1..., Bruno [/bib_ref] Therefore, the therapeutic efficacy of cirrhotic patients should be improved in the upcoming DAA era. Continuous monitoring for complications of cirrhosis is needed, even after reaching SVR, since there is still a possibility of development of HCC. ## Treatment of patients with decompensated cirrhosis Therapeutic outcome in decompensated cirrhotic patients is poorer with more frequent treatment-related complications compared to compensated cirrhosis. A small study (n=10, 8 genotype 1 HCV patients, 2 genotype non-1 HCV patients) reported A SVR rate of 20.0% in treating decompensated cirrhotic patients by a combination therapy with peginterferon alpha plus ribavirin. [bib_ref] Clinical efficacy and safety of the combination therapy of peginterferon alpha and..., Cheong [/bib_ref] Therefore, antiviral treatment of CTP class B cirrhotic patients can be tried by experienced specialists with careful monitoring. Good therapeutic outcome is expected in case of low HCV RNA concentration, or HCV genotype 2 or 3. Although drug administration can be started with standard doses, more than half of the patients experience drug discontinuation or dose reduction. Thus, a careful approach starting with low accelerated dose regimen(starting with 90 μg/week of peginterferon alpha-2a or 0.5 μg/kg/week of peginterferon alpha-2b and 600 mg/day of ribavirin, and gradual increase of dose every 2 weeks up to the maximum tolerable dose) 374 might be helpful. The current standard treatment regimen is contraindicated in patients of CTP class C due to the likely possibility of severe complications including death. [bib_ref] Treatment of advanced hepatitis C with a low accelerating dosage regimen of..., Everson [/bib_ref] Efficacy and safety of DAAs have not been proven yet in treating decompensated cirrhosis. ## Liver transplantation and other organ transplants ## Treatment following liver transplantation Patients with HCV infection at the time of liver transplantation have higher graft failure rate (hazard ratio (HR), 1.30; 95% CI, 1.21-1.39) and mortality rate (HR, 1.23; 95% CI, 1.12-1.35) compared to patients without HCV infection. [bib_ref] The association between hepatitis C infection and survival after orthotopic liver transplantation, Forman [/bib_ref] HCV reinfection occurs within several hours after transplantation in most of patients with detectable HCV RNA at the time of the transplantation. [bib_ref] Hepatitis C virus kinetics during and immediately after liver transplantation, Garcia-Retortillo [/bib_ref] HCV-related liver diseases rapidly deteriorate following liver transplantation and around one-third of the patients progress to cirrhosis within 5 years after transplantation. [bib_ref] The association between hepatitis C infection and survival after orthotopic liver transplantation, Forman [/bib_ref] [bib_ref] High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection..., Prieto [/bib_ref] Successful elimination of HCV after transplantation improves survival rate of the graft and patients. [bib_ref] Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following..., Berenguer [/bib_ref] Treatment of HCV reinfection is recommended after histological confirmation of chronic hepatitis C at least 6 months after transplantation. The reason for this 6-month interval is that shortly after transplantation patients are heavily immunosuppressed and incompletely recovered from the surgery, resulting in high probability of drug intolerability as well as allograft rejection during interferon use. Antiviral treatment should be started as soon as possible when advanced fibrosis (numerous septa without cirrhosis) or portal hypertension is noted, since these conditions predict a rapid progression of liver diseases and graft failure. [bib_ref] Fibrosis progression after liver transplantation in patients with recurrent hepatitis C, Neumann [/bib_ref] [bib_ref] Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C..., Blasco [/bib_ref] In case of fibrosis limited to the portal tract without portal hyper-tension, antiviral treatment should be determined in consideration of treatment efficacy and risk of treatment-related complications. The SVR rate of antiviral treatment after transplantation is 30-40%, and genotype 2 or 3 has better therapeutic outcome compared to genotype 1. [bib_ref] Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following..., Berenguer [/bib_ref] [bib_ref] Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver..., Samuel [/bib_ref] [bib_ref] Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a..., Carrion [/bib_ref] Post-transplant patients reportedly show similar therapeutic outcomes (33% and 38% of SVR rates in each therapy) using either peginterferon alpha plus ribavirin combination therapy or peginterferon alpha monotherapy, which may be explained by frequent dose reduction or discontinuation of ribavirin due to complications. [bib_ref] A randomized study on Peg-interferon alfa-2a with or without ribavirin in liver..., Angelico [/bib_ref] Anemia is the most common cause of treatment discontinuation and recombinant erythropoietin is recommended in this case. [bib_ref] Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver..., Samuel [/bib_ref] [bib_ref] Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a..., Carrion [/bib_ref] Allograft rejection can occur related to interferon alpha use, and liver biopsy is required to differentiate the cause of liver function deterioration during antiviral treatment. The on-treatment virological response of triple therapy using boceprevir or telaprevir in patients with recurrent chronic hepatitis C after liver transplantation is reported to be 50-60% at week 24 of treatment. 384 ## Treatment following other organ transplants Patients of renal transplant with HCV infection display rapidly progressing hepatic fibrosis and show high mortality related to hepatic failure. Thus, the presence of cirrhosis must be screened for prior to kidney transplantation. [bib_ref] Management of chronic viral hepatitis before and after renal transplantation, Gane [/bib_ref] Sometimes liver biopsy is necessary to confirm cirrhosis. As hemorrhagic tendency exists in patients with end stage kidney disease (ESKD) due to platelet dysfunction, there is a concern that liver biopsy may cause procedure-related hemorrhagic complications. However, severe complications related to percutaneous liver biopsy have been rarely reported in patients with ESKD and the incidence of complications was not significantly higher than that of patients with normal renal function. [bib_ref] Percutaneous liver biopsy is safe in chronic hepatitis C patients with end-stage..., Pawa [/bib_ref] Administration of 0.3 μg/kg desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) can be used prior to liver biopsy when hemorrhagic complications are concerned. [bib_ref] Chronic hepatitis C infection in patients with end stage renal disease: characterization..., Sterling [/bib_ref] The combination therapy with peginterferon alpha plus ribavirin causes graft rejection in over 30% of patients, leading to graft failure and death. Thus, use of interferon-including regimen is an absolute contraindication in renal transplant patients except lifethreatening fibrosing cholestatic hepatitis. Fundamentally, treatment of HCV is recommended prior to renal transplantation. [bib_ref] Hepatitis C virus and kidney disease, Martin [/bib_ref] There have been two successful cases of anti-HCV treatment using interferon in heart transplant setting. [bib_ref] Hepatitis C status of heart transplant recipients, Fagiuoli [/bib_ref] [Recommendations] [bib_ref] A new strategy for estimating risks of transfusion-transmitted viral infections based on..., Busch [/bib_ref]. Treatment of HCV reinfection after liver transplantation is recommended with histological confirmation of chronic hepatitis C (B1). Antiviral treatment should be started as soon as possible when advanced fibrosis or portal hypertension is noted, since these conditions predict a rapid progression of liver diseases and graft failure (B2). Treatment regimen could be either combination therapy with peginterferon alpha plus ribavirin or monotherapy with peginterferon alpha (B2). [bib_ref] Impact of individual-donation nucleic acid testing on risk of human immunodeficiency virus,..., Vermeulen [/bib_ref]. Liver biopsy is often required to differentiate causes of liver function deterioration during antiviral treatment (C1). ## Use of interferon based regimen is absolutely contraindicated in kidney, heart, and lung transplants except in life-threatening fibrosing cholestatic hepatitis (c1). ## Patients receiving immunosuppressants or cytotoxic chemotherapy There is no universal consensus on definition of HCV reactivation, although the commonly used criteria include blood level of ALT and HCV RNA. One study defined HCV reactivation as reemergence or increase of HCV RNA plus elevation of ALT up to 3 times of the upper normal limit. [bib_ref] Reactivation of hepatitis B virus infection with cytotoxic therapy in non-Hodgkin's lymphoma, Ozguroglu [/bib_ref] The incidence of HCV reactivation in patients taking immunosuppressants or under cytotoxic chemotherapy is lower compared to that of HBV. [bib_ref] Reactivation of hepatitis B virus infection with cytotoxic therapy in non-Hodgkin's lymphoma, Ozguroglu [/bib_ref] [bib_ref] Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy:..., Yeo [/bib_ref] [bib_ref] Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving..., Kawatani [/bib_ref] [bib_ref] Reactivation of hepatitis B but not hepatitis C in patients with malignant..., Markovic [/bib_ref] [bib_ref] Reactivation of replication of hepatitis B and C viruses after immunosuppressive therapy:..., Vento [/bib_ref] For example, the reactivation rate of HCV was 0% (0 of 11) compared to 38% (3 of 8) of HBV in a study including 98 non-Hodgkin's lymphoma patients receiving chemotherapy. [bib_ref] Acute hepatic toxicity during cyclic chemotherapy in non Hodgkin's lymphoma, Faggioli [/bib_ref] However, another study of B cell non-Hodgkin's lymphoma reported higher incidence (26.3% vs. 2.1%) of significantly elevated ALT in HCV infected patients compared to patients without HCV infection, indicating that HCV reactivation does occur and may cause clinically significant morbidity. [bib_ref] Hepatitis C virus infection prevalence and liver dysfunction in a cohort of..., Nosotti [/bib_ref] Risk factors predicting HCV reactivation have not clearly identified. However reactivation has been reported to occur more frequently in patients with hematological malignancies. 392,397 HCV reactivation has also been reported in patients with solid cancer or stem cell transplantation. [bib_ref] Hepatitis C virus acute exacerbation during chemotherapy and radiotherapy for oesophageal carcinoma, De Pree [/bib_ref] [bib_ref] Withdrawal of immunosuppressive therapy in allogeneic bone marrow transplantation reactivates chronic viral..., Fan [/bib_ref] [bib_ref] Case report: fulminant hepatitis C viral infection after allogeneic bone marrow transplantation, Kanamori [/bib_ref] Although death due to HCV reactivation has rarely been documented, [bib_ref] Fulminant hepatitis on withdrawal of chemotherapy in carriers of hepatitis C virus, Vento [/bib_ref] the mortality is similar to that of HBV once severe hepatitis occurs with HCV reactivation. [bib_ref] Severe hepatitis related to chemotherapy in hepatitis B virus carriers with hematologic..., Nakamura [/bib_ref] [bib_ref] Hepatitis reactivation and liver failure in haemopoietic stem cell transplants for hepatitis..., Locasciulli [/bib_ref] [bib_ref] Retrospective study on the impact of hepatitis B and hepatitis C virus..., Hamaguchi [/bib_ref] Strategies to prevent HCV reactivation in these patients have not been established. Conservative therapy and discontinuation of offending drugs are currently recommended options. However, one should take into account hepatic morbidity from HCV reactivation and disadvantages from immunosuppressive drug discontinuation, and decisions should be individualized. Further studies are needed to explore how to prevent and treat HCV reactivation by using DAAs. ## Treatment of active intravenous drug users Intravenous drug abuse is the main route of HCV transmission and the abusers show significantly higher HCV infection rate compared to those without a history of drug abuse. [bib_ref] Diagnosis, management, and treatment of hepatitis C: an update, Ghany [/bib_ref] [bib_ref] The prevalence of hepatitis C virus infection in the United States, Armstrong [/bib_ref] Anti-HCV positive rate of Korean intravenous drug users has been reported as 48.4-79.2%. [bib_ref] Seropositivity of anti-HCV in intravenous drug abusers, Lee [/bib_ref] [bib_ref] Prevalence and associated clinical characteristics of hepatitis B, C, and HIV infections..., Min [/bib_ref] [bib_ref] Prevalence of anti-HCV among drug users in Korea, Kim [/bib_ref] Meanwhile, high HCV infection rate also has been reported in case of sharing cocaine inhalation tubes. [bib_ref] High prevalence of hepatitis C virus infection among noninjecting drug users: association..., Macias [/bib_ref] A meta-analysis including over 2,800 injection drug users showed SVR rates as 44.9% in HCV genotype 1 and 70.0% in HCV genotype 2 and 3 patients treated by combination therapy of peginterferon alpha and ribavirin. [bib_ref] Determinants of hepatitis C virus treatment completion and efficacy in drug users..., Dimova [/bib_ref] The standard therapy is recommended only to the patients with a history of drug abuse but not for those that are actively using ilicit drugs. Active drug users often show low willingness for HCV treatment, diminished ability to adhere to the treatment or abide by precautions regarding contraception, and higher possibilities of re-infection due to reuse of IV drugs. Therefore, it is important to clearly evaluate willingness of each patients for antiviral treatment and suspension from abusing ilicit drugs for 6-12 months is usually needed despite of weak evidence supporting it.Multidisciplinary cooperative treatment among medical and psychiatric counseling services, and social support showed a significant decrease of treatment interruption rate [bib_ref] Determinants of hepatitis C virus treatment completion and efficacy in drug users..., Dimova [/bib_ref] ## Treatment of patients with chronic kid-ney diseases HCV infection rate is high in chronic kidney disease patients. Yet, anti-HCV screening may not be needed for these patients. Screening should be selectively conducted when HCV-related glomerulonephritis clinically presenting as hematuria, albuminuria, or cryoglobulinemia is suspected. However, anti-HCV should be tested for in patients taking maintenance dialysis for the first time or transferred from other dialysis units. In addition, when unexplained abnormal liver-related biochemical tests is found or HCV exposure is suspected, anti-HCV should be tested and HCV RNA assay is needed in case of continuous negative detection of anti-HCV antibody. [bib_ref] Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following..., Berenguer [/bib_ref] HCV prevalence among the patients taking dialysis is reported variously ranging from 3-80% depending on location; 410 the prevalence rate in South Korea is reported as 5-15%. [bib_ref] Prevalence and risk factors of hepatitis C virus infectioin in chronic hemodialysis..., Kim [/bib_ref] [bib_ref] Prevalence of anti-HCV in hemodialysis patients in Taegu and Kyeongbuk, Shin [/bib_ref] The optimal surveillance interval for HCV infection in anti-HCV negative patients in dialysis unit should be between 6-12 months, considering the HCV infection rate of the dialysis unit where the patients are taken care of. Dialysis patients infected with HCV show higher mortality rate and rapid progress to cirrhosis or hepatocellular carcinoma compared to non-dialysis patients. [bib_ref] ESRD patient mortality with adjustment for comorbid conditions in Lombardy (Italy) versus..., Marcelli [/bib_ref] [bib_ref] Cancer in patients on dialysis for endstage renal disease: an international collaborative..., Maisonneuve [/bib_ref] Patients scheduled for kidney transplantation should receive an anti-HCV assay. Survival rate after the kidney transplantation tends to be low with a possibility of graft rejection when interferon therapy were to be initiated after the transplantation and also with a possibility of increased occurrence of diabetes and membranous nephritis. [bib_ref] Hepatitis C infection, time in renal-replacement therapy, and outcome after kidney transplantation, Bruchfeld [/bib_ref] [bib_ref] Natural history of hepatitis B and C in renal allograft recipients, Aroldi [/bib_ref] [bib_ref] Association of hepatitis C with posttransplant diabetes in renal transplant patients on..., Bloom [/bib_ref] [bib_ref] Diabetes mellitus after kidney transplantation: a French multicentre observational study, Kamar [/bib_ref] [bib_ref] Posttransplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of..., Fabrizi [/bib_ref] [bib_ref] De novo membranoproliferative glomerulonephritis in hepatitis C virusinfected renal allograft recipients, Roth [/bib_ref] [bib_ref] Recurrent glomerulonephritis after kidney transplantation, Choy [/bib_ref] Therefore, interferon based antiviral therapy is recommended when HCV infection is confirmed via HCV RNA assay before impending necessity of kidney transplantation. [bib_ref] Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following..., Berenguer [/bib_ref] Indications of HCV treatment in chronic kidney disease patients are to be determined considering liver disease condition and therapeutic complications. However, dose adjustment is needed depending on severity of kidney disease, since the clearance of both peginterferon alpha and ribavirin are reduced according to the degree of impaired kidney function. Moreover, ribavirin should be carefully used in case of creatinine clearance under 50 mL/min since ribavirin can cause severe hemolytic anemia. [bib_ref] Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients, Bruchfeld [/bib_ref] Patients with mild kidney disease (glomerular filtration rate (GFR) ≥60 mL/min) can be administered the same dose of the therapeutic drugs as patients without kidney disease. If the patient has severe kidney disease (GFR of 15-59 mL/min), 135 μg of peginterferon alpha-2a or 1 μg/kg of peginterferon alpha-2b along with 200-800 mg/day of ribavirin twice a day with gradual dose increase is recommended. [bib_ref] Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of..., Martino [/bib_ref] Patients on dialysis can take either interferon alpha or peginterferon alpha although combination with ribavirin is not recommended. SVR rate was variable as 7-97% in a study conducted using the combination therapy of peginterferon alpha (135 μg/week) and low-dose ribavirin (200 mg/day) in patients on dialysis, and most studies reported a high rate of treatment discontinuation. Dose adjustment of new drugs, such as boceprevir and telaprevir, is not necessary since they are metabolized in the liver and eliminated mostly through feces and negligibly through urine.However, SVR rates after the treatment with these drugs have not been reported yet in chronic kidney disease patients. Antiviral therapy for HCV can be conducted in patients having HCV-related cryoglobulinemia or membranous glomerulonephritis. Immunosuppressive therapy or plasma exchange can be done prior to the antiviral treatment in case of nephrotic syndrome or rapid decrease of kidney function among these patients. [bib_ref] Interferon-alpha in combination with ribavirin as initial treatment for hepatitis C virus-associated..., Garini [/bib_ref] [bib_ref] Treatment with peg-interferon alfa-2b and ribavirin of hepatitis C virus-associated mixed cryoglobulinemia:..., Mazzaro [/bib_ref] [bib_ref] Antiviral therapy for hepatitis C virus--associated mixed cryoglobulinemia vasculitis: a long-term followup..., Saadoun [/bib_ref] [Recommendations] 48. Anti-HCV should be tested to plan further treatment a n d m a n a g e m e n t i n p a t i e n t s p re p a ri n g k i d n ey replacement therapy, such as dialysis or kidney transplantation (B1). [bib_ref] Unsafe injections in low-income country health settings: need for injection safety promotion..., Kermode [/bib_ref]. HCV RNA should be tested to confirm HCV infection in patients having idiopathic liver diseases despite of negative anti-HCV results or in patients with positive anti-HCV (B1). [bib_ref] The German Hep-Net acute hepatitis C cohort: impact of viral and host..., Deterding [/bib_ref] ## Treatment of patients with hiv or hbv coinfection ## Chronic hepatitis c patients with hiv coinfection Coinfection rate of HIV and HCV is reported to be 25% in western countries 28 and 5.0-6.6% in South Korea. [bib_ref] Seroprevalence of sexually transmitted viruses in Korean populations including HIV-seropositive individuals, Kim [/bib_ref] [bib_ref] Trends of mortality and cause of death among HIV-infected patients in Korea, Lee [/bib_ref] [bib_ref] Causes of death and risk factors for mortality among HIV-infected patients receiving..., Lee [/bib_ref] Since the frequency of coinfection is relatively high, all HIV infected patients should receive HCV testing consisting primarily of an anti-HCV assay. However, antibody formation may fail to appear in about 6% of HIV infected patients and a HCV RNA assay should be conducted in patients with idiopathic liver disease and negative anti-HCV. [bib_ref] Effect of coexisting HIV-1 infection on the diagnosis and evaluation of hepatitis..., Bonacini [/bib_ref] [bib_ref] Hepatitis C virus (HCV) viremia in human immunodeficiency virus-seronegative and -seropositive patients..., Marcellin [/bib_ref] Chronic hepatitis C patients with risk factors of HIV infection should be tested for HIV. HIV coinfected patients show rapid progress of liver disease and 2-fold higher incidence rate of cirrhosis compared to HCV monoinfection. Therefore, liver diseases due to HCV is regarded as an important factor affecting morbidity and mortality rate in HIV infected patients, since highly active antiretroviral therapy (HAART) was introduced in 1996. [bib_ref] Increasing mortality due to end-stage liver disease in patients with human immunodeficiency..., Bica [/bib_ref] [bib_ref] Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection...., Palella [/bib_ref] [bib_ref] Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D..., Weber [/bib_ref] Especially, progression of liver disease speeds up as CD4+ lymphocyte count is lower and immune disorder is more severe. [bib_ref] Effect of antiretroviral therapy on liver-related mortality in patients with HIV and..., Qurishi [/bib_ref] Recovery of immune function by antiretroviral therapy can delay the progress of liver disease. [bib_ref] Hepatitis C viral kinetics during treatment with peg IFN-alpha-2b in HIV/HCV coinfected..., Avidan [/bib_ref] [bib_ref] Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults, Sulkowski [/bib_ref] Generally, antiretroviral therapy is recommended in HIV/HCV coinfected patients regardless of CD4+ lymphocyte count, since the benefits from antiretroviral therapy are bigger than risk of drug toxicity. However, antiretroviral therapy should be conducted carefully due to high risk of liver toxicity, especially in HIV/HCV coinfected patients with progressed liver disease. [bib_ref] Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral..., Brau [/bib_ref] [bib_ref] Fast fibrosis progression between repeated liver biopsies in patients coinfected with human..., Macias [/bib_ref] It is desirable to adapt antiretroviral therapy first when CD4+ lymphocyte count is low and to adapt HCV treatment after the recovery of CD4+ lymphocyte count. Meanwhile, antiretroviral therapy can be delayed in patients with a CD4+ lymphocyte count >500 cells/mm 3 .Peginterferon alpha can be used at same dose recommended for treating HCV monoinfection and ribavirin dose can be adjusted depending on body weight (1,000 mg/day for under 75 kg, 1,200 mg/day for over 75 kg), [bib_ref] Role of weight-based ribavirin dosing and extended duration of therapy in chronic..., Nunez [/bib_ref] regardless of HCV genotype in HIV coinfection. Treatment duration is usually recommended as 48 weeks, regardless of HCV genotype. A shortened duration of therapy down to 24 weeks can be effective in genotype 2 and 3 with RVR, and an extended duration of therapy up to 60-72 weeks can be helpful in genotype 1 and 4 with pEVR and no RVR. [bib_ref] Diagnosis, management, and treatment of hepatitis C: an update, Ghany [/bib_ref] [bib_ref] Role of weight-based ribavirin dosing and extended duration of therapy in chronic..., Nunez [/bib_ref] [bib_ref] Care of patients coinfected with HIV and hepatitis C virus: 2007 updated..., Soriano [/bib_ref] [bib_ref] Open, randomized, multicentre Italian trial on PEG-IFN plus ribavirin versus PEG-IFN monotherapy..., Cargnel [/bib_ref] [bib_ref] Efficacy and safety of pegylated interferon-alpha2b plus ribavirin for the treatment of..., Santin [/bib_ref] SVR rate of the combination therapy in HIV coinfection was reported as 29% in genotype 1 and 62% in genotype 2 and 3. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected..., Torriani [/bib_ref] Lower SVR rate compared to that of HCV monoinfection may be related to the high blood concentration of HCV RNA in HIV coinfected patients compared to that of HCV monoinfection. [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected..., Torriani [/bib_ref] [bib_ref] Interferon alpha for the treatment of chronic hepatitis C in patients infected..., Soriano [/bib_ref] [bib_ref] Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment..., Laguno [/bib_ref] Anemia related to ribavirin is a raising problem in treatment of HIV coinfection and especially it is more frequent and severe in patients taking zidovudine (AZT). [bib_ref] Zidovudine use but not weight-based ribavirin dosing impacts anaemia during HCV treatment..., Alvarez [/bib_ref] Ribavirin can deteriorate didanosine (ddI) toxicity by inhibition of inosine-5-monophosphate dehydrogenase and severe lactic acidosis has been reported in patients taking ddI along with ribavirin. [bib_ref] Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection, Lafeuillade [/bib_ref] [bib_ref] Mitochondrial toxic effects and ribavirin, Salmon-Ceron [/bib_ref] Therefore, patients receiving AZT and especially ddI should be switched to an equivalent antiretroviral agent before beginning combination therapy containing ribavirin. SVR rate of triple therapy using boceprevir was 60.7%, which is superior to the 26.5% reported in the dual combination therapy, and triple therapy using telaprevir showed higher SVR rate (74%) compared to 45% in the combination therapy. Adverse effects of the triple therapy in HIV coinfection have been reported to be similar to those occurring in HCV monoinfection although further studies are needed. [bib_ref] Current management of hepatitis C virus infection in patients with HIV co-infection, Sulkowski [/bib_ref] In addition, detailed monitoring is necessary when using the regimens including boceprevir or telaprevir due to possible drug-drug interactions. 422 ## [recommendations] ## All hiv infected patients should take anti-hcv test (b1). 53. HCV RNA assay should be conducted in patients having idiopathic liver disease even with negative anti-HCV or in patients with positive anti-HCV (B1). [bib_ref] Tattooing and the risk of transmission of hepatitis C: a systematic review..., Jafari [/bib_ref]. Peginterferon alpha should be used at same dose recommended for treating HCV monoinfection and ribavirin dose can be adjusted depending on body weight for 48 weeks regardless of HCV genot ype in HIV co-infected patients (B1). ## Chronic hepatitis c patients with hbv coinfection The number of HBV/HCV coinfected patients worldwide is estimated as 15,000,000, [bib_ref] Management of hepatitis C in HIV and/or HBV co-infected patients, Fernandez-Montero [/bib_ref] patients showed a occurrence rate of 45%, which was significantly higher. [bib_ref] Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis, Chiaramonte [/bib_ref] In addition, risks of severe and fulminant hepatitis increase and the incidence rate of cirrhosis and HCC increases in case of HBV/HCV coinfected patients compared to HBV monoinfection. [bib_ref] Comparison of liver histopathology between chronic hepatitis C patients and chronic hepatitis..., Lee [/bib_ref] [bib_ref] Influence of chronic coinfection with hepatitis B and C virus on liver..., Sagnelli [/bib_ref] [bib_ref] Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma..., Benvegnu [/bib_ref] In patients with HBV/HCV coinfection, blood levels of HCV RNA and HBV DNA representing replicative status of each virus should be evaluated, and if HCV infection is the dominant cause of the liver disease, the same antiviral therapy as for HCV monoinfection is recommended for an SVR rate, similar to that of HCV monoinfection. [bib_ref] Treatment of HBV/HCV coinfection, Potthoff [/bib_ref] [bib_ref] The HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the..., Potthoff [/bib_ref] [bib_ref] Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with..., Liu [/bib_ref] Reactivation of HBV is possible during or after HCV treatment, [bib_ref] Clinical features and treatment efficacy of peginterferon alfa plus ribavirin in chronic..., Kim [/bib_ref] and administration of oral antiviral agents may be indicated when significant proliferation of HBV is confirmed in this case. 464 ## [recommendation] ## After confirming the dominant cause of liver diseases in hbv/hcv coinfection, treatment based on the standard therapy of hcv monoinfection is recommended and oral administration of anti-hbv agents may be indicated when significant proliferation of hbv is confirmed (b1). ## Treatment of patients with hemophilia or thalassemia Accompanying HCV infection in patients with hemophilia or thalassemia causes significant increases of morbidity and mortality rates compared to patients without HCV infection. [bib_ref] Clinical features and treatment efficacy of peginterferon alfa plus ribavirin in chronic..., Kim [/bib_ref] [bib_ref] Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis, Chiaramonte [/bib_ref] [bib_ref] Comparison of liver histopathology between chronic hepatitis C patients and chronic hepatitis..., Lee [/bib_ref] [bib_ref] Influence of chronic coinfection with hepatitis B and C virus on liver..., Sagnelli [/bib_ref] [bib_ref] Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma..., Benvegnu [/bib_ref] [bib_ref] Treatment of HBV/HCV coinfection, Potthoff [/bib_ref] [bib_ref] The HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the..., Potthoff [/bib_ref] [bib_ref] Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with..., Liu [/bib_ref] [bib_ref] Asian Pacific Association for the Study of the Liver consensus statements on..., Mccaughan [/bib_ref] [bib_ref] Infections and thalassaemia, Vento [/bib_ref] [bib_ref] Mortality and causes of death in patients with hemophilia, 1992-2001: a prospective..., Plug [/bib_ref] [bib_ref] Correlates of spontaneous clearance of hepatitis C virus among people with hemophilia, Zhang [/bib_ref] [bib_ref] Non-invasive biomarkers of liver fibrosis in haemophilia patients with hepatitis C: can..., Maor [/bib_ref] Therefore, aggressive treatment of HCV infection should be considered and the combination therapy of peginterferon alpha and ribavirin is recommended. Therapeutic outcomes in both HCV infected cases with or without hemophilia were similar and there was no increase in complications regarding bleeding tendency. [bib_ref] Comparison of the efficacy of ribavirin plus peginterferon alfa-2b for chronic hepatitis..., Honda [/bib_ref] Severe anemia can occur due to ribavirin in thalassemia and up to 30-40% of cases may require blood transfusion to maintain 9-10 g/dL of hemoglobin at 3-4 week intervals. Therefore careful monitoring is required to confirm hematological complications. However, discontinuation of treatment or incidence of other main complications did not increased in these patients. [bib_ref] Asian Pacific Association for the Study of the Liver consensus statements on..., Mccaughan [/bib_ref] [Recommendation] [bib_ref] Occupational transmission of hepatitis C in healthcare workers and factors associated with..., Tomkins [/bib_ref]. The combination therapy of peginterferon alpha and ribavirin is recommended in treating chronic hepatitis C patients accompanying hemophilia or thalassemia (B1). ## Treatment of children with chronic hepatitis c A Korean study recruiting 2,080 children reported an anti-HCV positive rate of 0.82% in 1998. [bib_ref] The prevalence of anti-HCV positivity in healthy Korean children, Lee [/bib_ref] Transfusion of infected blood components or vertical transmission is the most common cause of HCV infection in children, [bib_ref] Evaluating progression of liver disease from repeat liver biopsies in children with..., Mohan [/bib_ref] although transfusion-related HCV transmission has been rarely reported after the introduction of screening test in 1991 in South Korea. The global HCV infection rate of pregnant women has been reported as 0.49-1.7%. [bib_ref] Transmission of hepatitis C virus from mothers to infants: its frequency and..., Moriya [/bib_ref] [bib_ref] Prospective reevaluation of risk factors in mother-to-child transmission of hepatitis C virus:..., Okamoto [/bib_ref] Korean studies including 5,000 pregnant women and another study on 20,000 pregnant women showed anti-HCV positive rate of 0.42-0.44%, where 57-60% of anti-HCV positive pregnant woman resulted in HCV RNA positive. [bib_ref] Hepatitis C virus infection in pregnancy, Kim [/bib_ref] [bib_ref] Prevalence of HCV infection in pregnant woman and vertical transmission, Kang [/bib_ref] Transmission of HCV was reported as 1-6.2% during the perinatal period [bib_ref] The management of HCV infected pregnant women and their children European paediatric..., Pembrey [/bib_ref] and the evidence of lowering the risk of vertical HCV transmission by Cesarean section is weak.An anti-HCV assay in children is recommended at over 18 months of age, since maternal antibodies can be delivered to newborns. [bib_ref] Risk factors for perinatal transmission of hepatitis C virus (HCV) and the..., Mast [/bib_ref] [bib_ref] Natural history of perinatal hepatitis C virus infection, Palomba [/bib_ref] HCV RNA assay may be performed at 1 or 2 months of age if an earlier diagnosis is desired, although the sensitivity of this assay is as low as 22% at that time; it is desirable to conduct the HCV RNA assay at the age over 6 months when the sensitivity reaches 85%. [bib_ref] Risk factors for perinatal transmission of hepatitis C virus (HCV) and the..., Mast [/bib_ref] [bib_ref] Accuracy of HCV-RNA PCR tests for diagnosis or exclusion of vertically acquired..., Polywka [/bib_ref] Spontaneous recovery is more frequent in children having high tendency of a normal ALT level 478 along with slow progress of hepatic fibrosis and, rarely, severe hepatic damage. However, aggressive treatment instead of waiting until the children grow has been suggested, since children usually have regular life cycle and show higher therapeutic compliance. Aggressive treatment is considered in case of continuously elevated serum AST/ALT or when progressed hepatic fibrosis is confirmed by liver biopsy. In addition, treatment can also be considered when serum AST/ALT is normal or fibrosis is mild by liver biopsy since evaluating tools of predicting disease progression are not sufficient in children. [bib_ref] NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants,..., Mack [/bib_ref] Although in the past studies on HCV infected children, treatment was limited to interferon alpha monotherapy due to the potential teratogenic effects of ribavirin, higher SVR rates have been reported with the addition of ribavirin to treatment http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2014.20.2.89 recently. [bib_ref] Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis..., González-Peralta [/bib_ref] [bib_ref] Recombinant alfa-interferon plus ribavirin therapy in children and adolescents with chronic hepatitis..., Wirth [/bib_ref] [bib_ref] Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis..., Wirth [/bib_ref] [bib_ref] The combination of ribavirin and peginterferon is superior to peginterferon and placebo..., Schwarz [/bib_ref] Therefore, most studies have adapted the combination therapy in children, since this approach is standard in adults. Use of peginterferon alpha in children over 3 years of age was approved in North America and Europe. [bib_ref] NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants,..., Mack [/bib_ref] The dose of peginterferon is 60 μg/m 2 /week for alpha-2b and 180 μg/1.73m 2 /week for alpha-2a and the dose of ribavirin is 15 mg/kg twice a day. Genotype 1 and 4 patients should be treated for 48 weeks and genotype 2 and 3 patients should be treated for 24 weeks, similar to adults. [bib_ref] NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants,..., Mack [/bib_ref] SVR rate after the combination therapy of peginterferon alphaand ribavirin (47-53% in genotype 1 and 80-100% in genotypes 2 and 3) is superior to that of the combination therapy of interferon alpha and ribavirin. [bib_ref] Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis..., Wirth [/bib_ref] [bib_ref] The combination of ribavirin and peginterferon is superior to peginterferon and placebo..., Schwarz [/bib_ref] Factors predicting SVR include genotype 2 and 3, and HCV RNA titer <600,000 IU/ mL. [bib_ref] Interferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis..., González-Peralta [/bib_ref] [bib_ref] The combination of ribavirin and peginterferon is superior to peginterferon and placebo..., Schwarz [/bib_ref] Efficacy and safety of boceprevir or telaprevir have not been proved yet in children <18 years of age. 422 ## [recommendations] 57. Diagnosis and evaluation of HCV in children should proceed following the similar steps as in adults (B1). 58. Anti-HCV assay in children is recommended at the age over 18 months since maternal antibodies can be delivered to newborns. If an earlier assay is required, HCV RNA assay may be considered after 6 months of age (B2). [bib_ref] Transmission of hepatitis C virus by occupational percutaneous injuries in South Korea, Ryoo [/bib_ref]. HCV infected children aged 3-17 years should be considered as appropriate treatment candidates according to the same criteria used in adults (B1). 60. The dose of peginterferon alpha is 60 μg/1.73 m 2 / week for 2b and 180 μg/1.73 m 2 /week for 2a and the dose of ribavirin is 15 mg/kg/day. Genotype 1 and 4 patients should be treated for 48 weeks and genotype 2 and 3 patients should be treated for 24 weeks (B1). [fig] Figure 1: Map of South Korea showing age and sex-adjusted anti-HCV seroprevalence in each area.11 [/fig] [fig] 80: in 2001, 3.19 in 2003, 2.69 in 2005, 1.83 in 2007, and 0.80 in 2009 per 100,000 person-year, showing significant decrease of HCV incidence in this population in South Korea. 14 According to surveillance sample data from the Korea Centers for Disease Control and Prevention (KCDC), the number of reported hepatitis C cases was 1,927 in 2002, 6,407 in 2008, and 4,280 in 2012. Future studies are needed for evaluation of nation- [/fig] [fig] [: Recommendations] 22. Optimal treatment of genotypes 1 and 4 (Fig. 2) 1) Treatment with one of two peginterferon alpha molecules in combination with ribavirin should be planned for 48 weeks (A1). Peginterferon alpha-2a should be injected 180 μg subcutaneous once a week, regardless of patient body weight with ribavirin using doses of 1,000 mg/d for those ≤75 kg in weight and 1,200 mg/day for those > 75 kg. Peginterferon alpha-2b is to be injected at 1.5 μg/kg/week with ribavirin using doses of 800 mg for those <65 kg in weight, 1,000 mg for 65-85 kg, 1,200 mg for 85-105 kg, and 1,400 mg for >105 kg (A1). [/fig] [fig] Figure 2: Treatment algorithm for patients with genotype 1 chronic HCV infection. This algorithm applies to genotype 4 at a B2 grade of evidence. The dotted lines indicated weaker strength of recommendation compared with the solid lines. * Negative factors for response include advanced liver fibrosis or cirrhosis, obesity, and insulin resistance. [/fig] [fig] Figure 3: Treatment algorithm for patients with genotype 2, 3 chronic HCV infection. The dotted lines indicate weaker strength of recommendation compared with the solid lines. * Negative factors for response may include advanced fibrosis, cirrhosis and others. ** The shortened therapy may result in higher relapse rate. Peginterferon + fixed dose ribavirin (800 mg///www.e-cmh.org http://dx.doi.org/10.3350/cmh.2014.20.2.89 [/fig] [table] Table 1: Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) [/table] [table] Table 3: Persons for whom HCV screening is recommended 114 http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2014.20.2.89 [/table] [table] Table 4: Comparison of scoring systems for histological stage114 [/table] [table] Table 6: Persons for whom therapy should be individualized 114 Acute hepatitis C No or mild fibrosis on liver biopsy Decompensated cirrhosis Liver transplant recipients Current users of illicit drugs or alcohol Chronic renal disease Co-infection with HIV Age <18 years [/table] [table] Table 5: Contraindications to treatment with peginterferon alpha and ribavirin 114 Uncontrolled psychiatric illness or depression Uncontrolled autoimmune disease Transplantation of solid organ except liver Untreated thyroid illness Pregnancy or unwilling to comply with adequate contraception Severe concurrent medical illness, such as poorly controlled hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes mellitus, and chronic obstructive pulmonary disease Age ≤ 2 years Hypersensitivity to peginterferon alpha or ribavirin http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2014.20.2.89 [/table] [table] Table 8: Predictors of SVR [/table] [table] Table 9: Adverse events of peginterferon alpha or interferon alpha and ribavirin [/table]	None	None	Practice Guidelines for Management of Hepatitis C were first established in 2004. Since then, many study results have been published concerned with epidemiology, clinical outcomes and related factors, concept of response-guided therapy, therapeutic strategy, and results. Moreover, as direct acting antivirals (DAA) have been recently developed and adapted to practice, treatment of hepatitis C is rapidly evolving. Therefore, the Korean Association for the Study of the Liver (KASL) revised the guidelines based on a systematic approach that reflects evidence-based medicine and expert opinions. The clinical practice guidelines for the management of hepatitis C have been revised to be useful for treatment, research, and education. These recommendations are not absolute standards of care, and adoption of the guidelines in clinical practice may differ for individual patients.
2a13baa2e0dacdcd8c27f2bbf10ecc48bb4e9761	pubmed	None	## Incidence and epidemiology Major salivary gland cancers (SGCs) comprise 5% of head and neck cancers in Europe. The worldwide crude and ageadjusted incidence rates are 0.69 and 0.57 cases per 100 000 people per year, respectively, with 53 583 new patients in 2020. In Europe, crude and age-adjusted incidence rates are 1.3 and 0.67 cases per 100 000 people per year, respectively, with 9917 new patients in 2020.Data for minor SGCs are limited, but the RARECARENet project estimated the crude incidence of minor salivary gland-type cancers of the head and neck to be 0.4 cases per 100 000 people in the 2000-2007 diagnosis period; minor SGCs have a slight predominance in males and incidence is highest in the elderly (>65 years).History of head and neck cancer and cervicofacial radiotherapy (RT) have both been associated with an increased risk of major SGC [odds ratio (OR) 17.06, 95% confidence interval (CI) 4.34-67.05 and OR 31.74, 95% CI 2.48-405. [bib_ref] Management of salivary gland tumours: United Kingdom National Multidisciplinary Guidelines, Sood [/bib_ref] , respectively]. [bib_ref] Risk factors for salivary gland cancers in France: results from a case-control..., Radoi [/bib_ref] [bib_ref] Current state of knowledge on salivary gland cancers, Lin [/bib_ref] Industries such as cereal and other crop production, furniture manufacturing, interurban road transport and industrial cleaning have also been associated with an increased risk of major SGC. [bib_ref] Risk factors for salivary gland cancers in France: results from a case-control..., Radoi [/bib_ref] [bib_ref] Current state of knowledge on salivary gland cancers, Lin [/bib_ref] [bib_ref] Air pollution from industrial waste gas emissions is associated with cancer incidences..., Cong [/bib_ref] Smoking only seems to increase the risk of developing major SGCs other than mucoepidermoid carcinoma (MEC) (OR 5.15, 95% CI 2.06-12.87) [bib_ref] Heterogeneous impact of smoking on major salivary gland cancer according to histopathological..., Sawabe [/bib_ref] ; however, ionising radiation is the only wellestablished risk factor. [bib_ref] Incidence of carcinoma of the major salivary glands according to the WHO..., Boukheris [/bib_ref] SGCs include >20 distinct histological subtypes. Given their rarity and heterogeneity, population-based epidemiological studies providing incidence rates according to histology are limited. SGC typically occurs in the sixth and seventh decades of life and has a male predominance 2 ; however, age at diagnosis and gender predominance vary by histology. MEC, adenoid cystic carcinoma (AdCC) and acinic cell carcinoma (AcCC) tend to occur at an earlier age than adenocarcinoma and squamous cell carcinoma (SCC). MEC, AdCC and AcCC are more common in females up to w50 years of age; however, incidence of AdCC and AcCC is similar for females and males at older ages, whereas MEC has a higher incidence rate among older males. [bib_ref] Incidence of carcinoma of the major salivary glands according to the WHO..., Boukheris [/bib_ref] The ratio of tumour diagnoses in parotid, submandibular, minor and sublingual subsites is 100:10:10:1, and the proportion of malignant tumours at these sites is 20%, 50%, 50% and 80%, respectively. [bib_ref] Incidence of salivary gland neoplasms in a defined UK population, Bradley [/bib_ref] SGC incidence has not increased between 1995 and 2007 in Europe 10 or between 1995 and 2010 in the United States. [bib_ref] Incidence of carcinoma of the major salivary glands according to the WHO..., Boukheris [/bib_ref] The 5-year relative survival rate (estimated as the ratio of observed to expected survival in the general population, matched by age, sex, calendar year and geographical area) for patients with major SGC is 63% (95% CI 62% to 63.7%) in Europe. [bib_ref] Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet..., Gatta [/bib_ref] This decreases with age, from w90% (95% CI 91% to 97%) in patients aged <25 years, to 70% (95% CI 69% to 71%) in patients aged 25-64 years and 53% (95% CI 52% to 55%) in those aged >65 years. Five-year relative survival is higher in females (72%, 95% CI 71% to 74%) than in males (55%, 95% CI 54% to 56%). Furthermore, 5-year relative survival differs across European regions, with the highest rate of 74% (95% CI 71% to 78%) reported in Nordic countries (Finland, Iceland, Norway) and the lowest rate of 52% (95% CI 50% to 54%) reported in Eastern European countries (Bulgaria, Czech Republic, Estonia, Latvia, Lithuania, Poland, Slovakia). SGC relative survival has not improved in Europe between 1999 and 2007.The 5-year relative survival rate for minor salivary glandtype cancers of the head and neck is 67% and is higher in females than in males. Five-year survival rates are highest in children (>90%) and patients aged <25 years, and then decrease to 60% in patients aged >65 years. In Europe during the period 1999-2007, 5-year survival remained stable and was highest in Nordic countries (84%) and lowest in Eastern European countries (55%). ## Diagnosis, pathology and molecular biology SGC should be classified according to the World Health Organization (WHO) Classification of Head and Neck Tumours.Including both benign and malignant tumours, there are over 30 distinct salivary gland tumour types in the latest WHO classification system (see , available at https://doi.org/10.1016/j.esmoop. 2022.100602, for classification of the malignant tumour types). ## Diagnostic work-up The symptoms of SGC depend on tumour location. Symptoms that should prompt consideration of SGC include pain in the face or mouth, an externally or submucosally growing lump or (facial) nerve paralysis. Cytology or histology is mandatory. Ultrasound-guided salivary gland fine-needle aspiration (FNA) cytology has become the accepted minimally invasive method for evaluating parotid and submandibular gland tumours preoperatively. This can distinguish malignant from benign disease in 90% of cases if examined by a pathologist experienced in salivary gland disease.The Milan system for reporting salivary gland cytopathology is recommended. It facilitates standardised reporting and links each diagnostic category to a risk of malignancy (ROM); risks were recently confirmed in a large meta-analysis. [bib_ref] Retrospective assessment of the effectiveness of the Milan system for reporting salivary..., Farahani [/bib_ref] The Milan system facilitates ROMassociated therapeutic approaches, e.g. initial treatment can be intensified when high-grade malignancy is suspected (one study reported 99% diagnostic accuracy 14 ) (see , available at https://doi.org/10. 1016/j.esmoop.2022.100602).If FNA is non-diagnostic or if the clinical situation requires more information on histotype, core needle biopsy, while more demanding and with a slightly increased risk of complications, [bib_ref] Evaluation: fine needle aspiration cytology, ultrasound-guided core biopsy and open biopsy techniques, Howlett [/bib_ref] has less inadequate sampling (risk ratio 0.85) and a higher diagnostic yield than FNA. [bib_ref] Comparison of core needle biopsy and fineneedle aspiration in diagnosis of malignant..., Cho [/bib_ref] It is thus an accepted next step in the diagnostic work-up. [bib_ref] Fine-needle aspiration with selective use of core needle biopsy of major salivary..., Romano [/bib_ref] Open biopsies should be avoided in major salivary gland lesions due to the risk of complicating definitive surgical treatment and the risk of spillage, with the exception of skin ulcerating tumours. For minor salivary gland tumours, an experienced surgeon should take a biopsy of the tumour and surrounding stroma. [bib_ref] Why is the histomorphological diagnosis of tumours of minor salivary glands much..., Ihrler [/bib_ref] Incisional biopsy is recommended for submucosally extending tumours, and an incisional or forceps biopsy should be taken for ulcerating lesions. Ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and [ 18 F]2-fluoro-2-deoxy-D-glucosee positron emission tomography (FDGePET) are the imaging techniques most commonly used to assess lesions in the major salivary glands, with MRI being the preferred modality (see [fig_ref] Figure 1: Work-up of major salivary gland nodules [/fig_ref]. Diagnostic imaging techniques are described in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2022.100602. ## Histological tumour type and molecular biology The SGC histological type essentially defines its biological behaviour, which influences prognosis and patterns of recurrence, and thus clinical management. Some SGC types, such as basal cell adenocarcinoma, lowgrade MEC, intraductal carcinoma and conventional AcCC, are indolent, with high risk of locoregional recurrence but low rates of nodal involvement and distant metastases. [bib_ref] An update on grading of salivary gland carcinomas, Seethala [/bib_ref] Immunohistochemistry (IHC) on the surgical specimen provides supplementary visualisation of cell compartments and cell populations, thus improving SGC taxonomy. The role of molecular diagnostics in SGC is evolving. Many monomorphic SGCs are now known to harbour defining balanced translocations, some of which are readily evaluable on paraffin-embedded materials either by FISH, RTePCR or next-generation sequencing (NGS). [bib_ref] The role of molecular testing in the differential diagnosis of salivary gland..., Skalova [/bib_ref] Recently, NGS has provided significant input on the molecular characterisation of SGC subtypes, improving diagnostic differentiation between morphologically similar tumour types and also identifying novel driver pathways that determine tumour biology and which may be amenable to targeted pathological findings, especially FNA. Pathological staging is carried out after surgical resection of the primary tumour. There is currently no clear recommendation on differential staging of intraparotid versus cervical nodal metastases; findings from a recent study suggest that these differences should be addressed in future editions of the TNM classification. [bib_ref] The impact of nodal status in major salivary gland carcinoma: a multicenter..., Lombardi [/bib_ref] Pathological report and staging For correct management of major SGC, the pathological report should follow the International Collaboration on Cancer Reporting guidelines. [bib_ref] Data set for the reporting of carcinomas of the major salivary glands:..., Seethala [/bib_ref] Operative procedure; specimens submitted; tumour site, focality and dimensions; histological tumour type and grade; perineural invasion; lymphovascular invasion; extent of invasion and margin status are required (see Section 3 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop. 2022.100602). [bib_ref] Data set for the reporting of carcinomas of the major salivary glands:..., Seethala [/bib_ref] The UICC pathological TNM (pTNM) staging system for SGC of the major salivary glands is presented in Supplementary ## Surgery Surgical management of the primary in parotid gland cancer. The treatment of parotid gland cancer is based on complete surgical excision with free margins. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] The difficulty of this surgery lies in achieving free margins without functional and aesthetic sequelae. Revision surgery following an unexpected post-operative diagnosis of malignancy carries a great risk to an already dissected facial nerve; therefore, every effort should be made to identify malignancy preoperatively, allowing for immediately adequate surgical removal. [bib_ref] Management of salivary gland tumours: United Kingdom National Multidisciplinary Guidelines, Sood [/bib_ref] It is imperative, if preoperative MRI, FNA or core needle biopsy suggests malignancy, to warn the patient of a possibly more extensive procedure. In case of extraparotid or facial nerve extension, an extended surgery sacrificing these elements [e.g. seventh nerve (nVII), infratemporal fossa, mandible, skin] with possible reconstruction must be considered. Functional or aesthetic disorders arising from resection should be considered during treatment planning. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] Resectability should be assessed in a multidisciplinary team meeting, bearing in mind that surgery, if possible, is the optimal treatment. A cancer should be considered unresectable if macroscopic tumour is likely to be left behind. The reference procedure is a total parotidectomy. For low-grade, early-stage (cT1-T2N0) tumours in the superficial lobe, a superficial parotidectomy can suffice, especially if malignancy is a post-operative discovery on the definitive histology. For advanced-stage (all but cT1-T2N0) and/or preoperatively known intermediate-or high-grade tumours, a total parotidectomy is preferable. No consensus exists in the literature on how many millimetres thick a margin must be to be considered 'free'. The presence or absence of facial nerve paralysis before surgery influences the choice of procedure: it is logical to try to preserve the facial nerve if there is no preoperative paralysis and to sacrifice it in case of preoperative paralysis. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] In the absence of preoperative paralysis and in case of intra-operative macroscopic invasion of the facial nerve, sacrifice or preservation of the nerve is decided on a caseby-case basis, depending on the histology of the tumour and extent of invasion of the nerve, as well as the age and wishes of the patient. It is important to collect as much information as possible about the tumour before surgery, discuss scenarios with the patient and be able to do a graft during the ablative procedure. A remote dissection of the nerve branches with an extended resection and frozen section analysis of the nerve section limits may be necessary, especially in AdCC, which is characterised by tumour extensions along and in nerves. [bib_ref] Adenoid cystic carcinoma: a review of recent advances, molecular targets, and clinical..., Dillon [/bib_ref] Preoperative facial paralysis is a major negative prognostic factor. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] It imposes a wide surgery with often unsatisfactory excisional limits. Addressing the nerve deficit during resection is the appropriate therapeutic approach. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] [bib_ref] Reconstruction of facial nerve after radical parotidectomy, Renkonen [/bib_ref] Surgical management of the primary in minor SGC and cancer of the sublingual gland. Minor SGC, a rare entity, may arise in all mucous membranes of the head and neck (including the nasal cavity, nasopharynx, oropharynx, hypopharynx, cervical oesophagus, larynx, trachea and oral cavity). Cancer of the sublingual gland is 10 times less frequent than minor SGC. 9 ## Esmo open C. van Herpen et al. Surgery is the mainstay of treatment for primary resectable disease with the traditional open approach being the most widely used, although endoscopic and robot-assisted approaches have recently been described. [bib_ref] National analysis of oropharyngeal salivary gland malignancies treated with transoral robotic surgery, Bollig [/bib_ref] In a series of 450 patients with minor SGC, multivariate analysis showed advanced clinical stage and unfavourable histological subtype to be associated with poor disease-specific survival. [bib_ref] Minor salivary gland tumors of the head and neck-Memorial Sloan Kettering experience:..., Hay [/bib_ref] This was confirmed in a large Surveillance, Epidemiology and End Results (SEER) database study of 1426 patients with minor SGC of the oropharynx. [bib_ref] Minor salivary gland carcinoma of the oropharynx: a population-based analysis of 1426..., Goel [/bib_ref] It is generally accepted that a 1-cm free margin is adequate in most tumours; however, it is often the case that only millimetric margins are achievable. AdCC is particularly known for perineural spread (as described earlier), requiring detailed surgical planning and wide margins, including resection of bony structures. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] Surgical management of the primary in submandibular gland cancer. The most common submandibular gland malignant tumour type is AdCC. [bib_ref] Patterns of lymph node metastasis and their influence on outcomes in patients..., Han [/bib_ref] [bib_ref] Submandibular gland cancer: specific features and treatment considerations, Aro [/bib_ref] Tumours confined within the submandibular gland require resection of the gland and the surrounding level Ib lymph nodes to ensure negative margins. In case of high-grade malignancy without clinical evidence of cervical lymph node involvement, selective neck dissection involving level I, II and III lymph nodes is standard procedure as the prevalence of cervical lymph node metastasis in submandibular gland malignancies is high, exceeding that of the parotid malignancies. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] [bib_ref] Submandibular gland cancer: specific features and treatment considerations, Aro [/bib_ref] [bib_ref] Prognostic factors for long term results of the treatment of patients with..., Vander Poorten [/bib_ref] Careful surgical planning is needed for AdCC, as clear margin surgery may require resection of important structures such as the lingual, hypoglossal and marginal mandibular nerves, floor of the mouth muscles and the skin. Although the risk of nodal metastasis in AdCC is low, this tumour has a propensity for infiltrating the adjacent lymph nodes and perineural spread. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] [bib_ref] Patterns of lymph node metastasis and their influence on outcomes in patients..., Han [/bib_ref] [bib_ref] Submandibular gland cancer: specific features and treatment considerations, Aro [/bib_ref] While it can be difficult to distinguish between direct invasion and embolic lymph node metastasis, some studies have identified a higher nodal spread than expected. [bib_ref] Patterns and treatment of neck metastases in patients with salivary gland cancers, Yoo [/bib_ref] Elective neck dissection (END) for submandibular gland malignancies should be planned based on cytological and radiological findings. Whenever malignancy is suspected, frozen section analysis can dictate extension of surgery locally and to involve at least level Ib but most frequently level I, II and III lymph nodes. 32 Management of the cND neck in salivary gland malignancies. The reported incidence of positive neck nodes in parotid carcinomas varies between 10% and 40% and they occur more frequently in patients with high-grade malignancy, advanced T status, facial nerve involvement and extraglandular invasion. [bib_ref] High incidence of lymph node metastasis in major salivary gland cancer, Stennert [/bib_ref] [bib_ref] Major and minor salivary gland tumors, Guzzo [/bib_ref] The most frequently involved lymph node levels are II, III and IV 38 ; however, involvement of levels I and V is also non-negligible. [bib_ref] Patterns and treatment of neck metastases in patients with salivary gland cancers, Yoo [/bib_ref] [bib_ref] Treatment of the neck in carcinoma of the parotid gland, Ali [/bib_ref] When carrying out therapeutic neck dissection for clinically or radiologically positive lymph nodes (cNþ), the recommendation is to carry out a comprehensive neck dissection of levels I-V. [bib_ref] Patterns and treatment of neck metastases in patients with salivary gland cancers, Yoo [/bib_ref] [bib_ref] Treatment of the neck in carcinoma of the parotid gland, Ali [/bib_ref] The incidence of lymph node metastasis for submandibular carcinomas at initial presentation is around 8%-33%. [bib_ref] The indications for elective treatment of the neck in cancer of the..., Armstrong [/bib_ref] Positive lymph nodes are often found in level I followed by levels II and III, although all lymph nodes can be involved with the possibility for skip metastases in levels IV and V. Some series have even shown positive lymph node involvement of 40% and 25% in levels IV and V, respectively, warranting a level I-V neck dissection for submandibular gland carcinomas with cNþ disease. [bib_ref] Patterns of lymph node metastasis and their influence on outcomes in patients..., Han [/bib_ref] For minor SGC, the same applies, but depending on the origin of the primary, lymph nodes outside the neck may be involved that are relatively inaccessible for surgery, such as retropharyngeal or mediastinal nodes. END for the cN0 neck in parotid gland carcinoma. In a cN0 neck parotid gland carcinoma with clinical and histopathological factors indicating a 15%-20% chance of occult regional metastasis, END is strongly recommended. Clinical prognostic factors for pathologically positive lymph nodes (pNþ) are age >54 years, pain, nVII dysfunction and >T2 status. [bib_ref] Predicting occult lymph node metastasis in parotid cancer, Frankenthaler [/bib_ref] [bib_ref] Multivariate analysis of risk factors for neck metastases in surgically treated parotid..., Santos [/bib_ref] A study using END in T1-T2 N0 patients reported a cN0 pNþ rate of 17%. [bib_ref] Occurrence of lymph node metastasis in early-stage parotid gland cancer, Stenner [/bib_ref] ## Esmo open AdCC. [bib_ref] High incidence of lymph node metastasis in major salivary gland cancer, Stennert [/bib_ref] [bib_ref] The indications for elective treatment of the neck in cancer of the..., Armstrong [/bib_ref] AcCC and low-grade MEC were previously considered to have low pNþ rates but routine ENDs have revealed higher than expected rates, especially for highgrade AcCC. [bib_ref] High incidence of lymph node metastasis in major salivary gland cancer, Stennert [/bib_ref] [bib_ref] Patterns of lymph node spread and its influence on outcome in resectable..., Klussmann [/bib_ref] [bib_ref] Treatment of the neck in carcinoma of the parotid gland, Ali [/bib_ref] [bib_ref] Occurrence of lymph node metastasis in early-stage parotid gland cancer, Stenner [/bib_ref] [bib_ref] Indication for elective neck dissection for N0 carcinoma of the parotid gland:..., Kawata [/bib_ref] [bib_ref] Salivary acinic cell carcinoma: reappraisal and update, Vander Poorten [/bib_ref] Regarding the best treatment strategy, some clinicians use END followed by postoperative RT, while others prefer to use elective neck irradiation (ENI) (see RT section). [bib_ref] Predicting occult lymph node metastasis in parotid cancer, Frankenthaler [/bib_ref] [bib_ref] Patterns of nodal involvement for clinically N0 salivary gland carcinoma: refining the..., Lau [/bib_ref] [bib_ref] The role of radiotherapy in the treatment of malignant salivary gland tumors, Terhaard [/bib_ref] [bib_ref] Patterns of nodal relapse after surgery and postoperative radiation therapy for carcinomas..., Chen [/bib_ref] [bib_ref] Elective neck management for high-grade salivary gland carcinoma, Herman [/bib_ref] Some clinicians propose a routine END for every patient with suspected or known parotid gland cancer; reported rates of cN0 pNþ range from 22% to 45% in series where all patients underwent END. [bib_ref] High incidence of lymph node metastasis in major salivary gland cancer, Stennert [/bib_ref] [bib_ref] Occurrence of lymph node metastasis in early-stage parotid gland cancer, Stenner [/bib_ref] [bib_ref] Elective neck dissection versus observation in primary parotid carcinoma, Zbaren [/bib_ref] [bib_ref] Head and neck salivary gland carcinomas-elective neck dissection, yes or no?, Nobis [/bib_ref] The lymph node levels to address are II, III and IV. 39,40 A significant proportion (53%-80%) of patients with pNþ disease on neck dissection will also have metastatic deposits in the 'first echelon' intraparotid lymph nodes (see earlier Surgical management of the primary in parotid gland cancer section). [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] [bib_ref] The indications for elective treatment of the neck in cancer of the..., Armstrong [/bib_ref] [bib_ref] Deep lobe parotidectomy: clinical rationale in the management of primary and metastatic..., Olsen [/bib_ref] In one study, 1-11 parotid lymph nodes were retrieved, with 80% of parotid nodes involved in cN0 pNþ patients. [bib_ref] Patterns of lymph node spread and its influence on outcome in resectable..., Klussmann [/bib_ref] There is still no direct evidence that resection of these nodes increases locoregional control. Taken together, three scenarios exist: 1. Low risk of occult nodal disease (T1-T2 tumours, lowgrade tumours, young patients) After resection of the primary, a watch-and-wait policy to the neck can be defended [bib_ref] Treatment of the neck in carcinoma of the parotid gland, Ali [/bib_ref] Most clinicians will carry out a level II dissection with frozen section, converting into a comprehensive neck dissection in the rare pNþ cases, [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] END for the cN0 neck in minor SGC. For minor SGC, when the neck is surgically entered as an approach to the primary, it is logical to also address the neck surgically. The occult metastatic rate for laryngeal, sinonasal, external acoustic meatus and lacrimal gland origin is too low to justify END. In oral cavity (levels I, II, III and IV) and oropharyngeal (levels II, III and IV) minor SGC, and in high-grade MEC and AdCC, the occult rates largely exceed 20% and END is indicated. [bib_ref] Recent trends in the management of minor salivary gland carcinoma, Vander Poorten [/bib_ref] [bib_ref] Cervical lymph node metastasis in high-grade transformation of head and neck adenoid..., Hellquist [/bib_ref] END is frequently advocated for all high-stage and high-grade tumours. In a recent French study, however, no benefit in terms of event-free survival was demonstrated when comparing patients with cN0 AdCC undergoing END with those who did not, except when the site of origin was the oral cavity. In this series, the majority (58%) of 322 cases were of minor salivary gland origin. [bib_ref] Should a neck dissection be performed on patients with cN0 adenoid cystic..., Atallah [/bib_ref] In a large series of 3005 patients with MEC of the oral cavity and oropharynx, END was associated with a survival benefit for patients with high-grade and clinical stage T3-4 disease. [bib_ref] Prognostic factors and occult nodal disease in mucoepidermoid carcinoma of the oral..., Ellis [/bib_ref] END for the cN0 neck in submandibular gland carcinoma. For preoperatively known submandibular gland cancers with otherwise cN0 neck, inclusion of the submandibular gland in a selective neck dissection (levels I, II and III) is considered the standard procedure, revealing occult metastasis rates of 21%-23%. [bib_ref] Prognostic factors for long term results of the treatment of patients with..., Vander Poorten [/bib_ref] [bib_ref] Patterns of nodal involvement for clinically N0 salivary gland carcinoma: refining the..., Lau [/bib_ref] [bib_ref] Perez & Brady's Principles and Practice of Radiation Oncology, Halperin [/bib_ref] The use of intensity-modulated RT (IMRT) or volumetric modulated arc therapy (VMAT) is recommended. For parotid gland cancer invading the deep lobe, the infratemporal fossa and the parapharyngeal space should be included in the field. After incomplete resection, a dose of 33 Â 2 Gy is described for the primary tumour region plus a 1 cm margin, with 30 Â 2 Gy after a clear resection. [bib_ref] Patterns of nodal involvement for clinically N0 salivary gland carcinoma: refining the..., Lau [/bib_ref] [bib_ref] Perez & Brady's Principles and Practice of Radiation Oncology, Halperin [/bib_ref] In case of extensive perineural invasion the nerve pathway to the base of the skull should be delineated. [bib_ref] Guidelines for clinical target volume definition for perineural spread of major salivary..., Armstrong [/bib_ref] Indications for ENI (25 Â 2 Gy over 5 weeks) are the same as the indications for END. In general, ENI is indicated in case of T3-T4 cN0 tumours and high-or intermediate-grade subtypes, and also depends on the primary site. [bib_ref] Perez & Brady's Principles and Practice of Radiation Oncology, Halperin [/bib_ref] The ipsilateral neck node levels II and III should be treated in parotid gland tumours and ipsilateral levels I, II and III in submandibular gland tumours. Bilateral ENI is indicated for tumours crossing the midline. For minor SGC, the highest risk for subclinical neck disease is a pharyngeal location, high-grade disease and T3-T4 tumours. Ipsilateral ENI is recommended for levels I, II and III. Post-operative RT is indicated for all cases of pNþ neck. A dose of 30 Â 2 Gy is recommended for the involved level, and 33 Â 2 Gy in case of extranodal disease. For the ipsilateral elective levels I-V, a dose of 25 Â 2 Gy is recommended. [bib_ref] Perez & Brady's Principles and Practice of Radiation Oncology, Halperin [/bib_ref] Combining post-operative RT with chemotherapy. There are no large series analysing the role of combined chemotherapy (ChT) and RT in the post-operative setting in SGC. In the phase II Radiation Therapy Oncology Group (RTOG) 1008 study (NCT01220583) both scenarios are being compared, but no results are available yet. Combining post-operative ChT with RT in major SGC has been evaluated retrospectively using data from the US National Cancer Database. The addition of ChT was restricted to late-stage tumours with adverse features and did not result in a survival benefit. [bib_ref] Adjuvant therapy in major salivary gland cancers: analysis of 8580 patients in..., Cheraghlou [/bib_ref] In a retrospective cohort study, platinum-based post-operative chemoradiotherapy (n ¼ 37) was compared with post-operative RT only (n ¼ 103). In the chemoradiotherapy group, more patients had Nþ disease, positive surgical margins and perineural invasion. In multivariate analysis, progressionfree survival (PFS) was not improved by the addition of ChT. [bib_ref] Adjuvant radiotherapy versus concurrent chemoradiotherapy for the management of highrisk salivary gland..., Mifsud [/bib_ref] Comparable results were reported in a subset of patients with high-risk SGC. [bib_ref] Concurrent chemoradiotherapy in the adjuvant treatment of high-risk primary salivary gland malignancies, Gebhardt [/bib_ref] [bib_ref] Association of adjuvant chemoradiotherapy vs radiotherapy alone with survival in patients with..., Amini [/bib_ref] In an ongoing phase III, multicentre, randomised, open-label, French study, postoperative or primary RT alone is being compared with concomitant RT plus cisplatin on days 1, 22 and 43 for SGC and nasal cancer. No results are available yet. [bib_ref] A rationale for chemoradiation (vs radiotherapy) in salivary gland cancers? On behalf..., Cerda [/bib_ref] The level of evidence for combining ChT with RT is low and this treatment is not recommended outside of a clinical study. Primary RT for unresectable SGC. The primary treatment for SGC without distant metastasis is surgery with postoperative RT when indicated; however, curative primary RT is indicated for patients with functionally unresectable disease or who are unsuitable for surgery due to comorbidities. Taking locoregional control, survival and complications into account, the treatment options are photon treatment or particle treatment with protons, neutrons or carbon ions (C12). In most institutes, primary photon therapy up to 70 Gy is still applied. Particle treatment, particularly C12 and especially for AdCC and tumours involving the base of the skull, may be an alternative with a potentially higher locoregional cure rate compared with photons; however, these treatment options have limited availability. The literature supporting the use of particle treatment is described in Section 5 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2022.100602. No randomised studies have been carried out to compare primary treatment with chemoradiotherapy versus RT alone. Most published studies report small series with different histological subtypes, using a variety of ChT regimens. [bib_ref] Concurrent chemoradiotherapy in the adjuvant treatment of high-risk primary salivary gland malignancies, Gebhardt [/bib_ref] There is currently no evidence to support the combination of particle therapy and simultaneous ChT in SGC. 65 ## Esmo open ## Management of locally recurrent and metastatic disease ## Rt RT may be used for the management of locally recurrent disease and/or for palliation. RT for recurrent disease. Local recurrence within the highdose area following initial RT remains a challenge. When surgery is not an option, systemic treatments (either ChT or targeted agents) offer limited benefit with very moderate overall response rates and are therefore rarely successful in alleviating local symptoms. Before the introduction of particle therapy, re-irradiation with photons was used with utmost caution, especially in anatomically challenging sites. Meanwhile, three groups have shared their experience of reirradiation using scanned C12 in SGC, [bib_ref] Reirradiation of salivary gland tumors with carbon ion radiotherapy at CNAO, Vischioni [/bib_ref] [bib_ref] Feasibility of re-irradiation using carbon ions for recurrent head and neck malignancies..., Hayashi [/bib_ref] [bib_ref] Re-irradiation of adenoid cystic carcinoma: analysis and evaluation of outcome in 52..., Jensen [/bib_ref] reporting 1-year and 2-year overall survival (OS) rates of up to 90% and 64%, respectively, although late toxicities were observed. Based on these studies, re-irradiation with C12 appears feasible with response rates of around 60% and moderate toxicities in heavily pre-treated patients; however, C12 has limited availability in Europe. Protons are becoming more widely available, but evidence is lacking to support the added value. Further dose escalation should be employed cautiously. There is no evidence to support the combination of re-irradiation and ChT for primary treatment of SGC. RT for palliation. In the RTOG 8502 study, an RT regimen of 4 Â 3.7 Gy over 2 days was repeated in cycles of 4 weeks. Seven out of 75 patients had salivary gland histology. Palliative response was observed in 65% of patients, significantly correlating with the number of cycles. [bib_ref] Palliative head and neck radiotherapy with the RTOG 8502 regimen for incurable..., Lok [/bib_ref] For palliative RT of head and neck cancer, the 'Christie scheme' (16 Â 3.125 Gy over 4 weeks) resulted in a 45% complete response rate and 28% partial response rate. [bib_ref] Hypofractionated radiotherapy denoted as the "Christie scheme": an effective means of palliating..., Tans [/bib_ref] This schedule may also be considered in patients with metastatic SGC with a relatively long life expectancy. For patients with AdCC or AcCC and a WHO performance status score of 0-1, an even more prolonged RT schedule for palliation of locoregional disease or symptomatic distant metastases might be considered. Nevertheless, in case of short life expectancy or a WHO performance status of 2-3, a short fractionation schedule is usually preferred. Oligometastatic disease. For oligometastatic disease, locoregional treatments such as surgery, 71-73 radiofrequency ablation 74 or stereotactic RT 75 can be considered in selected cases, especially in AdCC. In one study, a prolonged diseasefree interval (>36 months) and radical resection were the main prognostic factors in 109 patients with AdCC and lung metastases who underwent metastasectomy. [bib_ref] Lung metastasectomy in adenoid cystic cancer: is it worth it?, Girelli [/bib_ref] Systemic treatment for recurrent and/or metastatic disease In case of R/M disease, systemic treatment is challenging but can be urgent, depending on tumour subtype and behaviour. For all types of SGC with distant metastases (71% of patients will present or develop R/M disease), median OS is 15 months and 1-, 3-and 5-year OS rates are 54.5%, 28.4% and 14.8%, respectively. [bib_ref] Risk factors and survival associated with distant metastasis in patients with carcinoma..., Nam [/bib_ref] This, however, varies widely between subtypes. The rarity of SGC and its extensive heterogeneity hinders large-scale patient accrual in prospective trials. The number of clinical trials evaluating systemic therapy in R/M SGC is low and their interpretation is difficult because most phase II studies include all SGC subtypes, pathological review for correct histopathological subtyping is missing and data on efficacy are not presented by subtype. [bib_ref] Advances and challenges in precision medicine in salivary gland cancer, Lassche [/bib_ref] An overview of targeted therapies evaluated in SGC is presented in Supplementary MEC. The reported risk of distant metastasis in MEC is 16% at 10 years. [bib_ref] Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and..., Terhaard [/bib_ref] In R/M MEC, responses with cisplatin alone or in combination with other agents [e.g. cisplatineadriamycinecyclophosphamide (CAP) or cisplatinegemcitabine] and paclitaxel as monotherapy have been observed in small patient cohorts (three responses on paclitaxel monotherapy in 14 patients in the largest MEC cohort). [bib_ref] Systemic therapy in metastatic salivary gland carcinomas: a pathology-driven paradigm?, Alfieri [/bib_ref] The CRTC1-MAML2 gene fusion, which is commonly present in MECs, causes up-regulation of the epidermal growth factor receptor (EGFR) ligand amphiregulin, [bib_ref] Aberrantly activated AREG-EGFR signaling is required for the growth and survival of..., Chen [/bib_ref] suggesting a potential role for EGFR inhibitors. Reports of clinical benefit with an EGFR inhibitor in patients with MEC are, however, anecdotal and require further investigation. AdCC. To date, no systemic treatment has been shown to improve OS in patients with R/M AdCC. Metastatic AdCC is generally characterised by multiple locoregional recurrences accompanied by distant metastases in about half of cases. The lung is the most common site of distant spread followed by the lymph nodes, bone, liver, etc. Despite these characteristics, survival of patients with R/M AdCC is generally prolonged, with an OS rate of 40% at 10 years. [bib_ref] Lung metastasectomy in adenoid cystic cancer: is it worth it?, Girelli [/bib_ref] In this context, active surveillance could be a rational proposal in highly selected patients (asymptomatic, low tumour burden, lung metastases and stable disease). Lung metastasectomy should be considered in patients without other R/M tumour deposits, provided that a complete surgical resection is feasible and disease-free interval from primary diagnosis is >36 months. [bib_ref] Lung metastasectomy in adenoid cystic cancer: is it worth it?, Girelli [/bib_ref] Systemic treatment should be reserved for patients with progressive and/or symptomatic disease that is not otherwise manageable. A cisplatin-based regimen seems to guarantee the highest response rate: 13% with cisplatin alone and 25% (95% CI 11% to 39%) with CAP. [bib_ref] Systemic therapy in the management of metastatic or locally recurrent adenoid cystic..., Laurie [/bib_ref] Duration of response ranges widely from 7 to 77 months. Carboplatin seems to have limited activity, and no response has been reported with paclitaxel or gemcitabine. [bib_ref] Systemic therapy in the management of metastatic or locally recurrent adenoid cystic..., Laurie [/bib_ref] Compounds tailored for actionable targets such as EGFR, KIT and fibroblast growth factor receptor have failed to demonstrate any activity. [bib_ref] Systemic therapy in metastatic salivary gland carcinomas: a pathology-driven paradigm?, Alfieri [/bib_ref] Strategies focused on pathogenetic targets seem more promising. Clinical trials are currently evaluating two agents with different strategies: CB103, which targets NOTCH oncogene transcription factors (NCT03422679), and AL101, which inhibits gamma secretase (ACCURACY; NCT03691207). Partial response was observed in 15% of patients (6/39) treated with AL101 at 4 mg, and further drug titration is being studied. [bib_ref] 919MO ACCURACY a phase II trial of AL101, a selective gamma secretase..., Ferrarotto [/bib_ref] Trials targeting MYB, the hallmark of AdCC, are underway. A study combining MYB DNA vaccination with anti-programmed cell death protein 1 immunotherapy is currently recruiting patients (MYPHISMO; NCT03287427). Antiangiogenic agents (sorafenib, lenvatinib and axitinib) have been investigated in recent years, but response rates did not exceed 15% 79 (see , available at https://doi.org/10. 1016/j.esmoop.2022.100602). In this context, axitinib was the first agent to demonstrate a significant PFS prolongation compared with placebo in a phase II randomised trial (hazard ratio 0.25, 95% CI 0.14-0.48), [bib_ref] Randomized phase II study of axitinib versus observation in patients with recurred..., Kang [/bib_ref] becoming the new backbone for future trials. The activity of immune checkpoint inhibitors alone is null in patients with R/M AdCC. [bib_ref] Systemic therapy in metastatic salivary gland carcinomas: a pathology-driven paradigm?, Alfieri [/bib_ref] Given the disappointing results of systemic treatments, participation in clinical trials is strongly recommended. ## Esmo open AcCC. Distant metastases occur in 19% of patients with AcCC. No data on ChT are available and the role of the HTN3-MSANTD3 fusion gene (present in 4% of patients) is unknown and not targetable yet. Nevertheless, NTRK gene fusion analysis must be carried out in patients with R/M AcCC because secretory carcinoma is often misclassified as AcCC, and tumours with NTRK fusion genes respond extremely well to targeted therapy (see below). Polymorphous adenocarcinoma. The prognosis of patients with polymorphous adenocarcinoma is generally good and distant metastases are rare, reported in only 4.3% of patients at presentation. [bib_ref] Polymorphous adenocarcinoma of the salivary glands: reappraisal and update, Vander Poorten [/bib_ref] No data on ChT or targeted therapy are available. Adenocarcinoma NOS. CAP, paclitaxel monotherapy and gemcitabine or vinorelbine in combination with cisplatin have led to limited response rates in adenocarcinoma NOS. If the tumour is androgen receptor positive and/or has HER2 amplification, it is most likely a salivary duct carcinoma and must be treated in the same way as salivary duct carcinoma (see below). [bib_ref] Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCs), Locati [/bib_ref] Salivary duct carcinoma. Fifty-four percent of patients with salivary duct carcinoma treated with curative intent will develop locoregional recurrences and/or distant metastases. In patients with distant metastases, spread to lungs (54%) and bones (46%) has been reported most frequently, but a high rate of brain metastasis has also been observed (18%). [bib_ref] Systemic therapy in the management of recurrent or metastatic salivary duct carcinoma:..., Uijen [/bib_ref] Given the dismal prognosis and high prevalence of distant metastasis (also in case of local or locoregional recurrence), systemic therapy is often required. The median OS for patients with R/M disease receiving best supportive care is only 5 months. [bib_ref] Androgen deprivation therapy for androgen receptor-positive advanced salivary duct carcinoma: a nationwide..., Boon [/bib_ref] Agents targeting androgen receptors and/or HER2 are promising and are the best studied therapies in patients with salivary duct carcinoma. A prospective phase II trial evaluating the effect of combined androgen blockade with leuprorelin acetate and bicalutamide in 36 patients with SGC (of which 34 were salivary duct carcinoma) demonstrated partial or complete response in 41.7% of patients (95% CI 25.5% to 59.2%) and stable disease in 44.4% (95% CI 27.9% to 61.9%). [bib_ref] A prospective phase II study of combined androgen blockade in patients with..., Fushimi [/bib_ref] Given the low rate of grade 3/4 toxicity, combined androgen blockade plays an important role in the palliative treatment of androgen receptorpositive salivary duct carcinoma. Androgen deprivation therapy (ADT) may also be beneficial in the adjuvant setting. Based on retrospective data, adjuvant ADT results in significantly improved 3-year disease-free survival in patients with stage IVa androgen receptor-positive salivary duct carcinoma [48.2% (95% CI 14.0% to 82.4%) versus 27.7% (95% CI 18.5% to 36.9%) in the control group, which did not receive adjuvant ADT]. [bib_ref] Adjuvant androgen deprivation therapy for poor-risk, androgen receptorpositive salivary duct carcinoma, Van Boxtel [/bib_ref] In HER2-positive salivary duct carcinoma, trastuzumab combined with taxane-based ChT is the best studied regimen, with an overall response rate of 70.2% (95% CI 56.6% to 81.6%) and median OS of 39.7 months (95% CI not reached) reported for trastuzumabedocetaxel in 57 patients with salivary duct carcinoma. [bib_ref] Phase II trial of trastuzumab and docetaxel in patients with human epidermal..., Takahashi [/bib_ref] This combination could potentially be amplified with the addition of another agent targeting HER2 (e.g. pertuzumab, lapatinib) or, after progressive disease, replacement of trastuzumab with the antibodyedrug conjugate trastuzumabeemtansine (T-DM1). An oral presentation at the American Society of Clinical Oncology congress in 2019 emphasised the potential of T-DM1 in HER2-amplified SGC, as 9 out of 10 patients (0-3 lines of prior treatment, median of 2) responded to this treatment. Presumably most of these patients had salivary duct carcinoma. Median PFS was not reached after a median follow-up of 12 months. [bib_ref] Ado-trastuzumab emtansine in patients with HER2 amplified salivary gland cancers (SGCs): results..., Li [/bib_ref] In analogy with the positive results achieved in HER2-positive breast cancer by adding pertuzumab to docetaxeletrastuzumab and the cases reported for this combination in salivary duct carcinoma, this triple combination deserves pursuit in clinical studies in salivary duct carcinoma. In patients co-expressing HER2 and androgen receptors, it is currently unclear whether targeting androgen receptors or HER2 is the best approach. In case of extensive or rapidly progressive disease, HER2targeting therapy in combination with taxane-based ChT is the reasonable choice over antihormonal therapy, as in breast cancer, but there is no evidence for this approach (expert opinion). Besides androgen receptors and HER2, a number of mutations are observed in lower frequencies in salivary duct carcinoma, which form a genetic landscape highly similar to apocrine breast cancer. [bib_ref] Comprehensive molecular characterization of salivary duct carcinoma reveals actionable targets and similarity..., Dalin [/bib_ref] These include mutations in TP53 (53%-68%), PIK3CA (18%-26%), HRAS (16%-23%), BRAF (4%) and AKT1 (1.5%). Reports of use of these targets in clinical practice are scarce. [bib_ref] First-line treatment of widely metastatic BRAF-mutated salivary duct carcinoma with combined BRAF..., Lin [/bib_ref] When these mutations are identified, patients should be preferably treated in basket studies. The most frequently used ChT regimen in R/M salivary duct carcinoma is carboplatinepaclitaxel. [bib_ref] Systemic therapy in metastatic salivary gland carcinomas: a pathology-driven paradigm?, Alfieri [/bib_ref] Although 30%-60% of salivary duct carcinomas demonstrate IHC positivity for programmed death-ligand 1, no phase II data with immune checkpoint inhibitors are available. [bib_ref] The immune microenvironment and expression of PD-L1, PD-1, PRAME and MHC I..., Xu [/bib_ref] Secretory carcinoma. The body of evidence for the efficacy of tropomyosin receptor kinase (TRK) inhibitors (e.g. larotrectinib, entrectinib, repotrectinib, in patients with secretory carcinoma and NTRK gene fusions is expanding. [bib_ref] NTRK fusion-positive cancers and TRK inhibitor therapy, Cocco [/bib_ref] A recent phase II trial evaluating the efficacy of larotrectinib in NTRK fusion-positive patients included 12 patients with secretory carcinoma and reported a response rate of 75%. Median PFS was not reached after a median follow-up of 9.9 months. [bib_ref] Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children, Drilon [/bib_ref] Responses in patients with secretory carcinoma have also been observed with entrectinib and repotrectinib. [bib_ref] NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and..., Solomon [/bib_ref] For treatment with TRK inhibitors, RNA confirmation is needed. Other SGC subtypes. For some histological subtypes, little or no clinical evidence is available to make hard recommendations for additional IHC staining or molecular evaluation to identify therapeutic targets. For these subtypes, IHC staining for androgen receptors and evaluation of HER2 expression, preferably by IHC staining and FISH, are advocated. Besides this, use of an NGS panel which includes frequently affected genes in other cancers that are currently targetable with anticancer drugs (e.g. PIK3CA, BRAF, NRAS, MET) is suggested. Regarding gene fusions, which are often not present in commercially available panels, it is important to test specifically for NTRK gene fusions, as these have great implications for individual patients. ## Recommendations ## Rt Re [bib_ref] Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell..., Dykewicz [/bib_ref] [bib_ref] Purpose of quality standards for infectious diseases, Gross [/bib_ref] Statements without grading were considered justified standard clinical practice by the authors. Future updates to this CPG will be published on esmo.org as a Living Guideline version or an eUpdate, to be made available at: https://www.esmo.org/ guidelines/head-and-neck-cancers/salivary-gland-cancer. and Merck, personal fees as an invited speaker for Sanofi and fees paid to his institute as local Principal Investigator (PI) for BMS. LDL reports personal fees for advisory board membership of Eli Lilly, Merck Serono and MSD, personal fees as an invited speaker for Biogen, EISAI, IPSEN, Sanofi Regeneron and SunPharma and fees paid to her institute as local PI for EISAI. She also reports non-remunerated leadership roles with the Endocrine Tumour Group and as an Officer for the Scientific Chairs Council of European Organisation for Research and Treatment of Cancer (EORTC), affiliate for the Italian Association of Medical Oncology (AIOM) and the Multidisciplinary Salivary Gland Society (MSGS) and an advisory role for Associazione Italiana Oncologia Cervico Cefalica (AIOCC). JH reports personal fees from stocks/shares from RiverD/ MarginGuide. EK reports personal fees for full-or part-time employment as the Consumer Lead for the National Cancer Research Institute (NCRI) and a non-remunerated role as a member of the Board of Directors of Salivary Gland Cancer UK. CE reports personal fees for advisory board membership of BMS, MSD, Merck Serono and Innate Pharma, fees paid to her institute for advisory board membership for F-star [fig] Figure 1: Work-up of major salivary gland nodules. Purple: general categories or stratification; white: other aspects of management. AdCC, adenoid cystic carcinoma; CNB, core needle biopsy; CT, computed tomography; FDGePETeCT, [ 18 F]2-fluoro-2-deoxy-D-glucoseepositron emission tomographyecomputed tomography; FNA, fine-needle aspiration; MRI, magnetic resonance imaging. a CNB considered when FNA is non-diagnostic or if more histological information is required. [/fig] [fig] Figure 3: Treatment algorithm for minor or sublingual SGC. Purple: general categories or stratification; red: surgery; dark green: radiotherapy; white: other aspects of management; blue: systemic anticancer therapy. ChT, chemotherapy; END, elective neck dissection; ND, node dissection; RT, radiotherapy; SGC, salivary gland cancer. a Definition of high-grade tumours is described in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2022.100602. [/fig] [fig] Figure 4: Treatment algorithm for submandibular gland cancer. Purple: general categories or stratification; red: surgery; dark green: radiotherapy; white: other aspects of management; blue: systemic anticancer therapy. ChT, chemotherapy; CNB, core needle biopsy; FNA, fine-needle aspiration; ND, node dissection; RT, radiotherapy. a Definition of high-grade tumours is described in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2022.100602. [/fig] [fig] ACKNOWLEDGEMENTS: Manuscript editing support was provided by Louise Green and Jennifer Lamarre (ESMO Guidelines staff) and Angela Corstorphine and Sian-Marie Lucas of Kstorfin Medical Communications Ltd (KMC); this support was funded by ESMO. Nathan Cherny, Chair of the ESMO-MCBS Working Group, Urani Dafni, ESMO-MCBS Working Group Member/ Frontier Science Foundation Hellas and Giota Zygoura of Frontier Science Foundation Hellas provided review and validation of the ESMO-MCBS scores. Nicola Latino (ESMO Scientific Affairs staff) provided coordination and support of the ESMO-MCBS scores and Angela Corstorphine and Sian-Marie Lucas of KMC provided medical writing and editing support in the preparation of the ESMO-MCBS table; this support was funded by ESMO. Joaquin Mateo (Chair of the ESMO Translational Research and Precision Medicine Working Group) and Dr Svetlana Jezdic (ESMO Medical Affairs Advisor) provided validation support for ESCAT scores. [/fig] [fig] FUNDING: No external funding has been received for the preparation of this guideline. Production costs have been covered by ESMO from central funds.DISCLOSURE VVP reports fees paid to his institute as an invited speaker from Atos Medical, Bristol Myers Squibb (BMS) and Ethicon e Johnson & Johnson and non-remunerated roles as a member of the Board of Directors and Secretary General of the Multidisciplinary Salivary Gland Society. BB reports personal fees for advisory board participation from Merck Sharp & Dohme [/fig] [table] Table S5 ,: available at https://doi.org/10. 1016/j.esmoop.2022.100602. Minor SGCs are staged similarly to SCC, according to the site in which they arise (e.g. oral cavity, pharynx, sinuses, etc.). [/table] [table] Table S6 ,: available at https:// doi.org/10.1016/j.esmoop.2022.100602. [/table]	None	None	None
ffc94541e5acaf4159a88f2ef9c0b769069fcadd	pubmed	Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype	Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype Although guidelines are available for hereditary hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at # Introduction Although guidelines are available for hereditary hemochromatosis (HH), a high percentage of the recommendations within them are not shared between the different guidelines [bib_ref] The quality of hereditary haemochromatosis guidelines: a comparative analysis, Vanclooster [/bib_ref]. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. The final version of these recommendations was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles. ## Whom to treat and when to start Patients with HFE p.Cys282Tyr (C282Y/C282Y) homozygous genotype and biochemical evidence of iron overload, i.e., increased serum ferritin ([ 300 lg/L in male and postmenopausal female and [ 200 lg/L in premenopausal female) and increased fasting transferrin saturation (C 45%) [bib_ref] Diagnosis and management of hemochromatosis, Bacon [/bib_ref]. ## Considerations - A judgement has to be made for each individual patient taking into account their ferritin level (according to local reference value), age, gender, and co-morbidities. - Patients with other genotypes should be referred for further advice. - Recent studies observed a beneficial effect of early and sustained management of patients with iron excess, even when iron load is mild or moderately elevated serum ferritin [bib_ref] Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE..., Bardou-Jacquet [/bib_ref] [bib_ref] Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron):..., Ong [/bib_ref]. ## Treatment Phlebotomy (venesection therapy) is the standard treatment for patients with HH having been used for more than 60 years. It is effective in reducing morbidity and mortality of HH [bib_ref] Survival and causes of death in cirrhotic and in noncirrhotic patients with..., Niederau [/bib_ref]. Iron overload leads to tissue injury mainly through the production of reactive oxygen species which damage cell membranes and organelles, ending up with cellular death. Thus, to start the treatment is important. Each 500 mL phlebotomy withdraws approximately 250 mg of iron which is subsequently released, in a compensatory process, from overloaded tissues (especially the liver), ending up, with phlebotomy repetition, to the total removal of body iron excess. ## How to treat ## Initial or induction phase A phlebotomy schedule of the order of 400-500 mL, considering body weight, weekly or every 2 weeks has been proposed [bib_ref] Optimizing the diagnosis and the treatment of iron overload diseases, Brissot [/bib_ref]. The objective in this phase is usually to reach serum ferritin at 50 lg/L provided that there is no anemia. Serum ferritin should be checked once a month until the values reach the upper normal limits, and every 2 weeks thereafter, until the final goal of serum ferritin is reached [bib_ref] Diagnosis and management of hemochromatosis, Bacon [/bib_ref] [bib_ref] Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron):..., Ong [/bib_ref]. ## Considerations - The volume and frequency of the phlebotomies should be adapted to the clinical characteristics and (individual) tolerance of the patient. - Tolerance: clinical data (general tolerance and blood pressure); hemoglobin (levels should not decrease below 11 g/dL) [bib_ref] Optimizing the diagnosis and the treatment of iron overload diseases, Brissot [/bib_ref]. - Phlebotomies can be performed in a clinic, hospital, transfusion/blood donor centers or in certain circumstances at home (by a nurse under medical supervision). - Patients should be well hydrated and fed. ## Maintenance phase The maintenance phase follows the induction phase. The patient with HH needs lifelong follow-up. One phlebotomy every 1-4 months, depending on the patient's iron status [bib_ref] Optimizing the diagnosis and the treatment of iron overload diseases, Brissot [/bib_ref]. Efficacy: the usual aim is to maintain ferritin levels around 50 lg/L (without anemia) [bib_ref] Diagnosis and management of hemochromatosis, Bacon [/bib_ref] [bib_ref] Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron):..., Ong [/bib_ref]. ## Considerations - The frequency of maintenance phlebotomy varies among individuals, ranging from one per month to one per year [bib_ref] Diagnosis and management of hemochromatosis, Bacon [/bib_ref]. - Hemoglobin levels should not be \ 11 g/dL. - Hemoglobin value, typically, should be assessed preceding phlebotomy, especially in older patients, who are more susceptible to anemia and chronic blood losses. - Serum ferritin should be checked at every other phlebotomy (at the same time as hemoglobin), at least yearly. - Fasting transferrin saturation should also be checked, at least once a year. - In certain countries, a growing number of patients with uncomplicated hemochromatosis donate blood or qualify as blood donors. Blood removed from therapeutic phlebotomy may be used at the discretion of the blood service [bib_ref] Is blood of uncomplicated hemochromatosis patients safe and effective for blood transfusion?..., Buck [/bib_ref]. ## When to stop Patients who have had iron overload should never stop having their iron status monitored and their treatment planned in the light of their iron status, general condition, and age. ## Additional considerations Diet A healthy varied diet should be eaten, avoiding foods with iron fortification such as breakfast cereals. Iron and vitamin C supplementation and high alcohol consumption should also be avoided [bib_ref] Diagnosis and management of hemochromatosis, Bacon [/bib_ref]. In certain geographical regions (especially subtropical), HH patients should avoid raw shellfish and undercooked pork because of the risk of severe infections. Dietary restriction should not replace phlebotomy therapy. ## Chelation therapy Iron chelation is usually indicated for iron overload related to chronic anemias that need repeated transfusions. However, iron chelators are an alternative treatment (or adjuvant) only used in rare and special cases of HH, when phlebotomies are medically contraindicated, simply impossible owing to poor vein conditions, or the efficacy was not achieved with phlebotomies. ## Possible future of hh therapeutics Hepcidin-based therapies might, in future, become a potential adjunct treatment to phlebotomy in the induction phase or a replacement for the phlebotomy maintenance phase. The possibility of using hepcidin is based on the diminishing of hepcidin levels in HH patients, which is responsible for increased serum iron and transferrin saturation, and subsequently to tissue iron overload [bib_ref] Hepcidin: a promising therapeutic target for iron disorders: a systematic review, Liu [/bib_ref]. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creative commons.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. [bib_ref] Diagnosis and management of hemochromatosis, Bacon [/bib_ref] Inserm Unit 1241, University Hospital Pontchaillou, Rennes, France [bib_ref] Decreased cardiovascular and extrahepatic cancer-related mortality in treated patients with mild HFE..., Bardou-Jacquet [/bib_ref] HI -Haemochromatosis International, London, UK [bib_ref] Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron):..., Ong [/bib_ref] European Federation of Associations of Patients with Haemochromatosis, Seine, France ## Compliance with ethical standards	None	https://link.springer.com/content/pdf/10.1007%2Fs12072-018-9855-0.pdf	None
2633bdea89dde35e2091da88ed104336c0ad2d6d	pubmed	American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma	American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and European Society for Blood and Marrow Transplantation Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma # Introduction Mantle cell lymphoma (MCL) is a B cell lymphoma that displays significant clinical and molecular heterogeneity. In most cases, it follows an aggressive clinical course; however, a subset of patients can have indolent disease [bib_ref] Outcome of deferred initial therapy in mantle-cell lymphoma, Martin [/bib_ref]. Similarly, the management of MCL varies greatly in clinical practice in the United States and worldwide [bib_ref] ESMO Guidelines Committee. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical..., Dreyling [/bib_ref] [bib_ref] European MCL Network and the Lymphoma Working Party of the European Society..., Robinson [/bib_ref]. This variability applies to both the frontline and relapsed/refractory (R/R) settings. Pertaining to frontline therapy, some advocate induction chemoimmunotherapy followed by high-dose therapy (HDT) and then autologous hematopoietic cell transplantation (auto HCT) consolidation, whereas others prefer combination chemoimmunotherapy regimens alone without subsequent HDT consolidation. Treatment strategies are even more discordant in the presence of high-risk features, such as TP53 alterations and a high proliferation index [bib_ref] TP53 mutations identify younger mantle cell lymphoma patients who do not benefit..., Eskelund [/bib_ref] [bib_ref] Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON):..., Jerkeman [/bib_ref] [bib_ref] Expression of TP53 is associated with outcome of MCL independent of MIPI..., Aukema [/bib_ref]. In the R/R setting, there is also variability in practice, which is made even more complex by the advent of newer treatment modalities, such as Bruton's tyrosine kinase (BTK) inhibitors [bib_ref] Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma, Wang [/bib_ref] , lenalidomide, and chimeric antigen receptor (CAR) T cell therapy [bib_ref] KTE-X19 CAR T-cell therapy in relapsed or refractory mantle cell lymphoma, Wang [/bib_ref]. Auto-HCT consolidation has been used for over 20 years in the management of MCL patients [bib_ref] Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in..., Dreyling [/bib_ref] [bib_ref] Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma:..., Fenske [/bib_ref] , and is associated with improved progression-free survival (PFS) and potentially overall survival (OS) following conventional chemoimmunotherapy in both prospective and retrospective studies [bib_ref] Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in..., Dreyling [/bib_ref] [bib_ref] Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma:..., Fenske [/bib_ref] [bib_ref] Autologous stem cell transplantation in first remission significantly prolongs progression-free and overall..., Zoellner [/bib_ref] [bib_ref] Survival outcomes of younger patients with mantle cell lymphoma treated in the..., Gerson [/bib_ref]. However, it is less clear whether auto-HCT has a benefit following more intensive chemoimmunotherapy, such as rituximab-hyper CVAD/cytarabine/methotrexate [bib_ref] Comparative outcome of initial therapy for younger patients with mantle cell lymphoma:..., Lacasce [/bib_ref]. Allo-HCT is a potentially curative modality for MCL [bib_ref] Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma:..., Fenske [/bib_ref] [bib_ref] Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis..., Hamadani [/bib_ref] ; however, with a 1-year treatment-related mortality ranging from 10% to 20% and the additional risk of chronic graft-versus-host disease (GVHD), allo-HCT generally has been reserved for the R/R setting [bib_ref] ESMO Guidelines Committee. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical..., Dreyling [/bib_ref] [bib_ref] Allogeneic stem cell transplantation for mantle cell lymphoma: final report from the..., Krüger [/bib_ref]. There have been recent important advances in MCL therapy, including the demonstration of a survival benefit with rituximab maintenance following auto-HCT [bib_ref] Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma, Gouill [/bib_ref] , the advent of first and second-generation BTK inhibitors for R/R MCL [bib_ref] Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or..., Owen [/bib_ref] , and the recent approval of the first commercially available CAR T cell therapy (brexucabtagene autoleucel) for MCL [bib_ref] KTE-X19 CAR T-cell therapy in relapsed or refractory mantle cell lymphoma, Wang [/bib_ref]. For brexucabtagene autoleucel, the reported objective and complete response rates were 93% and 67%, respectively, with durable remission seen in >50% of patients. Importantly, although this registration trial exclusively studied MCL patients who had been previously treated with BTK inhibitor therapy, US regulatory approval provides an indication for all patients with R/R MCL regardless of previous exposure to a BTK inhibitor. Given these novel treatment options, guidance on the contemporary role, optimal timing, and sequencing of cellular therapies in MCL is warranted. Clinical practice recommendations addressing areas of clinical ambiguity not only can aid the treating transplantation and cellular therapy physicians, but also can inform lymphoma experts' and community hematologists' practice for referring these patients to transplantation and cellular therapy programs. The American Society of Transplantation and Cellular Therapy (ASTCT), Center of International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) undertook a joint project to formulate consensus recommendations regarding the role, timing, and sequencing of auto-HCT, allo HCT, and CAR T cell therapy for patients with newly diagnosed and R/R MCL. # Methods ## Panel composition The development of practice recommendations was approved by the ASTCT, CIBMTR, and EBMT, the 3 leading international organizations in the field of HCT and cellular therapies. As an initial step, a Steering Committee was formed comprising 6 members including 2 project leaders/coordinators; 1 representative each from the ASTCT, EBMT, and CIBMTR; and an independent methodologist with expertise in systematic reviews, meta-analysis, and the RAND-modified Delphi method. The Steering Committee was responsible for drafting the protocol, producing the initial draft of the consensus statements based on clinical expertise and clinical practice considerations, and setting up the expert panel [bib_ref] American Society of Clinical Oncology Clinical Practice Guidelines: formal systematic review-based consensus..., Loblaw [/bib_ref]. The aim was to put together an expert panel with a balanced distribution of MCL and cellular therapy and transplant experts, to have broad expertise, and to cover a wide spectrum of views while keeping administrative efforts manageable, as previously recommended [bib_ref] Consensus development methods, and their use in clinical guideline development, Murphy [/bib_ref] [bib_ref] Recommendations on disease management for patients with advanced human epidermal growth factor..., Ramakrishna [/bib_ref]. The panel of experts consisted of physicians with a diverse geographical representation and expertise in the field, as demonstrated by their track records of peer-reviewed publications, leadership on clinical trials relevant to the consensus project, and involvement in national and international lymphoma or transplantation organizations. In addition, the panel included a physician representing a community-based practice (N.G.), as previously recommended [bib_ref] American Society of Clinical Oncology Clinical Practice Guidelines: formal systematic review-based consensus..., Loblaw [/bib_ref]. The final Consensus Panel consisted of 33 physicians and investigators, including all members of the Steering Committee except the (nonclinical) independent methodologist (A.K.), who did not vote on the recommendations. # Consensus methodology The RAND-modified Delphi method was used to generate consensus statements addressing the role, timing, and sequence of HCT and CAR T cell therapies in patients with newly diagnosed and R/R MCL. In the Delphi method, the participants rate the statements anonymously in at least 2 rounds of evaluations. In the modified version of the Delphi method, a face-to-face meeting with presentation of the results precedes the second round of rating [bib_ref] American Society of Clinical Oncology Clinical Practice Guidelines: formal systematic review-based consensus..., Loblaw [/bib_ref] [bib_ref] Consensus development methods, and their use in clinical guideline development, Murphy [/bib_ref] [bib_ref] Recommendations on disease management for patients with advanced human epidermal growth factor..., Ramakrishna [/bib_ref]. Owing to the ongoing COVID-19 pandemic, a virtual platform (Zoom, San Jose, CA) was used in lieu of a face-to-face meeting. Details of the systematic step-by-step approach used in this project are provided in . After Consensus Panel selection, a baseline demographics and scope (BD&S) survey was developed to determine the scope of the project. Participants were invited to submit their suggestions regarding the scope of the consensus project and provide input about the clinical issues relevant to clinical practice (details in Supplementary Material). Once the scope of the consensus project was finalized, the Steering Committee formulated preliminary consensus statements based on expert opinion for the first round of voting (details in Supplementary Tables S1 and S2). The first voting survey included 19 consensus statements. Consensus Panel members rated each statement electronically. The Steering Committee methodologist analyzed and summarized the results while keeping the individual ratings anonymous. A specific proposed statement was defined as having achieved formal consensus if ≥75% of the panel members voted to agree with it. The results of the first voting survey, along with the statements not reaching the threshold of consensus, were presented at the virtual teleconference of the panel members. Consensus statements that met the predefined criteria for formal consensus were recommended for approval. Statements that failed to achieve predefined criteria for consensus were discussed during the virtual meeting, and based on the discussions, were modified for revoting or dropped. The second voting survey was sent to all Consensus Panel members for rating the reformulated or newly added statements. All surveys were administered online using Qualtrics software (Qualtrics, Provo, UT), and results were reviewed and collated independently by the methodological expert. At each step of the process, the electronic survey also allowed the participating members to provide written feedback and comments about each statement. Collated results were shared via email with the Consensus Panel members in real time after each step was completed to ensure transparency of the process. The final consensus statements were graded based on the strength and level of the supporting evidence, according to the Agency of Healthcare Research and Quality grading system. [fig_ref] Table 2: Demographic Information of Consensus Panel Members [/fig_ref] summarizes the baseline characteristics of Consensus Panel members. Included were transplantation and cellular therapy physicians (>75% of practice time in HCT), non-cellular therapy academic physicians, mixed practitioners, and a community-based practitioner. A mixed practice was defined as practitioners devoting approximately 50% of their clinical time to HCT and the other 50% to non-cellular therapy-related lymphoma treatment. In general, panelist participation and response rates were excellent. During the voting process, 100% (n = 33) panel member participation was noted for the BD&S, first voting, and second voting surveys. The virtual meeting was attended by 26 members, including 4 members who provided their absentee vote by providing written feedback in advance of (n = 1) or after the meeting, after reviewing the video recordings of the teleconference (n = 3). # Results ## Member participation ## First voting survey The first voting survey consisted of 19 statements specific to the role of auto-HCT in eligible newly diagnosed MCL patients (6 statements) and R/R MCL patients (2 statements), allo-HCT for newly diagnosed MCL patients (3 statements), and allo-HCT and/or CAR T cell therapy for R/R MCL patients (8 statements). All but 5 statements achieved consensus by predefined criteria (Supplementary . The results of the first voting survey were shared electronically with all panel members. The 5 statements not achieving consensus (<75% agreement) during the previous voting process were reviewed by the Steering Committee and presented to the Consensus Panel members at the virtual video conference. The ensuing discussion resulted in one statement regarding auto-HCT being abandoned and all other statements being revised. A total of 3 statements were proposed (2 reformulated statements and 1 merged statement) for the second voting survey. Supplementary [fig_ref] Table 2: Demographic Information of Consensus Panel Members [/fig_ref] presents the outcomes of the virtual video conference. ## Second voting survey All statements included in the second voting survey (2 reformulated statements and 1 merged statement) met the predefined criteria for consensus (Supplementary [fig_ref] Table 2: Demographic Information of Consensus Panel Members [/fig_ref]. The final consensus recommendations on auto-HCT, allo-HCT, and CAR T cell therapy for upfront and relapsed MCL consisting of 17 consensus statements are provided in [fig_ref] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref]. # Discussion In this project, a broadly representative panel of lymphoma, transplantation, and cellular therapy experts with diverse practice experience and geographical representation, endorsed by the ASTCT, EBMT, and CIBMTR, was formed to provide consensus recommendations on the roles of auto-HCT, allo-HCT, and CAR T cell therapy in treating newly diagnosed and R/R MCL. Considering the limitations of existing data on treatments with cellular immunotherapy for MCL and the recently approved CAR T cell therapy (brexucabtagene autoleucel) for R/R MCL [bib_ref] KTE-X19 CAR T-cell therapy in relapsed or refractory mantle cell lymphoma, Wang [/bib_ref] , the optimal sequencing of these treatments in the era of other novel therapies like BTK inhibitors is unknown. Therefore, this undertaking was conceived to provide a rational basis for clinical guidance where evidence is limited, and it resulted in 17 consensus recommendations. ## Recommendations in the front-line setting without tp53 aberrations Seven consensus statements were generated for transplantation and CAR T cell treatments in the frontline setting for MCL [fig_ref] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref]. Taking into account the European MCL Network randomized study for upfront auto-HCT consolidation in MCL [bib_ref] European MCL Network and the Lymphoma Working Party of the European Society..., Robinson [/bib_ref] [bib_ref] Autologous stem cell transplantation in first remission significantly prolongs progression-free and overall..., Zoellner [/bib_ref] and several other historical prospective trials [bib_ref] Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma, Gouill [/bib_ref] [bib_ref] Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle..., Geisler [/bib_ref] [bib_ref] A phase II clinical trial of intensive chemotherapy followed by consolidative stem..., Evens [/bib_ref] [bib_ref] Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients..., Hermine [/bib_ref] , the panel recommended auto-HCT as consolidation therapy in eligible, newly diagnosed MCL patients (without TP53 mutation or biallelic deletion) in complete remission or partial remission after first-line therapies (grade A recommendation; [fig_ref] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 1). Although this is in keeping with current guidelines [bib_ref] ESMO Guidelines Committee. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical..., Dreyling [/bib_ref] , the Consensus Panel did acknowledge that, owing to the lack of evidence of a survival benefit with upfront auto-HCT consolidation, some experts and centers do not routinely recommend this modality after front-line intensive induction regimens. In addition, the panel did not recommend auto-HCT as consolidative therapy in MCL patients with disease refractory (or unresponsive) to the most recent line of therapy (grade B recommendation; [fig_ref] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 2). Finally, given the lack of prospective data to guide consolidative auto-HCT based on the presence (or absence) of measurable residual disease (MRD), the panel did not recommend using MRD testing to determine whether auto-HCT consolidation should be applied, outside of a clinical trial (grade C recommendation; [fig_ref] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 3). In an effort to bridge this knowledge gap, the ongoing US Intergroup phase III study (ECOG-ACRIN 4151; NCT03267433) is randomizing MRD-negative MCL patients to undergo auto-HCT, followed by maintenance rituximab or maintenance rituximab alone. The Consensus Panel was not able to reach a consensus on recommending the collection and storage of peripheral blood hematopoietic progenitor cells (HPCs) for patients not undergoing upfront auto-HCT [fig_ref] Table 2: Demographic Information of Consensus Panel Members [/fig_ref]. The costs of collecting and storing HPCs for future use [bib_ref] Utilization and cost implications of hematopoietic progenitor cells stored for a future..., Chhabra [/bib_ref] , as well as ambiguity about the role of auto-HCT in the R/R setting in the CAR T cell therapy era, were among the major concerns raised by the panel. In addition, it was felt that if necessary, peripheral blood HPC collection is feasible at a later point in the disease process. Although a number of prognostic factors can be used to predict outcomes for MCL, including the MCL International Prognostic Index (MIPI) score [bib_ref] Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle..., Geisler [/bib_ref] [bib_ref] Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle cell lymphoma:..., Damon [/bib_ref] [bib_ref] Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of..., Hoster [/bib_ref] , owing to a lack of supporting data, the Consensus Panel did not recommend using the MIPI prognostic score as a criterion for selecting patients for auto-HCT as consolidation therapy (grade C recommendation; [fig_ref] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 4). Although the Consensus Panel anticipates that future trials will investigate the role of CAR T cell therapies as consolidation following frontline treatment, it does not recommend this approach outside the setting of a clinical trial (grade C recommendation; [fig_ref] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 6). ## Recommendations in the front-line setting with tp53 aberrations The Consensus Panel recognized that that outcomes of MCL patients with a TP53 mutation (or biallelic deletion) who are in complete or partial remission after first-line treatments are poor following auto-HCT consolidation [bib_ref] TP53 mutations identify younger mantle cell lymphoma patients who do not benefit..., Eskelund [/bib_ref]. Although there is preliminary evidence that both allo-HCT and CAR T cell therapies may overcome any treatment resistance conferred by TP53 aberrations [bib_ref] KTE-X19 CAR T-cell therapy in relapsed or refractory mantle cell lymphoma, Wang [/bib_ref] [bib_ref] Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with..., Lin [/bib_ref] , no alternative strategies have been shown to improve the outcomes of first-line therapy in such patients in a randomized trial. Therefore, the panel cautiously recommended considering auto-HCT consolidation as well as other alternative consolidation strategies (eg, CAR T cell therapy, allo-HCT) for such patients, ideally in the context of a clinical trial (grade C recommendation; [fig_ref] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 7). ## Recommendations in the r/r setting The Consensus Panel acknowledges that in the modern era of novel immunotherapies, auto-HCT likely will have a limited role in the management of R/R MCL, particularly in the presence of TP53 aberrations, where the panel does not recommend auto-HCT (grade B recommendation; [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 1). However, among standard-risk MCL patients (eg, those lacking a TP53 mutation or biallelic deletion) not having undergone auto-HCT in first remission, the panel felt that considering HDT consolidation therapy in the subset of patients who have achieved complete remission after second-line chemoimmunotherapy, particularly after a long first remission, is reasonable and supported by observations in more recent registry and other retrospective studies (grade B recommendation; [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 9) [bib_ref] Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma:..., Fenske [/bib_ref]. Brexucabtagene autoleucel was approved by the US Food and Drug Administration (FDA) for treating R/R MCL on July 24, 2020, before the first voting survey. The Consensus Panel felt that the FDA label did not identify the optimal timing of CAR T cell therapy in R/R MCL. Considering the cost of this modality and the availability of other active targeted therapy options, the panel recommended that CAR T cell therapy is best applied in R/R MCL patients who are intolerant to or relapsed after treatment with at least one BTK inhibitor (grade B recommendation; [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 5). This appears to be in accordance with the European label for brexucabtagene autoleucel granted by the European Medicines Agency (EMA) in December 2020 (after completion of this consensus project) approving this CAR T cell therapy for R/R MCL after 2 lines of systemic therapy including a BTK inhibitor. However, owing to the preliminary evidence of activity of CAR T cell therapy in patients with a TP53 mutation [bib_ref] KTE-X19 CAR T-cell therapy in relapsed or refractory mantle cell lymphoma, Wang [/bib_ref] , the use of CAR T cell therapy as a second-line therapy (ie, even without prior BTK inhibitor exposure) may be considered for such patients (grade B recommendation; [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 3). With the approval of CAR T cell therapy for R/R MCL, the role of allo-HCT merits reevaluation. The Consensus Panel recognizes the increased toxicities and life-threatening complications of allo-HCT and thus recommends considering CAR T cell treatments before allo-HCT. In practical terms and taking into account recommendation 5 [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] for R/R disease, this means that the treatment sequence would be to treat with BTK inhibitors until failure or intolerance, then move to CAR T cell therapy, and reserve allo-HCT for CAR T cell therapy failure. However, given the lack of comparative data of CAR T cell therapy versus allo-HCT, the panel acknowledges that this recommendation represents an expert opinion for clinicians to consider (grade C recommendation, [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 4). Thus, allo-HCT remains an option as part of second-line treatment in eligible patients who achieve only a partial response to BTK inhibitors (ie, the majority of BTK inhibitor responders [bib_ref] Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma, Wang [/bib_ref] [bib_ref] Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an..., Dreyling [/bib_ref] , particularly in areas where CAR T cell therapies are not available (grade B recommendation; [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 7). In addition, the Consensus Panel considered allo-HCT to be a reasonable treatment option in R/R MCL patients who have relapsed after CAR T cell therapy, particularly if the disease remains sensitive to subsequent treatment attempts (grade C recommendation; [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 8) [bib_ref] Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis..., Hamadani [/bib_ref] [bib_ref] Allogeneic stem cell transplantation for mantle cell lymphoma: final report from the..., Krüger [/bib_ref] [bib_ref] Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma, Khouri [/bib_ref] [bib_ref] Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation..., Maris [/bib_ref] [bib_ref] Long-term results of fludarabine/melphalan as a reduced intensity conditioning regimen in mantle..., Cruz [/bib_ref]. This recommendation also can be considered for those patients with persistent yet not progressive disease detectable beyond 3 months after CAR T cell administration (grade C recommendation; [fig_ref] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell... [/fig_ref] , recommendation 10), taking into account the low probability of durable disease control in this subset [bib_ref] KTE-X19 CAR T-cell therapy in relapsed or refractory mantle cell lymphoma, Wang [/bib_ref]. # Conclusions In clinical scenarios in which data from prospective studies are either scarce or unavailable, or in situations where therapeutic advances or new drug indications make patient populations included in published trials less relevant to contemporary clinical practice, formal consensus recommendations can be an invaluable resource in informing clinical decision making [bib_ref] Maintenance therapies for Hodgkin and non-Hodgkin lymphomas after autologous transplantation: a consensus..., Kanate [/bib_ref]. Expert opinions and recommendations in the form of review articles and treatment guidelines, although useful, lack methodological clarity and may be subject to bias [bib_ref] Maintenance therapies for Hodgkin and non-Hodgkin lymphomas after autologous transplantation: a consensus..., Kanate [/bib_ref]. In contrast, the formulation of expert recommendations using established approaches, such as the RAND-modified Delphi method [bib_ref] American Society of Clinical Oncology Clinical Practice Guidelines: formal systematic review-based consensus..., Loblaw [/bib_ref] , provides a formal, reproducible, and systematic process. With the rapidly changing landscape of therapeutic advances in cellular immunotherapies for MCL, the timing, sequence, and feasibility of these novel therapies represent challenges. We envision that clinical trials using CAR T cell therapies potentially in earlier lines of treatment or in combination with BTK inhibitors, may emerge. As a result, treatment algorithms for this disease are likely to continue to evolve. We hope that these clinical practice recommendations will serve as a tool to guide clinicians managing patients with newly diagnosed and R/R MCL. # Supplementary material Refer to Web version on PubMed Central for supplementary material. # Acknowledgments Financial disclosure: The CIBMTR is supported primarily by Public Health Service Grant U24CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); Grant U24HL138660 from the NHLBI and NCI; Grants ## Conflict of interest statement: M.H. reports receiving research support/funding from Takeda Pharmaceutical, Spectrum Pharmaceuticals, and Astellas Pharma; serving as a consultant for Janssen, Incyte, ADC Therapeutics, Celgene, Omeros, Verastem, and MorphoSys; and serving on speakers bureaus for Sanofi Genzyme, AstraZeneca, and BeiGene. T.S.F. reports receiving research support/funding from Novartis, Portola, Curis; serving as a consultant to Adaptive Biotechnologies, AbbVie, KaryoPharm, Kite Pharma, MorphoSys, Pharmacyclics, and Sanofi; and serving on speakers bureaus for Sanofi, Seattle Genetics, AstraZeneca, Celgene/Bristol-Myers Squibb, and Adaptive Biotechnologies. P.N.M. reports serving on speakers bureaus for Kite Pharma and Incyte. J.V.C. reports serving on consulting/advisory boards for Janssen, Adicet, BeiGene, Cellectar, Kite Pharma/Gilead, Adaptive, Aptitude Health, AstraZeneca, and Loxo and receiving research support/funding from Novartis, BMS/Celgene, Takeda, Genentech, AstraZeneca, Loxo, LAM, Atara, and BeiGene. N.G. reports serving on speakers bureau for Kite Pharma, AstraZeneca, AbbVie, Janssen, BMS, and Epizyme; serving on consulting/advisory boards for Kite Pharma, AstraZeneca, AbbVie, Janssen, BMS, Incyte, Epizyme, Karyopharma, Genmab, Adaptive Biotech, TG Therapeutics, ADC Therapeutics, and BeiGene; and receiving research funding from Genentech/Roche, BMS, TG Therapeutics, Pharmacyclics, and Kite Pharma. M.K. reports receiving research support/funding from TG Therapeutics and Genentech; serving as a consultant for AbbVie, KaryoPharm, Kite Pharma, AstraZeneca, Celgene/Bristol-Myers Squibb, Adaptive Biotechnologies, and Curio Science; and serving on the speakers bureau for SeaGen. M.J. reports receiving research support/funding from Janssen, Celgene, Abbvie, Gilead, and Roche, and serving as a consultant for Janssen, Incyte, Gilead, Roche, Bristol-Myers Squibb, Acerta, and BioInvent. J.W.F. served on data safety and monitoring boards for Bayer, Ascerta, and Novartis. C.C.-S. reports receiving research support/funding from ADC Therapeutics, Sanofi, and Roche; serving on consultant/advisory boards for Sanofi, ADC Therapeutics, Roche, Karyopharm Therapeutics, Celgene/Bristol-Myers Squibb, and Incyte; receiving honoraria from Bristol-Myers Squibb, Janssen Oncology, and AstraZeneca; and receiving travel grants from Roche, Janssen, Takeda, and ADC Therapeutics. V.B. reports serving on advisory boards for Kite Pharma and Gamida Cell and receiving research support/funding from Incyte, Gamida Cell, and GT Biopharma. T.P. reports receiving research support/funding from Incyte, BMS/Celgene, Bayer, Abbvie, and Genentech; serving as a consultant for BMS, Bayer, AbbVie, Genentech, Gilead, Gilead/Kite TG Therapeutics, ADC Therapeutics, Incyte, MorphoSys, BeiGene, AstraZenca, and Epizyme. F.L.L. reports receiving research support/funding from Kite Pharma; serving as a scientific advisor for Allogene, Amgen, bluebird bio, BMS/Celgene, Calibr, Celgene, GammaDelta Therapeutics, Iovance, Kite Pharma/Gilead, Legend Biotech, Novartis, and Wugen; and serving as a consultant for Cellular Biomedicine Group, Cowen Consulting, Gerson Lehrman Group, EcoR1, and Emerging Therapies. B.K. reports receiving research support/funding from AbbVie, Acerta, AstraZeneca, Beigene, Celgene, and Genentech and serving as a consultant for AbbVie, Acerta, AstraZeneca, Beigene, Celgene, Kite Pharma, Genentech, Pharmacyclics, and Janssen. M.A.K-D. reports serving as a consultant for Pharmacyclics and Daiichi Sankyo. A.F.H. reports serving as a consulting/advisor for Bristol-Myers Squibb, Merck, Seattle Genetics, Karyopharm, Genentech/Roche; receiving institutional research funding from Bristol-Myers Squibb, Genentech/Roche, Merck, Seattle Genetics, ADC Therapeutics, and Gilead/Kite Pharma; and receiving travel, accommodations, and expenses from Bristol-Myers Squibb. K.J.M. reports receiving research funding from Pharmacyclics, BMS, Merck, and Novartis and serving as a consultant for Pharmacyclics, Janssen, Morphosys, Celgene, Beigene, Kite Pharma, Karyopharm, ADC Therapeutics, and Seattle Genetics. V.P.K. reports research funding from Novartis. D.I. reports research funding from Acerta Pharma. C.S.S. reports serving on consultancy/ advisory boards for Juno Therapeutics, Sanofi-Genzyme, Spectrum Pharmaceuticals, Novartis, Genmab, Precision Biosciences, Kite Pharma, Celgene/BMS, Gaqmida Cell, Karyopharm Therapeutics, and GSK and receiving 7. If a TP53 mutation (or biallelic deletion) is present, the panel recognizes that outcomes are poor for MCL patients in complete or partial remission after first-line therapies who then undergo autologous transplantation. However, no specific alternative strategy has yet been shown to improve outcomes in such patients. Therefore, the panel recommends considering autologous transplantation consolidation as well as alternative consolidation strategies (eg, CAR T cell therapy or allogeneic transplantation), ideally in the context of a clinical trial, for such patients. 3. If a TP53 mutation (or biallelic deletion) is present, the panel recommends treatment with CAR T cells in relapsed MCL patients, with disease unresponsive to last antilymphoma therapy. A: There is good research-based evidence to support the recommendation. B: There is fair research-based evidence to support the recommendation. C: The recommendation is based on expert opinion and panel consensus. X: There is evidence of harm from this intervention. [table] Table 2: Demographic Information of Consensus Panel Members (N = 33) [/table] [table] Table 3: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell Treatments in the First-Line Setting for MCL1. The panel recommends autologous HCT as consolidation therapy in eligible, newly diagnosed MCL patients (without TP53 mutation or biallelic deletion) in complete remission or partial remission after first-line therapies. The panel does not recommend autologous transplantation as consolidation therapy in MCL patients with disease not responsive to most recent antilymphoma therapy. [/table] [table] Table 4: Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell Treatments for R/R MCL 1. If a TP53 mutation (or biallelic deletion) is present, the panel does not recommend autologous transplantation in relapsed MCL patients achieving a complete or partial remission after second or subsequent lines of therapy. The panel recommends both CAR T cell therapy or allogeneic transplant consolidation as acceptable options, in relapsed MCL patients with TP53 mutation (or biallelic deletion) in a complete or partial remission after second or subsequent lines of therapy. [/table]	None	None	None
19201ec3c23b1db30ae9f8424771ac1328dd650d	pubmed	First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)–Pan-American League of Associations of Rheumatology (PANLAR)	First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)–Pan-American League of Associations of Rheumatology (PANLAR) Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidelines are developed. The objective of the study is to develop clinical practice guidelines for Latin American patients with lupus. Two independent teams (rheumatologists with experience in lupus management and methodologists) had an initial meeting in Panama City, Panama, in April 2016. They selected a list of questions for the clinical problems most commonly seen in Latin American patients with SLE. These were addressed with the best available evidence and summarised in a ## Recommendation box 1 gladel-panlar latin american guidelines for the treatment of systemic lupus erythematosus Overarching principles a. Treatment should be individualised, specialists and generalists should work together and the active involvement of patients and their family members on the overall therapeutic plan should be emphasised. b. The therapeutic goal should be to reach and maintain remission or low-disease activity as soon as the diagnosis is made and for as long as possible. c. Treatment should include photo-protection, osteoporosis, cardiovascular, metabolic syndrome and infection prevention, psychological support and pregnancy counselling. d. All patients with lupus should receive AMs, except those who refuse them or who have absolute contraindications to take them. e. GCs, if clinically needed, regardless of patient's disease manifestations, should be prescribed at the lowest possible dose and for the shortest period of time. AM, antimalarials; GC, glucocorticoid; GLADEL, Grupo Latino Americano de Estudio del Lupus; PANLAR, Pan-American League of Associations of Rheumatology. standardised format following the Grading of Recommendations Assessment, Development and Evaluation approach. All preliminary findings were discussed in a second face-to-face meeting in Washington, DC, in November 2016. As a result, nine organ/system sections are presented with the main findings; an 'overarching' treatment approach was added. Special emphasis was made on regional implementation issues. Best pharmacologic options were examined for musculoskeletal, mucocutaneous, kidney, cardiac, pulmonary, neuropsychiatric, haematological manifestations and the antiphospholipid syndrome. The roles of main therapeutic options (ie, glucocorticoids, antimalarials, immunosuppressant agents, therapeutic plasma exchange, belimumab, rituximab, abatacept, low-dose aspirin and anticoagulants) were summarised in each section. In all cases, benefits and harms, certainty of the evidence, values and preferences, feasibility, acceptability and equity issues were considered to produce a recommendation with special focus on ethnic and socioeconomic aspects. Guidelines for Latin American patients with lupus have been developed and could be used in similar settings. # Introduction Systemic lupus erythematosus (SLE) is a complex multisystemic autoimmune disease resulting, oftentimes, in irreversible damage, diminished quality of life and reduced life expectancy. [bib_ref] The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with..., Pons-Estel [/bib_ref] [bib_ref] Systemic lupus erythematosus in three ethnic groups. IX. Differences in damage accrual, Alarcón [/bib_ref] [bib_ref] Systemic lupus erythematosus in three ethnic groups. VII [correction of VIII]. Predictors..., Alarcón [/bib_ref] Genetic and environmental factors play important roles in its pathogenesis. [bib_ref] Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases..., Alarcón-Segovia [/bib_ref] [bib_ref] Understanding the epidemiology and progression of systemic lupus erythematosus, Pons-Estel [/bib_ref] [bib_ref] Impact of genetic ancestry and sociodemographic status on the clinical expression of..., Sánchez [/bib_ref] [bib_ref] Genome-Wide association study in an amerindian ancestry population reveals novel systemic lupus..., Alarcón-Riquelme [/bib_ref] [bib_ref] Cytokine gene polymorphisms in Colombian patients with systemic lupus erythematosus, Guarnizo-Zuccardi [/bib_ref] Disease manifestations and severity vary according to the patients' racial/ethnic background and socioeconomic status (SES). [bib_ref] The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with..., Pons-Estel [/bib_ref] although diagnostic delays may occur. [bib_ref] The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with..., Pons-Estel [/bib_ref] They also experience more severe disease, have higher disease activity levels, 1 accrue more organ damage 2 and have higher mortality rates, 1 succumbing mainly to disease activity and/or infections. Although guidelines for SLE treatment do exist and there is scarce evidence to support specific therapies for Latin American patients with lupus, 16-21 this regional effort has considered the impact of racial/ethnic background 1 10 22-28 and SES on lupus outcomes and treatment response. Other medication variables such as cost and availability were also taken into account since they affect adherence and are relevant in decision-making. GLADEL and the Pan-American League of Associations of Rheumatology have joined efforts to produce these guidelines, [bib_ref] Therapeutic Guidelines for Latin American Lupus Patients: Methodology, Cardiel [/bib_ref] which are presented by organ systems, although manifestations usually occur in more than one. Nevertheless, treatment is usually tailored to the more severe manifestation(s), which usually benefits the less severe. # Methods Two working teams on logistics and methodological issues constituted by experienced Latin American rheumatologists and experts in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guideline system developed a framework for these guidelines. Nine organ/system sections were prepared with the main findings. Special emphasis was placed on reviewing local problems and regional publications. The GRADE approach was followed in the process (http:// www. gradeworkinggroup. org) answering the clinical questions voted most relevant by the panel. The description of the methodology followed to develop these guidelines has already been published. [bib_ref] Therapeutic Guidelines for Latin American Lupus Patients: Methodology, Cardiel [/bib_ref] All authors listed in this manuscript have participated in planning, drafting, reviewing, final approval and are accountable for all aspects of the manuscript. No ethical approval was required by institutions. We present the final recommendations and their supporting information. Comments from three patients with SLE were also considered. # Results For each of the subheadings listed below, the panel considered interventions based on experience, availability, affordability and a stepwise therapeutic approach of the different alternatives. Standard of care (SOC) was defined as the use of hydroxychloroquine (HCQ) and, if clinically indicated, low-dose glucocorticoids (GC) (prednisone ≤7.5 mg or equivalent for the shortest time). [bib_ref] Anti-malarials exert a protective effect while Mestizo patients are at increased risk..., Pons-Estel [/bib_ref] Chloroquine remains an alternative for some of the Latin American countries where HCQ is not available and careful monitoring of eye side effect is recommended. Overarching principles are shown in box 1. Tables summarising the evidence that was considered in the process are shown in online supplementary tables in https:// doi. org/ 10. 5061/ dryad. bg8452h. ## Musculoskeletal manifestations a. Which is the best treatment for adult patients with SLE and musculoskeletal (MSK) manifestations? 2, S12.2-S12.5, S12.8-S12.10). ## Benefits and harms Although the panel judged that compared with SOC alone, adding MTX, LFN, belimumab or ABT is possibly associated with beneficial effects, a significant proportion of patients will achieve adequate symptom control with SOC and could be spared the adverse effects/excess costs associated to those other options. ## Recommendation The panel suggests SOC alone over adding other immunosuppressant (IS) in adult patients with SLE with MSK manifestations (weak recommendation based on low certainty of the evidence). It suggests also adding either MTX, LFN, belimumab or ABT to those failing to respond to SOC (weak recommendation based on low to moderate certainty of the evidence). Cost and availability may favour MTX. ## Cutaneous manifestations a. Which is the best treatment for adult patients with different manifestations of cutaneous lupus? ## Benefits and harms The panel judged that a significant proportion of patients will achieve adequate symptom control with SOC and could be spared the adverse effects/costs of the other therapies. ## Recommendation The panel suggests SOC alone over adding other IS in adult patients with SLE with cutaneous manifestations (weak recommendation based on low certainty of the evidence). It also suggests adding MTX, AZA, MMF, CsA, CYC or belimumab to patients failing to respond to SOC (weak recommendation based on low to moderate certainty of the evidence). Cost and availability may favour MTX and AZA. ## Adult kidney manifestations a. Which is the best induction treatment for adult patients with lupus nephritis? ## Interventions considered (1) GCs; (2) GCs plus high-dose CYC; (3) GCs plus low-dose CYC; (4) GCs plus MMF; (5) GCs plus RTX plus MMF; (6) GCs plus tacrolimus (TAC); (7) GCs plus AZA (online supplementary tables S1.1.1.2, S1.1.1.7, S1.1.1.8, S1.1.1.10, S1.1.2.2, S1.1.2.5, S1.1.2.7, S1.1.3.2, S1.1.4.1, S1.2.6). ## Benefits and harms Based on the identified evidence the panel concluded that compared with GCs alone, the addition of other IS (CYC, MMF or TAC) is associated with significant benefits, higher remission rates and lower progression rates to end-stage renal disease (ESRD). Head-to-head comparisons between MMF, TAC and high-dose CYC showed that MMF and TAC are associated with less adverse effects than high-dose CYC. Between low and highdose CYC the balance favours the former because of better safety profile and comparable efficacy, although this conclusion is based on one trial that included predominantly Caucasians. RTX did not provide additional benefits when combined with MMF. ## Recommendation The panel recommends SOC (GCs and antimalarials (AM)) in addition to an IS (CYC in high or low doses, MMF or TAC) over GCs alone, for induction in patients with SLE-related kidney disease (strong recommendation based on moderate certainty of the evidence). Although more African-American descendants and Hispanic patients responded to MMF than CYC [bib_ref] Influence of race/ethnicity on response to lupus nephritis treatment: the ALMS study, Isenberg [/bib_ref] , limited access to MMF and TAC in several Latin American countries, due primarily to cost issues, makes CYC the best alternative for induction (high or low dose) in these regions [fig_ref] Table 2: GLADEL-PANLAR recommendations for adult and childhood-onset lupus nephritis Induction therapy for adult... [/fig_ref]. b. Which is the best maintenance treatment for adult patients with lupus nephritis? ## Interventions considered Recommendations are applicable to patients showing partial or total remission after induction therapy aiming at sustaining renal remission, preventing relapses and achieving the best long-term outcome. The following interventions were considered: (1) AZA; (2) MMF; (3) CYC; (4) TAC; and (5) CsA (online supplementary tables S1.1.1.7, S1.1.2.1, S1.1.2.2, S1.2.1, S1.2.3, S1.2.4, S1.2.5, S1.2.6, S1.2.7). ## Benefits and harms The panel concluded that long-term IS agents during maintenance therapy prolong stable renal function, reduce proteinuria, extend renal survival and minimise the toxicity of GCs. AZA, CYC, MMF and CsA seem to be equivalent regarding efficacy but MMF and AZA have a better safety profile, particularly regarding gonadal toxicity and blood pressure control. We found very low certainty of the evidence for TAC as maintenance therapy, with studies mostly restricted to Asian populations. ## Recommendation ## Recommendation The panel recommends AZA or MMF over CYC for maintenance in patients with SLE-related nephritis (strong recommendation based on low certainty of the evidence, since certainty in better efficacy of MMF or AZA over CYC is low but certainty of fewer adverse effects is high). Cost and availability issues may favour AZA [fig_ref] Table 2: GLADEL-PANLAR recommendations for adult and childhood-onset lupus nephritis Induction therapy for adult... [/fig_ref]. ## Childhood-onset lupus nephritis a. Which is the best induction treatment for childhood-onset lupus nephritis (cLN)? Interventions considered ## Benefits and harms The panel concluded that both MMF plus high-dose GCs (prednisone 1-2 mg/kg/day, maximum 60 mg/day) and CYC plus highdose GCs are associated with significant benefits in comparison to GCs alone. No significant differences between these two alternatives were noted. The panel pointed that differential pharmacokinetic effects of MMF in cLN may exist, which could require dosing increase. [bib_ref] Pharmacokinetics and pharmacodynamics of mycophenolic acid and their relation to response to..., Sagcal-Gironella [/bib_ref] Risk of reduction of ovarian reserve and sperm abnormalities should be considered in patients with cLN treated with CYC. ## Recommendation The panel suggests high-dose GCs plus MMF or CYC over highdose GCs alone in patients with cLN as induction therapy (weak recommendation based on low certainty of the evidence). Cost and availability may favour CYC despite the risk of gonadal toxicity ( ## Benefits and harms The panel concluded that MMF or AZA decreases the occurrence of ESRD without significant adverse events, as maintenance therapy for cLN. The panel pointed that differential pharmacokinetic effects of MMF in cLN may exist, which may require dosing increase. [bib_ref] Pharmacokinetics and pharmacodynamics of mycophenolic acid and their relation to response to..., Sagcal-Gironella [/bib_ref] ## Recommendation The panel suggests MMF or AZA over CYC for patients with cLN who responded, partially or completely, to induction therapy (weak recommendation based on low certainty of the evidence). Cost and availability may favour AZA [fig_ref] Table 2: GLADEL-PANLAR recommendations for adult and childhood-onset lupus nephritis Induction therapy for adult... [/fig_ref]. ## Cardiac manifestations a. Which is the best treatment for adult patients with lupus-related acute pericarditis? Interventions considered ## Benefits and harms Based on the identified evidence the panel concluded that the use of SOC combined with colchicine is associated with significant benefits (decrease in pericarditis recurrence rate) compared with SOC alone. Belimumab probably made little or no difference in pericarditis-related symptom improvement. ## Recommendation The panel suggests SOC plus colchicine over SOC plus NSAIDs or belimumab for patients with acute SLE-related pericarditis (weak recommendation based on low certainty of the evidence) [fig_ref] Table 3: GLADEL-PANLAR recommendations for cardiac and pulmonary manifestationsIn adult patients with lupus-related acute... [/fig_ref]. ## Pulmonary manifestations a. Which is the best treatment for lupus-related diffuse alveolar haemorrhage (DAH)? ## Benefits and harms In the absence of trustworthy evidence regarding the effects of the different interventions in this scenario and considering DAH's high mortality rate, the panel decided that intense and early approach is mandatory without prioritising one intervention over another. ## Recommendation The panel recommends that patients with SLE-related DAH be treated with intravenous GCs plus CYC and/or intravenous Ig and/or TPE and/or RTX over GCs alone (strong recommendation based on very low certainty of the evidence, since possible benefits exist in a life-threatening situation). Cost and availability may favour GC plus CYC [fig_ref] Table 3: GLADEL-PANLAR recommendations for cardiac and pulmonary manifestationsIn adult patients with lupus-related acute... [/fig_ref]. ## Neuropsychiatric manifestations a. Which is the best treatment for adult patients with lupus-related severe, acute neuropsychiatric manifestations? ## Benefits and harms The panel concluded that both options (GCs plus CYC and GCs plus RTX) were associated with large benefits and moderate harms in comparison to GCs plus placebo in patients with acute neurological manifestations. No studies comparing these two options were identified. In terms of SLE and severe neurological manifestations, clinical trials with GCs plus CYC focused on both general neurologic manifestations, and on seizures, psychosis, myelitis, peripheral neuropathy, brain stem disease and optic neuritis, specifically. No data were found regarding other neuropsychiatric manifestations. The panel significantly weighted the fact that the certainty of the evidence was better for CYC than RTX and that RTX was only evaluated in refractory patients. ## Recommendation The panel suggests using GCs plus CYC over GCs alone or GCs plus RTX for the treatment of severe neurologic manifestations in patients with SLE (weak recommendation based on low certainty of the evidence). Cost and availability may favour CYC. ## Haematological manifestations a. Which are the best interventions for patients with severe acute lupus-related haemolytic anaemia (haemoglobin ≤8 g/dL)? ## Interventions considered (1) High-dose GCs; (2) GCs plus RTX (online supplementary tables S7. [fig_ref] 1: MMF plus GCs [/fig_ref]. ## Benefits and harms The panel concluded that compared with GCs as the first-line therapy, the addition of RTX provided moderate beneficial effects (reducing the risk of flare) and moderate harms (increasing the risk of infections). However, the panel significantly weighted the risks associated with RTX as well as availability and cost issues. ## Recommendation The panel suggests using high-dose GCs for patients with severe haemolytic anaemia (weak recommendation based on low certainty of the evidence). It also suggests RTX for patients with life-threatening haemolytic anaemia and/or for those in whom high-dose GC treatment fails (weak recommendation based on low certainty of the evidence). Cost and availability, however, may prompt the use of IS instead of RTX although no data support this assertion ( ## Benefits and harms The panel concluded that compared with GCs as the first-line therapy, RTX and intravenous Ig provided moderate beneficial effects (increasing the platelet count). The harmful effects were judged as moderate for RTX (increase in infections) and small for intravenous Ig (infusion reactions). The panel significantly weighted the risks associated with RTX as well as availability and cost issues. In life-threatening situations, the panel significantly weighted intravenous Ig's and RTX's beneficial effect on platelet count. ## Recommendation ## Recommendations The panel suggests using high-dose GCs in patients with lupus with severe lupus thrombocytopenia (weak recommendation based on moderate certainty of the evidence). It also recommends intravenous Ig with/without GCs or RTX plus GCs for patients who are refractory to high-dose GCs, those with life-threatening bleeding, those requiring urgent surgery and those with infections (strong recommendation based on moderate certainty of the evidence). Cost and availability, however, may prompt the use of IS instead of RTX although there are no data to support this assertion. ## Antiphospholipid syndrome a. Which is the best treatment for adult patients with SLE with antiphospholipid syndrome (APS) and venous thromboembolic disease (VTD)? ## Interventions considered (1) Extended anticoagulation (AC) with vitamin K antagonist (compared with not-extended AC); (2) high-intensity AC (international normalised ratio (INR) 3-4.5) compared with moderate-intensity AC (INR 2-3) (online supplementary tables S10.2.1 and S10.2.2). ## Benefits and harms The panel judged the effect of extended AC as a large benefit, reducing VTD with increase in bleeding risk as a moderate harm. For the comparisons of different AC intensities, the panel decided to use the evidence from observational studies because it judged that it probably better reflects reality given that the randomised controlled trials (RCT) are severely flawed (indirectness of intervention as most patients did not reach the INR >3 goal). They judged the reduction in VTD as a large benefit and the bleeding increase as a large harm. Hence, the panel considered that the balance could favour the intervention only when the risk of VTD recurrence is particularly high. ## Recommendation The panel recommends extended AC with vitamin K antagonist therapy for patients with APS with VTD (strong recommendation based on moderate certainty of evidence). The panel recommends standard (INR 2.0-3.0) over high-intensity (INR 3.0-4.0) AC for patients with APS with VTD (strong recommendation based on very low certainty of the evidence, since certainty of the effect on VTD recurrence is very low but certainty in bleeding risk is high (significant increase in major bleeding with INR 3.0-4.0)). b. Which is the best treatment for adult patients with SLE with APS and stroke? ## Interventions considered Extended antithrombotic therapy with: (1) vitamin K antagonist; (2) low-dose aspirin (LDA: 81-100 mg/day); (3) vitamin K antagonist plus LDA; (4) high-intensity AC (INR 3-4.5) (online supplementary tables S10.3.1 and S10.3.2). ## Benefits and harms The panel decided to use the body of evidence provided by observational studies because it probably better reflects reality as the RCTs are severely flawed (indirectness of population as most patients were inadequately diagnosed with APS). The panel judged the observed reduction in arterial thrombosis with high-intensity AC as a large benefit, and the bleeding increase as a large harm. Also, it was noted that the observed basal risk (risk with LDA) of thromboembolic recurrence in patients with APS and arterial events was particularly high, compared with the risk of recurrence in patients with VTD. ## Recommendation The panel suggests extended high-intensity (INR 3.0-4.0) over standard-intensity AC (INR 2.0-3.0) or LDA alone for patients with SLE with APS and stroke (weak recommendation based on very low certainty of the evidence). c. Which is the best treatment for pregnant SLE women with antiphospholipid antibodies and recurrent pregnancy loss? ## Interventions considered (1) HCQ plus LDA; (2) HCQ plus LDA plus heparin; (3) HCQ plus intravenous Ig (online supplementary tables S10.5.1, S10.5.2, S10.5.3, S10.5.4, S10.5.5, S10.5.6, S10.5.7, S10.5.8). ## Benefits and harms The panel judged the observed reduction in pregnancy loss with the addition of heparin to LDA as a large benefit. This intervention was not associated with significant harms. The addition of GCs or intravenous Ig to heparin plus LDA was associated with large harms (significant increase in premature delivery) without relevant benefits. Regarding heparin administration, the panel considered the reduction in pregnancy loss with low molecular weight heparin (LMWH) in comparison with unfractionated heparin (UFH) as a large benefit without significant adverse effects. No additional benefits were observed with LMWH-enoxaparin 80 mg compared with 40 mg. ## Recommendation The panel recommends HCQ plus LMWH plus LDA over HCQ plus LDA or adding GCs or intravenous Ig for pregnant patients with SLE with antiphospholipid antibodies and recurrent pregnancy loss (strong recommendation based on moderate certainty of the evidence (LMWH plus LDA vs other alternatives) and very low certainty of the evidence (GCs and intravenous Ig vs other alternatives), since high certainty of harms related to GCs (increased premature delivery) and intravenous Ig (costs increase, burden related to drug administration) exists). It also suggests LMWH at a dose of 40 mg/day over UFH or higher doses of LMWH (weak recommendation based on low certainty of the evidence) (table 5). # Discussion Treatment of SLE in Latin America remains a challenge despite several guidelines published on the management of this disease. [bib_ref] Diagnosis and treatment of lupus nephritis. Consensus document from the systemic auto-immune..., Ruiz Irastorza [/bib_ref] [bib_ref] Report of a Task Force of the EULAR Standing Committee for International..., Bertsias [/bib_ref] [bib_ref] American College of Rheumatology guidelines for screening, treatment, and management of lupus..., Hahn [/bib_ref] [bib_ref] A consensus of the Chilean Nephrology and Rheumatology Societies on renal involvement..., Aguirre [/bib_ref] [bib_ref] Consensus of the Brazilian Society of Rheumatology for the diagnosis, management and..., Klumb [/bib_ref] [bib_ref] The British Society for Rheumatology guideline for the management of systemic lupus..., Gordon [/bib_ref] The distinct epidemiology, healthcare resources, socioeconomic issues and priorities were considered to develop these guidelines. Although these guidelines consider region limitations, the inclusion of alternative approaches for tailoring treatment did not exclude the task of providing physicians with the state-ofthe-art findings in the field. This was a major advantage of the present work since highlighting these advances provides valuable basis for future requirement of government authorisation of new drugs in these countries. Of note, problems faced by Latin American countries are shared by several developing nations. Therefore, it is expected that these guidelines will also be very useful for them. Furthermore, due to ever increasing globalisation and the increase of migratory movements of people from countries with more susceptible SLE groups in terms of frequency and disease severity both in terms of race/ethnicity (Mestizos, Asians, Africans) and low SES to countries with better life opportunities, we consider that these guidelines may be used by physicians anywhere in the world, even in developed countries, where such individuals may migrate to and seek care for their lupus. We acknowledge as a limitation that certainty of the evidence was not as high as desirable for most recommendations and probably biased by few randomised clinical trials. Although regional information was published on several topics 1 4 10 11 23 we recognise that these guidelines should be updated as researchbased changes in our understanding of SLE emerge. Regardless, the publication of these guidelines must be followed by health system engagement and implementation by specialists, major steps towards improvement of lupus treatment in Latin America and low/middle-income countries. [fig] 1: MMF plus GCs; (2) CYC plus GCs; (3) GCs (online supplementary table S9.2.3). [/fig] [table] Table 3: GLADEL-PANLAR recommendations for cardiac and pulmonary manifestationsIn adult patients with lupus-related acute pericarditis Use SOC plus colchicine over SOC plus NSAIDs or belimumab.In adult patient with lupus-related diffuse alveolar haemorrhageUse intravenous GCs plus CYC and/or intravenous Ig and/or TPE and/or RTX over GCs alone.Strong recommendation supported on possible benefits in the context of a lifethreatening situation. CYC, cyclophosphamide; GC, glucocorticoid; GLADEL, Grupo Latino Americano de Estudio del Lupus; Ig, immunoglobulin; NSAID, non-steroidal anti-inflammatory drug; PANLAR, Pan-American League of Associations of Rheumatology; RTX, rituximab; SOC, standard of care; TPE, therapeutic plasma exchange. [/table] [table] Table 2: GLADEL-PANLAR recommendations for adult and childhood-onset lupus nephritis Induction therapy for adult patients with lupus-related nephritis Use SOC (GCs and AMs) plus another IS agent (CYC, MMF or TAC) over GCs alone. Maintenance therapy for adult patients with lupus-related nephritis Induction therapy for childhood patient with lupus-related nephritis Maintenance therapy for childhood patient with lupus-related nephritis Use MMF or AZA over CYC. Low Weak Strong recommendation supported on high certainty in less adverse events with MMF or AZA than with CYC. AM, antimalarials; AZA, azathioprine; CYC, cyclophosphamide; GC, glucocorticoid; GLADEL, Grupo Latino Americano de Estudio del Lupus; IS, immunosuppressant; MMF, mycophenolate mofetil; PANLAR, Pan-American League of Associations of Rheumatology; SOC, standard of care; TAC, tacrolimus. [/table] [table] Table 5: GLADEL-PANLAR recommendations for adult patients with SLE with antiphospholipid antibodies or antiphospholipid syndrome In adult patients with lupus with APs and venous thromboembolic disease Use extended over time-limited anticoagulation. Moderate Strong In adult patients with sLE with APs and stroke In pregnant lupus women with obstetric APs and recurrent pregnancy losses Use HCQ plus LMWH plus LDA over HCQ plus LDA, or adding GCs or intravenous Ig. Moderate Strong *Strong recommendation supported on high certainty in significant bleeding risk increase with high-intensity anticoagulation. APS, antiphospholipid syndrome; GC, glucocorticoid; GLADEL, Grupo Latino Americano del Estudio de Lupus; HCQ, hydroxychloroquine; Ig, immunoglobulin; INR, international normalised ratio; LDA, low-dose aspirin; LMWH, low molecular weight heparin; PANLAR, Pan-American League of Associations of Rheumatology; SLE, systemic lupus erythematosus. [/table]	None	https://ard.bmj.com/content/annrheumdis/77/11/1549.full.pdf	Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidelines are developed. The objective of the study is to develop clinical practice guidelines for Latin American patients with lupus. Two independent teams (rheumatologists with experience in lupus management and methodologists) had an initial meeting in Panama City, Panama, in April 2016. They selected a list of questions for the clinical problems most commonly seen in Latin American patients with SLE. These were addressed with the best available evidence and summarised in a standardised format following the Grading of Recommendations Assessment, Development and Evaluation approach. All preliminary findings were discussed in a second face-to-face meeting in Washington, DC, in November 2016. As a result, nine organ/system sections are presented with the main findings; an ‘overarching’ treatment approach was added. Special emphasis was made on regional implementation issues. Best pharmacologic options were examined for musculoskeletal, mucocutaneous, kidney, cardiac, pulmonary, neuropsychiatric, haematological manifestations and the antiphospholipid syndrome. The roles of main therapeutic options (ie, glucocorticoids, antimalarials, immunosuppressant agents, therapeutic plasma exchange, belimumab, rituximab, abatacept, low-dose aspirin and anticoagulants) were summarised in each section. In all cases, benefits and harms, certainty of the evidence, values and preferences, feasibility, acceptability and equity issues were considered to produce a recommendation with special focus on ethnic and socioeconomic aspects. Guidelines for Latin American patients with lupus have been developed and could be used in similar settings.
b946cac696181e91bbfd16378b70c7458034f193	pubmed	Diagnostic criteria and severity assessment of acute cholangitis: Tokyo Guidelines	Diagnostic criteria and severity assessment of acute cholangitis: Tokyo Guidelines # Introduction The pathogenesis of acute cholangitis is biliary infection associated with partial or complete obstruction of the biliary system caused by any of various etiologies including choledocholithiasis, benign and malignant strictures, biliary-enteric anastomotic malfunction, and indwelling biliary stent malfunction. Biliary infection alone does not cause clinical cholangitis unless biliary obstruction raises the intraductal pressure in the bile duct to levels high enough to cause cholangiovenous or cholangiolymphatic refl ux. [bib_ref] Acute cholangitis, Lipsett [/bib_ref] Thus, acute cholangitis progresses from local biliary infection to the systemic infl ammatory response syndrome (SIRS), and advanced disease leads to sepsis with or without organ dysfunction. Prior to the 1970s the mortality rate of patients with acute cholangitis was reported to be over 50%, [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency, Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] but advances in intensive care, new antibiotics, and biliary drainage dramatically reduced the mortality rate to less than 7% by the 1980s. [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] [bib_ref] Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis, Tai [/bib_ref] However, even in the 1990s the reported mortality rates in severe cases still ranged from 11% to 27%, [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] [bib_ref] Acute biliary septic shock, Liu [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] and even now the severe form of acute cholangitis remains a fatal disease unless appropriate management is instituted. The clinical diagnosis of acute cholangitis is made on the basis of the clinical fi ndings, such as Charcot's triad,in combination with the laboratory data and imaging fi ndings, and severity assessment is important because urgent biliary drainage is essential in "severe" cases. However, no standard criteria for the diagnostis and severity assessment of acute cholangitis have ever been established. In this portion of the Tokyo Guidelines, we propose diagnostic criteria and severity assessment criteria for acute cholangitis based on a review of the literature and the consensus of experts reached at the International Consensus Meeting for the Management of Acute Cholecystitis and Cholangitis, held on April 1-2, 2006, in Tokyo. ## Diagnostic criteria for acute cholangitis A variety of different names and defi nitions of acute cholangitis are found in the literature, depending on the authors. [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Factors in management of acute cholangitis, Thompson [/bib_ref] [bib_ref] Acute cholangitis. Multivariate analysis of risk factors, Gigot [/bib_ref] [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Acute bacterial cholangitis: an analysis of clinical manifestation, O'connor [/bib_ref] [bib_ref] Acute suppurative cholangitis. Experience with 15 consecutive cases, Haupert [/bib_ref] [bib_ref] The urgency of diagnosis and surgical treatment of acute suppurative cholangitis, Welch [/bib_ref] [bib_ref] Clinical management of acute cholangitis, Saharia [/bib_ref] Some authors defi ned acute cholangitis based on clinical sign's such as Charcot's triad (fever and/or chills, abdominal pain, and jaundice), 6,16-17 while others emphasized the presence of biliary obstruction or the properties of the bile (suppurative cholangitis), 10,13-14 as a result, there are no standard diagnostic criteria for acute cholangitis. The clinical information used to establish the diagnosis of acute cholangitis includes a history of biliary disease, symptoms and signs, laboratory data, and imaging fi ndings. ## Clinical context and manifestations A history of biliary disease suggests a clinical diagnosis of cholangitis in patients who present with clinical manifestations such as fever, abdominal pain, and jaundice. Patients with a history of gallstone disease, previous biliary surgery, or the insertion of a biliary stent are more likely to develop biliary infection. Clinical manifestations are an important factor in making the diagnosis of acute cholangitis. In 1877,Charcot was the fi rst to describe the clinical triad of fever, jaundice and abdominal pain as a clinical manifestation of acute cholangitis, and in 1959, Reynolds and Dragan 18 were the fi rst to describe a severe form of cholangitis that included Charcot's triad plus septic shock and mental status change (Reynold's Pentad). [fig_ref] Table 1: Incidence of clinical manifestation of acute cholangitis [/fig_ref] summarizes the incidence of each clinical manifestation reported in the literature. [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] [bib_ref] Treatment of choice for choledocholithiasis in patients with acute obstructive suppurative cholangitis..., Chijiiwa [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Factors in management of acute cholangitis, Thompson [/bib_ref] [bib_ref] Acute cholangitis. Multivariate analysis of risk factors, Gigot [/bib_ref] [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Acute bacterial cholangitis: an analysis of clinical manifestation, O'connor [/bib_ref] [bib_ref] Acute suppurative cholangitis. Experience with 15 consecutive cases, Haupert [/bib_ref] [bib_ref] The urgency of diagnosis and surgical treatment of acute suppurative cholangitis, Welch [/bib_ref] [bib_ref] Clinical management of acute cholangitis, Saharia [/bib_ref] Fever and abdominal pain are the most frequently observed clinical manifestations in acute cholangitis, with an incidence of each of up to 80% or more, whereas jaundice is observed in 60%-70% of cases. The incidence of Charcot's triad is reported in not more than 72% (range, 15.4% to 72%) of patients with acute cholangitis, and Reynolds' pentad is extremely rare, reported in only 3.5%-7.7% of the patients. ## Laboratory data Laboratory data indicative of infl ammation (e.g., leukocytosis and an elevated C-reactive protein [CRP] level), and evidence of biliary stasis (e.g., hyperbilirubinemia, elevation of biliary enzymes and liver enzymes) are frequently seen in patients with acute cholangitis, and such laboratory fi ndings support the diagnosis. [fig_ref] Table 2: Positive rates for blood tests in acute cholangitis WBC, white blood cells [/fig_ref] summarizes the positive rate for various blood tests in patients with acute cholangitis reported in the literature. [bib_ref] Abnormal pre-drainage serum creatinine as a prognostic indicator in acute cholangitis, Tai [/bib_ref] [bib_ref] Acute cholangitis. Multivariate analysis of risk factors, Gigot [/bib_ref] [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Clinical management of acute cholangitis, Saharia [/bib_ref] Imaging fi ndings It is usually impossible to identify evidence of bile infection itself by imaging modalities. Imaging evidence of biliary dilatation (evidence of biliary obstruction) and/ or the etiology of the underlying disease (tumor, gallstones, stent-related, etc.) can support the clinical diagnosis of cholangitis. [fig_ref] Table 3: Diagnostic criteria for acute cholangitis [/fig_ref] shows the diagnostic criteria for acute cholangitis that were fi nally adopted by the Organizing Committee. The basic concepts of the criteria are as follows: ## Diagnostic criteria for acute cholangitis (1) Charcot's triad is a defi nite diagnostic criterion for acute cholangitis, (2) if a patient does not have all the components of Charcot' s triad (acute cholangitis is suspected), then defi nite diagnosis can be achieved if both an "infl ammatory response" and "biliary obstruction" are demonstrated by the laboratory data (blood tests) and imaging fi ndings. ## Outcome of the tokyo consensus meeting More than 90% of the participants at the Tokyo Consensus Meeting agreed that the four criteria of: (1) a [formula] ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- B. Laboratory data 5. Evidence of infl ammatory response a 6. Abnormal liver function tests b ---------------------------------------------------------------------------------------------------------------------------------------------------------------------- C. [/formula] ## Severity assessment of acute cholangitis Patients with acute cholangitis may present with anything from a mild, self-limited illness to a severe, potentially life-threatening illness. Most cases respond to initial medical treatment consisting of general supportive therapy and intravenous antibiotics, but some cases do not respond to medical treatment, and the clinical manifestations and laboratory data do not improve. Such cases may progress to sepsis, with or without organ dysfunction, requiring appropriate management that includes intensive care, organ-supportive care, and urgent biliary drainage, in addition to medical treatment. [fig_ref] Table 4: Prognostic factors in acute cholangitis [/fig_ref] summarizes the risk factors reported in the literature for poor outcome in patients with acute cholangitis. [bib_ref] Acute suppurative cholangitis, a medical and surgical emergency, Andrew [/bib_ref] [bib_ref] Pathogenesis and clinical features of acute cholangitis accompanied by shock, Shimada [/bib_ref] [bib_ref] Emergency surgery for severe acute cholangitis. The high-risk patients, Lai [/bib_ref] [bib_ref] Risk factors and classifi cation of acute suppurative cholangitis, Csendes [/bib_ref] [bib_ref] Acute cholangitis. Multivariate analysis of risk factors, Gigot [/bib_ref] [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Acute suppurative cholangitis. Experience with 15 consecutive cases, Haupert [/bib_ref] Organ dysfunction is the most common predictor of a poor outcome. On the other hand, based on the pathophysiology, "severe" acute cholangitis can also be defi ned as that which accompanies organ dysfunction caused by sepsis. Thus, "the onset of organ dysfunction" is an important factor in the defi nition of severe (grade III) acute cholangitis. ## Severity assessment criteria Another factor for the severity assessment of acute cholangitis is "response to initial medical treatment"; treatment consisting of general supportive care and antibiotics should be instituted as soon as possible for all patients who are diagnosed with acute cholangitis. Patients diagnosed with acute cholangitis that is not complicated by organ dysfunction, who did not respond to medical treatment and who continue to have SIRS and/or sepsis require additional treatment that includes either a change of antibiotic or biliary drainage. The severity of such cases is classifi ed as moderate (grade II). Patients who respond to medical treatment and whose clinical manifestations and laboratory data improve are classifi ed as having mild (grade I) disease. and [fig_ref] Table 6: Defi nitions of severity assessment criteria for acute cholangitis [/fig_ref] show the concepts and criteria for the severity assessment of acute cholangitis. ## Outcome of the tokyo consensus meeting More than 70% of the participants at the Tokyo Consensus Meeting agreed that the severity of acute cholangitis should be divided into three gradesmild (grade I), moderate (grade II), and severe (grade III). To stratify acute cholangitis into the three grades, two different criteria were necessary, and it was decided to use "onset of organ dysfunction" and "response to the initial medical treatment" as criteria for the severity assessment of acute cholangitis . ## Discussion at the tokyo consensus meeting Diagnostic criteria for acute cholangitis "Acute cholangitis" is a clinical diagnosis. A defi nite diagnosis cannot be made on the basis of the results of any single test. The diagnosis of acute cholangitis is made on the basis of: (1) a history of biliary disease, (2) the clinical manifestations, (3) laboratory data that indicate the presence of infl ammation and biliary obstruction, and (4) imaging fi ndings that indicate biliary obstruction. More than 90% of participants at the International Consensus Meeting agreed that these four criteria were suitable for making the diagnosis of acute cholangitis (consensus was reached). In terms of the clinical context and manifestations, a history of biliary disease and the clinical presentation are important factors in reaching the diagnosis. A history of biliary disease, such as gallstones, a history of previous biliary surgery, and having an indwelling biliary stent play an important role in making the diagnosis, as agreed upon by many participants at the Consensus Meeting. The more important clinical manifestations are clinical signs, such as Charcot's triad (fever and/or chills, abdominal pain, and jaundice). According to the literature, 50%-70% of acute cholangitis patients present with Charcot's triad, meaning that more than onethird of acute cholangitis patients do not present with all the components of Charcot's triad. The laboratory data and imaging fi ndings can provide evidence to support the diagnosis in patients who have clinical manifestations of acute cholangitis but who do not show all the components of Charcot's triad (refer to [fig_ref] Table 3: Diagnostic criteria for acute cholangitis [/fig_ref]. ## Severity assessment criteria for acute cholangitis A systematic review of the literature revealed that there were no standard criteria for either the diagnosis or se-verity assessment of acute cholangitis. Some authors have defi ned acute cholangitis associated with Reynold's pentad (Charcot's triad plus "shock" and "disturbance of consciousness") or organ dysfunction as "severe", while others have referred to it as "toxic cholangitis" or "acute obstructive suppurative cholangitis (AOSC)". A proposal that the onset of dysfunction of at least one organ be used as the criterion for severe (grade III) disease was supported by more than 90% of the panelists at the International Consensus Meeting (consensus was reached). There was some argument about whether the score on an acute physiology scoring system, such as Acute physiology and chronic health evaluation (APACHE II) score or a multiple organ dysfunction scoring system, such as Marshall's system, or sepsis-related organ failure assessment (SOFA) system should be used as a criterion for severe (grade III) acute cholangitis. The principal advantage of these scoring systems is that they provide gradations of severity. The APACHE II system has been validated, especially for critical care patients, including patients with sepsis, and acute cholangitis can be interpreted as a subset of sepsis. The disadvantage of these scoring systems is that the scores are sometimes troublesome to calculate, and critically speaking, they have not been satisfactorily validated in patients with acute cholangitis. The vote on this argument showed that 37.8% of the panelists supported the use of APACHE II and 62.2% did not. As a result of this vote, the chairmen of this session, Drs. Yoshifumi Kawarada (Japan) and Henry Pitt (USA), proposed to remit the fi nal decision on whether or not APACHE II should be included as a criterion for severe (grade III) acute cholangitis to the Organizing Committee, and this proposal was approved by the audience. After the meeting, the Organizing Committee decided not to include the use of the APACHE II score as a criterion for the defi nition of severe (grade III) acute cholangitis, and we established the criteria by evaluating the presence or absence of the dysfunctions of six major organs/systems (refer to [fig_ref] Table 6: Defi nitions of severity assessment criteria for acute cholangitis [/fig_ref]. Deciding on the criteria for the assessment of acute cholangitis as moderate was the hardest part of this session. More than 70% of the participants agreed that a middle category of severity -moderate (grade II)was necessary for acute cholangitis (consensus was reached). The original defi nition of moderate (grade II) acute cholangitis was "acute cholangitis that requires biliary drainage but is not complicated by organ dysfunction." However, more than 80% of the participants voted against the need for biliary drainage as a criterion because it is a therapeutic intervention that should be selected only after the severity assessment has been completed. Thus, another criterion was needed in order to stratify acute cholangitis into three grades. Other criteria for assessing acute cholangitis as moderate (grade II) were suggested by the audience. The most accepted criterion during the discussion was "resistance to initial treatment", with some others being "recurrence of symptoms" and "SIRS". The chairmen of this session also proposed to remit the fi nal decision to the Organizing Committee, and this proposal was approved by the audience. After the Meeting, the Organizing Committee concluded that the criterion for assorting into moderate (grade II) and mild (grade I) acute cholangitis should be "response to initial medical treatment consisting of general supportive care (intravenous fl uid) and antibiotics," i.e., acute cholangitis that responds to medical treatment is defi ned as mild (grade I) acute cholangitis, whereas acute cholangitis that does not respond to the initial medical treatment but does not have organ dysfunction is defi ned as moderate (grade II) acute cholangitis [fig_ref] Table 6: Defi nitions of severity assessment criteria for acute cholangitis [/fig_ref]. No specifi c data or fi ndings were adopted as criteria, because it is impossible to predict the need for biliary drainage based on the laboratory data or other fi ndings. It was therefore concluded that we considered that it is important to stratify acute cholangitis as "severe" or "non-severe" at the time of diagnosis. Patients with the former require urgent biliary drainage in addition to general and organsupportive treatment, while patients with the latter should be monitored to determine whether they respond to the initial medical treatment. [table] Table 1: Incidence of clinical manifestation of acute cholangitis [/table] [table] Table 2: Positive rates for blood tests in acute cholangitis WBC, white blood cells; ALP, alkaline phosphatase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CA 19-9, carbohydrate antigen 19-9 [/table] [table] Table 3: Diagnostic criteria for acute cholangitis [/table] [table] Table 4: Prognostic factors in acute cholangitis [/table] [table] Table 6: Defi nitions of severity assessment criteria for acute cholangitis [/table]	None	https://link.springer.com/content/pdf/10.1007/s00534-006-1156-7.pdf	None
d45129ed04207f24bbe0d0dc539d722eb2f0e522	pubmed	Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology	Extracellular vesicles in diagnostics and therapy of the ischaemic heart: Position Paper from the Working Group on Cellular Biology of the Heart of the European Society of Cardiology Extracellular vesicles (EVs)-particularly exosomes and microvesicles (MVs)-are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis * Corresponding authors. Tel: þ31 88 75 575 67; fax: þ31 30 25 226 93, # Introduction ## Cellular secretion for communication; extracellular vesicles Cells in multicellular organisms must communicate efficiently with each other in order to propagate signals and co-ordinate function. In addition to distinct chemical signals (paracrine and endocrine) and direct cell-cell contact, a growing body of evidence shows that cells communicate via a variety of small, membrane-enclosed vesicles, collectively termed 'extracellular vesicles' (EVs). EVs ranging from $40 nm to several microns in size , are released into all extracellular fluids including blood. They transport a cell-specific cargo of proteins, lipids, metabolites, and nucleic acids that can affect target cells. This process occurs during normal cellular physiology as well as during stress and disease. In this rapidly evolving area of research, with its associated technical challenges, it is vital to establish standardized techniques for their isolation and criteria for their identification. EVs are released by all cardiac, endothelial and inflammatory cell types, suggesting they have an important role in the cardiovascular system, including the ischaemic heart. [bib_ref] Microvesicles and exosomes for intracardiac communication, Sluijter [/bib_ref] [bib_ref] Exosomes and cardiovascular protection, Davidson [/bib_ref] [bib_ref] Microvesicles and exosomes: new players in metabolic and cardiovascular disease, Lawson [/bib_ref] [bib_ref] Roles of exosomes in cardioprotection, Barile [/bib_ref] [bib_ref] Microparticles in cardiovascular diseases, Vanwijk [/bib_ref] [bib_ref] Exosomes: fundamental biology and roles in cardiovascular physiology, Ibrahim [/bib_ref] Therefore, the overall objective of this position paper is to provide a set of recommendations for the isolation, characterization, analysis, and translational application of EVs focussing mainly on the ischaemic heart, i.e. acute myocardial infarction and post-ischaemic heart failure. Coronary atherosclerosis is not discussed in this position paper in detail (see recent reviews and position papers of the European Society of Cardiology that covers this topic extensively 7-9 ). ## Isolation and characterization of evs ## Definition of evs Eukaryotic EVs include (i) exosomes released by exocytosis of multivesicular bodies (usually 50-150 nm), (ii) Microvesicles (MVs, also called microparticles or ectosomes), vesicles around 0.1-1 lm in diameter shed from the plasma membrane, [bib_ref] Characterization of physical properties of tissue factor-containing microvesicles and a comparison of..., Ettelaie [/bib_ref] [bib_ref] Highly-purified exosomes and shed microvesicles isolated from the human colon cancer cell..., Xu [/bib_ref] [bib_ref] Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection, Só Dar [/bib_ref] and (iii) apoptotic vesicles released by blebbing of apoptotic cells some of which are > 1 lm (apoptotic bodies), [bib_ref] Caco-2 cells infected with rotavirus release extracellular vesicles that express markers of..., Bautista [/bib_ref] [bib_ref] Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from..., Thery [/bib_ref] and (iv) large oncosomes released by migratory tumour cells (> 1 mm) [bib_ref] Large oncosomes in human prostate cancer tissues and in the circulation of..., Vizio [/bib_ref] [bib_ref] Large oncosomes contain distinct protein cargo and represent a separate functional class..., Minciacchi [/bib_ref]. However, since current isolation protocols only result in relative enrichment of vesicle subpopulations rather than their complete purification, [bib_ref] Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle..., Kowal [/bib_ref] and that no specific markers are available for the subpopulations, it is preferable to refer to purified vesicles as 'EVs' and accurately report the purification method used and characteristics present. An operational definition of small EVs (sEVs) is appropriate for the exosomeenriched population pelleting at high speeds. [bib_ref] Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle..., Kowal [/bib_ref] ## Methods for the isolation and characterization of evs Several methods of isolating EVs have been developed [fig_ref] Figure 3: Standard techniques used for isolating exosomes fromother EVs, protein, and lipoproteins present... [/fig_ref]. The optimal EV isolation procedure will depend on the source biofluid, the EV subpopulation of interest, and their intended end-use, whether that is to be diagnostic biomarker studies, mechanistic studies, or for in vivo administration. However, no EV isolation method yet exists that can be considered as a gold standard, since residual proteins and/or lipoproteins remains problematic. [bib_ref] Minimal experimental requirements for definition of extracellular vesicles and their functions: a..., Lö Tvall [/bib_ref] Complete removal of lipoproteins (present in both blood and tissue culture serum) remains challenging due to overlapping size and/or densities between EVs and different lipoprotein particles . [bib_ref] Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection, Só Dar [/bib_ref] [bib_ref] Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Thery [/bib_ref] [bib_ref] Co-isolation of extracellular vesicles and high-density lipoproteins using density gradient ultracentrifugation, Yuana [/bib_ref] Moreover, low density lipoprotein (LDL) and exosomes may associate, rendering their complete separation from blood samples impossible using any technique. [bib_ref] Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection, Só Dar [/bib_ref] This, however, might be used in isolating a subset of EVs co-precipitated with LDL or high density lipoprotein (HDL) particles. [bib_ref] Circulating TNFR1 exosome-like vesicles partition with the LDL fraction of human plasma, Zhang [/bib_ref] [bib_ref] Extracellular vesicle proteins associated with systemic vascular events correlate with heart failure:..., Zhang [/bib_ref] In the simplest technique based on precipitation (e.g. ExoQuick TM ), the biofluid sample is mixed and incubated with a hydrophilic polymer prior to low speed centrifugation. The polymers attract water molecules away from the solvation layer around the EVs causing their precipitation. Several manufacturers now market products based on this technique. However, they result in high levels of contaminants including serum proteins and lipoproteins as well as residual matrix that can affect EV biological functions. [bib_ref] Residual matrix from different separation techniques impacts exosome biological activity, Paolini [/bib_ref] Differential centrifugation has long been regarded as the gold standard technique. [bib_ref] Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Thery [/bib_ref] In the most commonly used protocol, cells are removed by centrifugation at 300 x g for 10 min; the supernatant is then cleared of apoptotic bodies by centrifugation at 2000 x g for 10 min followed by 10 000 x g for 30 min to preferentially pellet MVs; exosome-enriched sEVs are then purified from the supernatant by ultracentrifugation at [bib_ref] Co-isolation of extracellular vesicles and high-density lipoproteins using density gradient ultracentrifugation, Yuana [/bib_ref] Exosomes and MVs overlap in size with VLDL and chylomicrons, and in density with HDL/LDL particles. Exosome density is typically 1.06-1.20 g/mL. MV density is not well defined but they have been found between $1.03-1.08 g/mL. [bib_ref] Characterization of physical properties of tissue factor-containing microvesicles and a comparison of..., Ettelaie [/bib_ref] 100 000 x g for 70 min. [bib_ref] Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Thery [/bib_ref] However, optimal parameters are highly dependent on the type of centrifuge rotor used. [bib_ref] Isolation of exosomes by differential centrifugation: theoretical analysis of a commonly used..., Livshits [/bib_ref] For further purification of EVs from co-pelleted protein complexes [bib_ref] Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting..., Gyorgy [/bib_ref] and lipoproteins, a density gradient is recommended (sucrose or preferably iodixanol). [bib_ref] Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Thery [/bib_ref] Because of the number of steps involved and the length of the procedure, it is clearly unsuited for the analysis of large numbers of samples. More recently, concerns have been raised that ultracentrifugation can cause damage, fusion, and/or aggregation of vesicles. [bib_ref] High-speed centrifugation induces aggregation of extracellular vesicles, Linares [/bib_ref] There is increasing enthusiasm for the use of size-exclusion chromatography. [bib_ref] Single-step isolation of extracellular vesicles by size-exclusion chromatography, Boing [/bib_ref] Suitable matrices include Sepharose 2B, Sepharose CL-4B, or Sephacryl S-400. [bib_ref] Rito-Palomares M. Isolation of exosomes from blood plasma: qualitative and quantitative comparison..., Baranyai [/bib_ref] The resolution of size separation is dependent on column length. This technique is effective at separating EVs from proteins and some lipoproteins, but samples usually become considerably diluted and efficient separation of lipoproteins remain challenging. [bib_ref] Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection, Só Dar [/bib_ref] [bib_ref] Rito-Palomares M. Isolation of exosomes from blood plasma: qualitative and quantitative comparison..., Baranyai [/bib_ref] [bib_ref] Ready-made chromatography columns for extracellular vesicle isolation from plasma, Welton [/bib_ref] Other techniques are less well established. Filtration (0.2 lm-0.8 lm) aids in removal of larger vesicles, but under high pressure it is possible that it could cause the fragmentation of larger EVs into smaller vesicles. Immuno-affinity can be an effective means to isolate specific EV populations, using columns or magnetic beads for example, but for functional follow-up studies this is still challenging. Flow cytometry-based analysis of individual EVs is a valuable tool for EV characterization and quantification, although it remains challenging due to size and sensitivity limitations. [bib_ref] Dynamics of dendritic cell-derived vesicles: high-resolution flow cytometric analysis of extracellular vesicle..., Nolte-'t Hoen [/bib_ref] Progress has been made in developing these technologies for specific EV sorting, but some prerequisite steps need to be taken. [bib_ref] Prerequisites for the analysis and sorting of extracellular vesicle subpopulations by high-resolution..., Kormelink [/bib_ref] Furthermore, this approach requires certainty as to the specificity of epitopes expressed by the desired population of EVs-which may not be the case for exosomes.Other isolation techniques such as microfluidics are under development have not yet been rigorously tested. For pre-clinical or clinical studies of the ischaemic heart, measurement of EVs can be performed from in vivo blood, lymphatic or pericardial fluid samples, ex vivo heart perfusate samples, and tissue culture media samples that may require different isolation techniques. ## Isolation from blood Pre-analytical procedures can have a large impact on blood EV measurements. For example, since clotting may increase the number of EVs in blood by 10-fold, [bib_ref] Isolation of human platelet membrane microparticles from plasma and serum, George [/bib_ref] it is usually preferable to use plasma. On the other hand, serum may be useful when overall yield of platelet MVs is more important than accurate quantification of particle number. A crucial concern is the minimization of platelet activation and EV release. Standardized procedures to minimize platelet activation during plasma isolation should be followed. [bib_ref] Standardization of pre-analytical variables in plasma microparticle determination: results of the International..., Lacroix [/bib_ref] [bib_ref] Handling and storage of human body fluids for analysis of extracellular vesicles, Yuana [/bib_ref] Fasting before blood sampling can help to minimize chylomicron contamination. [bib_ref] Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection, Só Dar [/bib_ref] Blood should be collected in citrated or acid-citrate-dextrose anticoagulant tubes, [bib_ref] Standardization of pre-analytical variables in plasma microparticle determination: results of the International..., Lacroix [/bib_ref] [bib_ref] Improved circulating microparticle analysis in acid-citrate dextrose (ACD) anticoagulant tube, Gyö Rgy [/bib_ref] such as vacutainers, and the first tube of blood should be discarded. [bib_ref] Standardization of pre-analytical variables in plasma microparticle determination: results of the International..., Lacroix [/bib_ref] It is recommended to dilute blood plasma or serum at least 2x in Ca 2þ -free phosphate buffered saline (PBS) prior to centrifugation in order to reduce the viscosity. [bib_ref] Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Thery [/bib_ref] However, if annexin V binding will be assessed (which requires Ca 2þ ), PBS should be avoided in order to prevent formation of calcium-phosphate micro-precipitates. The plasma or serum should be centrifuged within 2 h, and agitation avoided. [bib_ref] Standardization of pre-analytical variables in plasma microparticle determination: results of the International..., Lacroix [/bib_ref] Extracellular vesicles in diagnostics and therapy of the ischaemic heart of the centrifuge brake, plasma can be carefully collected, and recentrifuged under identical conditions. This platelet-free-plasma may be snap frozen and stored at -80 C prior to analysis. Even when using the same protocol, inter-laboratory variability in plasma EV counts can vary by an order of magnitude. [bib_ref] Standardization of pre-analytical variables in plasma microparticle determination: results of the International..., Lacroix [/bib_ref] Given these problems of irreproducibility, The International Society on Thrombosis, and Haemostasis has advised that further refinements are required before flow cytometric enumeration of platelet MV numbers is ready for clinical use. [bib_ref] Standardization of pre-analytical variables in plasma microparticle determination: results of the International..., Lacroix [/bib_ref] ## Isolation from pericardial fluid Pericardial fluid contains EVs that may provide useful biomarker information about cardiac health. [bib_ref] Human pericardial fluid contains exosomes enriched with cardiovascular-expressed microRNAs and promotes therapeutic..., Beltrami [/bib_ref] [bib_ref] Exosomal clusterin, identified in the pericardial fluid, improves myocardial performance following MI..., Foglio [/bib_ref] As yet there is no consensus as to the ideal method for isolation of EVs from pericardial fluid. ## Isolation from conditioned media of cultured cells For the isolation of vesicles produced by cells in tissue culture the important considerations are quite different. The main potential source of contamination is typically from foetal calf serum (FCS) added to the culture medium. [bib_ref] Importance of exosome depletion protocols to eliminate functional and RNA-containing extracellular vesicles..., Shelke [/bib_ref] FCS contains large number of vesicles including exosomes as well as lipoproteins. Exosomes can be largely removed by pre-treating FCS by 18 h ultracentrifugation at 100 000 Â g, [bib_ref] Importance of exosome depletion protocols to eliminate functional and RNA-containing extracellular vesicles..., Shelke [/bib_ref] and removal is enhanced by diluting FCS five-fold in culture medium to reduce viscosity.Several companies market FCS which has been processed to remove exosomes, though the method used is not specified. However, some caution should be taken for FBS-associated RNA which might be co-isolated with cell-culture derived extracellular RNA (exRNA), thereby interfering with the downstream RNA analysis. [bib_ref] Fetal bovine serum RNA interferes with the cell culture derived extracellular RNA, Wei [/bib_ref] Alternatively, pre-defined serum or serum-free conditions can be used, and indeed is essential if preparing EVs for clinical use. [bib_ref] Applying extracellular vesicles based therapeutics in clinical trials-an ISEV position paper, Lener [/bib_ref] However, cells may undergo apoptosis or autophagy and release apoptotic bodies after extended periods in the absence of serum. Conditioned medium is usually collected after 24-48 h culture. Although sequential filtration offers the advantage of using large volumes of culture media, [bib_ref] Benchtop isolation and characterization of functional exosomes by sequential filtration, Heinemann [/bib_ref] its effect on biological activity of the isolated EVs has not been well characterized. HPLC has been successfully used to purify exosomes. [bib_ref] Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury, Lai [/bib_ref] ## Isolation from isolated heart perfusate EVs can be isolated from hearts perfused with buffer such as those mounted on a Langendorff apparatus. [bib_ref] Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by..., Giricz [/bib_ref] Pre-concentration of the perfusate by ultrafiltration may be necessary for a sufficient yield, but subsequently any of the techniques described above may be used. It is important to be aware that exosome-sized, calcium-phosphate nanoparticles form spontaneously in Ca 2þ -containing bicarbonate buffer, which can interfere with some analyses such as nanoparticle tracking analysis. [bib_ref] Calcium phosphate formation in vitro. I. Factors affecting initial phase separation, Termine [/bib_ref] ## Storage of evs EVs appear to be relatively stable when stored at -80 C or less, 48 but repeated freeze-thaw cycles should be avoided and cryo-preservatives such as glycerol and DMSO should not be added as they may lyse EVs. [bib_ref] Effect of storage on physical and functional properties of extracellular vesicles derived..., L} [/bib_ref] Trehalose has recently been proposed to preserve exosomes. [bib_ref] Trehalose prevents aggregation of exosomes and cryodamage, Bosch [/bib_ref] ## Visualization and quantitation of evs In most studies, it is informative to quantify EVs using either nanoparticle tracking analysis, tuneable resistive pulse sensing, or dynamic light scattering [fig_ref] Figure 4: Standard methods of characterizing EVs [/fig_ref]. Importantly, these methods usually do not discriminate EVs from non-vesicular events such as LDL particles. [bib_ref] Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection, Só Dar [/bib_ref] The ratio of particle number or lipid content to protein content of the preparations can give an indication of relative EV purity, as compared to protein concentration only. [bib_ref] How pure are your vesicles?, Webber [/bib_ref] [bib_ref] Improved characterization of EV preparations based on protein to lipid ratio and..., Osteikoetxea [/bib_ref] Exosome morphology should be confirmed by transmission electron microscopy, [bib_ref] Isolation and characterization of exosomes from cell culture supernatants and biological fluids, Thery [/bib_ref] cryo-electron microscopy, [bib_ref] Extracellular vesicles from blood plasma: determination of their morphology, size, phenotype and..., Arraud [/bib_ref] or atomic force microscopy. [bib_ref] Atomic force microscopy: a novel approach to the detection of nanosized blood..., Yuana [/bib_ref] In addition, presented images should contain multiple EVs per field [fig_ref] Figure 4: Standard methods of characterizing EVs [/fig_ref]. Using flow cytometry, the lower size-limit of detection is steadily decreasing, but it remains technically challenging to obtain comprehensive analyses of MVs let alone exosome-sized particles. [bib_ref] Prerequisites for the analysis and sorting of extracellular vesicle subpopulations by high-resolution..., Kormelink [/bib_ref] ## Characterization of evs Further characterization of EVs should include the detection of specific markers. It is generally recommended to demonstrate presence of tetraspanin proteins such as CD9, CD81, CD63, and the intra-vesicular protein Alix, which are involved in exosome biogenesis, in addition to other typical marker proteins such as HSP70, flotillin-1, or major histocompatibility complex (MHC) class I and class II. However, recent studies indicate some of these are not as specific for exosomes as thought. [bib_ref] Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle..., Kowal [/bib_ref] [bib_ref] Comparative marker analysis of extracellular vesicles in different human cancer types, Yoshioka [/bib_ref] Co-enrichment of CD63, CD9, and CD81 tetraspanins and endosome markers such as syntenin-1 and TSG101 may be seen as indicative of exosome presence. [bib_ref] Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle..., Kowal [/bib_ref] MV surface marker expression is a useful index of cell-type of origin, and can be quantified by flow cytometry in order to analyse sub-populations. In addition, MVs may be characterized as 'calcium-dependent annexin V binding' or 'calcium-independent lactadherin (MFGE8) binding'. Gating strategies for flow cytometry involve the use of fluorescent reference beads of known sizes. Preferred beads are the silica beads because their refractive index is close to the one of biological particles. [bib_ref] Single vs. swarm detection of microparticles and exosomes by flow cytometry, Van Der Pol [/bib_ref] Of note, not all MVs are detectable this way. To quantitatively detect exosome proteins, a nano-plasmonic exosome sensor was developed that comprises arrays of periodic nanoholes patterned in a metal film. The arrays are functionalized with affinity ligands for different exosomal protein markers and offers highly sensitive and label-free exosome analyses by continuous and real-time monitoring of molecular binding. [bib_ref] Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor, Im [/bib_ref] In order to demonstrate EV functionality it may be useful to demonstrate their interaction with, fusion, or uptake into recipient cells. To this end, EVs can be fluorescently labelled with lipophilic dyes, or by transfection of parent cells with GFP-tagged proteins packaged in EVs. Control experiments using 'dye-only' samples prepared in parallel the same way as EVs are essential to confirm the involvement of EVs 57 and that free dye has been removed, which can otherwise form micelles. Density gradient ultracentrifugation is a frequently used approach to remove this non-EV-associated dye. Co-incubation with receptor antagonists or uptake inhibitors will provide insights in mechanisms of uptake although these compounds are notorious for their toxicity and limited specificity. [bib_ref] Microparticles from human atherosclerotic plaques promote endothelial ICAM-1-dependent monocyte adhesion and transendothelial..., Rautou [/bib_ref] ## Analysis of nucleic acid, protein, and lipid contents of evs Proteomics can provide a more comprehensive description of EV protein content, but the isolation protocol must be carefully optimized in order to remove plasma protein contamination in blood EV samples. [bib_ref] The impact of disparate isolation methods for extracellular vesicles on downstream RNA..., Van Deun [/bib_ref] [bib_ref] Mass spectrometry of extracellular vesicles, Pocsfalvi [/bib_ref] Similar concerns arise with transcriptomic analyses of miRNA, mRNA, or DNA contents, particularly with regard to potentially contaminating HDL particles and argonaute 2-RNA complexes, which are known to transport miRNA. [bib_ref] Intercellular transport of microRNAs, Boon [/bib_ref] Care must be taken to avoid haemolysis which can affect circulating miRNA levels. [bib_ref] Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker..., Pritchard [/bib_ref] EV proteomics has been studies in large clinical cohorts, [bib_ref] The diagnostic and prognostic potential of plasma extracellular vesicles for cardiovascular disease, Bank [/bib_ref] but undoubtedly the greatest interest is currently focused at the RNA content of EVs as potential biomarkers. [bib_ref] The diagnostic and prognostic potential of plasma extracellular vesicles for cardiovascular disease, Bank [/bib_ref] EV lipidomics is an interesting but under-explored area. [bib_ref] Mass-spectrometry-based molecular characterization of extracellular vesicles: lipidomics and proteomics, Kreimer [/bib_ref] Nucleic acid, protein and lipid entries from EV studies are available in EV databases (http://www.exocarta.org/, http://student4.postech.ac.kr/evpedia2_xe/xe/ and http://microvesicles. org/ (10 November 2017, date last accessed)). However, because of the diversity of EV isolation protocols used, these database entries should be treated with caution. ## Technical control experiments RNase or protease may be applied to remove extra-vesicular nucleic acids and proteins and confirm intra-vesicular localization. Detergent control during flow cytometry or sizing performed by tuneable resistive pulse sensing or dynamic light scattering enables distinguishing EVs from protein aggregates (the latter being more resistant to detergents lysis than EVs). [bib_ref] Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting..., Gyorgy [/bib_ref] [bib_ref] Improved flow cytometric assessment reveals distinct microvesicle (cellderived microparticle) signatures in joint..., Gyorgy [/bib_ref] [bib_ref] Circulating immune complexes do not affect microparticle flow cytometry analysis in acute..., Amabile [/bib_ref] Of note, small and large EVs have different detergent sensitivities [bib_ref] Differential detergent sensitivity of extracellular vesicle subpopulations, Osteikoetxea [/bib_ref] and lipoproteins also show a limited sensitivity to detergent lysis. [bib_ref] Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection, Só Dar [/bib_ref] ## Recommendations for isolation and purification of evs At present, there is no universally agreed protocol for isolation of pure populations of EVs or subpopulations of EVs. Even their precise nomenclature is in flux, and will presumably remain so until clear surface protein signatures of individual EV subtypes will be established. Given the rapid ## A spoʃer's guide to evs under transmission electron microscopy Plasma lipoprotein parƟcles developments in this area it is important to remain cognizant of experimental limitations and caveats in order to avoid overstating conclusions. At present, it is challenging to isolate EVs from tissue homogenates. The likely contamination of EV preparations with proteins and lipoproteins renders many results suspect unless crucial control experiments are performed. Differential detergent lysis is a simple, inexpensive EV control for flow cytometry. [bib_ref] Detection and isolation of cell-derived microparticles are compromised by protein complexes resulting..., Gyorgy [/bib_ref] [bib_ref] Improved flow cytometric assessment reveals distinct microvesicle (cellderived microparticle) signatures in joint..., Gyorgy [/bib_ref] Furthermore, to avoid swarm detection at high particle concentrations, analysis of serial dilution of samples is recommended during flow cytometry. [bib_ref] Prerequisites for the analysis and sorting of extracellular vesicle subpopulations by high-resolution..., Kormelink [/bib_ref] A characterization of EV proteins will provide a basis on purity without excluding a potential biological role. provides a check-list of criteria for the successful isolation and characterization of EVs, as well as more specific criteria for exosomes. ## Mechanism of ev actions in the heart EVs appear to be released from all major cell types found in the heart. For example, exosomes have been shown to be released by primary adult cardiomyocytes, 68,69 primary cardiac endothelial cells, [bib_ref] Cardiac endothelial cell-derived exosomes induce specific regulatory B cells, Song [/bib_ref] primary cardiac fibroblasts, [bib_ref] Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy, Bang [/bib_ref] and vascular smooth muscle cells. [bib_ref] Vascular smooth muscle cell calcification is mediated by regulated exosome secretion, Kapustin [/bib_ref] Most MVs present in the plasma of healthy individuals are derived from platelets and erythrocytes, but plasma MVs also originate from leucocytes, endothelial cells, monocytes neutrophils, and lymphocytes. [bib_ref] Platelet microparticles: a wide-angle perspective, Horstman [/bib_ref] [bib_ref] Microvesicles as cell-cell messengers in cardiovascular diseases, Loyer [/bib_ref] Most mechanistic experiments to date use EVs isolated from cultured cells, since isolation of cell-type specific EVs in vivo is not currently feasible. Recently, a clear overview was provided on the role of EVs in coronary artery disease. [bib_ref] Extracellular vesicles in coronary artery disease, Boulanger [/bib_ref] This section will discuss the most relevant examples of the function of EVs released from cells of the heart tissue and their postulated mechanisms of action. ## Cardiomyocyte-derived evs Cardiomyocytes are potentially an important source of diagnostic EVs particularly in situations of stress such as myocardial ischaemia and failure. [bib_ref] Microvesicles and exosomes for intracardiac communication, Sluijter [/bib_ref] However, few studies have examined exosomes from adult as opposed to neonatal cardiomyocytes, and even here it is unclear to what extent this relates to the situation in vivo. In vitro, hypoxia and reoxygenation leads to the release of heat shock proteins (HSPs) HSP70 and HSP90, as well as HSP60, a 'danger signal', via exosomes in primary adult rat cardiomyocytes. [bib_ref] HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway, Gupta [/bib_ref] Cardiomyocytes also release EVs containing tumour necrosis factor (TNF)-a, [bib_ref] Mechanism of TNF-alpha autocrine effects in hypoxic cardiomyocytes: initiated by hypoxia inducible..., Yu [/bib_ref] potentially participating in the propagation of an inflammatory response. Glucose deprivation induced the loading of neonatal rat cardiomyocyte exosomes with functional glucose transporters and glycolytic enzymes. When internalized by endothelial cells, these exosomes increased glucose uptake, glycolytic activity, and pyruvate production in recipient cells. [bib_ref] Cardiomyocyte exosomes regulate glycolytic flux in endothelium by direct transfer of GLUT..., Garcia [/bib_ref] The transfer of exosomes from glucose-deprived H9C2 cardiac myoblasts to endothelial cells also induced changes in transcriptional activity of pro-angiogenic genes. [bib_ref] Glucose starvation in cardiomyocytes enhances exosome secretion and promotes angiogenesis in endothelial..., Garcia [/bib_ref] Hyperglycaemia altered cardiomyocyte-derived exosomes in a model of diabetes-associated cardiomyopathy, [bib_ref] Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer..., Wang [/bib_ref] as well as from the hypoxic myocardium which can activate in vitro cultured endothelial cells. [bib_ref] Cardiac-released extracellular vesicles can activate endothelial cells, Deddens [/bib_ref] [bib_ref] Circulating extracellular vesicles contain miRNAs and are released as early biomarkers for..., Deddens [/bib_ref] Finally, external stretch caused cardiomyocytes to release exosomes enriched Recommendations for the isolation and characterization of EVs [adapted from General recommendations for EVs (1) EVs can be isolated from either tissue culture supernatant or extracellular fluids. Reliable methods for EV isolation from tissue homogenates remain to be established. (2) Ensure consistency of pre-analytical procedures. (3) Report complete experimental details, including pre-analytical and isolation procedure and details of all antibodies used.Also include all negative data sets. (4) If EV function is analysed, include: a. a dose-response curve. b. systematic negative ('EV-depleted') controls. c. demonstrate an association between a protein/miRNA and EVs in support of any function ascribed to them, e.g. using immuno-EM, or co-purification on a density gradient. ## Specific recommendations for exosomes (1) Avoid precipitation methods of isolation, (4) Assess levels of contaminating proteins, e.g. serum albumin, extracellular matrix, mitochondrial, nuclear protein, argonaute, lipoproteins. It is not currently possible to state a 'minimum acceptable level' but protein contamination can form an important internal quality control. (5) If electron microscope images are shown, they should include more than 1 exosome per field. (6) Determine the size distribution using two orthogonal techniques, e.g.: nanoparticle tracking analysis, electron microscopy, tuneable resistive pulse sensing or dynamic light scattering. ## Specific recommendations for mvs (1) Establish rigorous guidelines for consistency of isolation methods, (2) Determine the accuracy and precision (coefficient of variation) of the quantification methods used. a Some markers such as CD63 may not be completely specific for exosomes. [bib_ref] Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle..., Kowal [/bib_ref] in functional angiotensin II type-1 receptors (AT1Rs). [bib_ref] Circulating exosomes induced by cardiac pressure overload contain functional angiotensin II type..., Pironti [/bib_ref] Administration of AT1R-enriched exosomes restored responsiveness to angiotensin II in the vessels of AT1R-KO mice. Together, these data indicates that cardiomyocytes respond to environmental changes by releasing specific EVs that specifically modulate neighbour-cell function. ## Cardiac progenitor cells-derived evs A variety of cells with the capacity to proliferate and differentiate into cardiac cells have been termed cardiac progenitor cells (CPCs). Exosomes released from these cell types appear to recapitulate the cardioprotective and regenerative benefits of their parent cells. [bib_ref] Exosomes as critical agents of cardiac regeneration triggered by cell therapy, Ibrahim [/bib_ref] [bib_ref] Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve..., Barile [/bib_ref] Hypoxia stimulated exosome release from CPCs and upregulated their expression of pro-angiogenic genes, anti-fibrotic genes, and a cluster of miRs, and increased their ability to improved cardiac function after IR injury in rats. [bib_ref] Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes..., Gray [/bib_ref] [bib_ref] Experimental, systems, and computational approaches to understanding the microRNA-mediated reparative potential of..., Agarwal [/bib_ref] Vrijsen et al. reported that human CPCs release exosomes into their environment, and that exosomes from CPCs are able to stimulate the migration of endothelial cells in an in vitro scratch wound assay. [bib_ref] Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells, Vrijsen [/bib_ref] They also showed that CPC-exosomes contain matrix metalloproteinases (MMPs) and the extracellular matrix metalloproteinase inducer (EMPRINN), which mediate their angiogenic potential. [bib_ref] Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via..., Vrijsen [/bib_ref] ## Endothelial cell-derived evs Endothelial cells are an important source of EVs. Vascular endothelial cells secrete exosomes and MVs that exchange biological messages with other cell types of the heart. [bib_ref] Roles of exosomes in cardioprotection, Barile [/bib_ref] [bib_ref] Extracellular vesicles in coronary artery disease, Boulanger [/bib_ref] There is extensive literature demonstrating the effects of endothelial MV in promoting angiogenesis (reviewed in . Endothelial exosomes have also been shown to stimulate angiogenesis via a mechanism that is believed to involve transfer of miR-146a. [bib_ref] Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce..., Van Balkom [/bib_ref] Hypoxia alters mRNA and protein composition of exosomes released by cultured endothelial cells. [bib_ref] Cellular stress conditions are reflected in the protein and RNA content of..., De Jong [/bib_ref] TNF-a-treated endothelial cells release exosomes expressing increased levels of intercellular adhesion protein (ICAM)-1. [bib_ref] Cellular stress conditions are reflected in the protein and RNA content of..., De Jong [/bib_ref] These findings exemplify the potential function of endothelial cell-derived exosomes and MV that may also make them useful as biomarkers of cardiac stress and disease. 4,9 ## Vascular progenitor cell-derived evs While their exact differentiation potential has been debated, it is evident that CD34 þ cells from bone marrow secrete exosomes that possess angiogenic characteristics, enhance tube formation of endothelial cells, and increase neovascularization in vivo. [bib_ref] Exosomes from human CD34(þ) stem cells mediate their proangiogenic paracrine activity, Sahoo [/bib_ref] Further analysis revealed enrichment of several pro-angiogenic miRs (miR-126 and 130a) in CD34 þ cell-derived exosomes. MVs derived from human vascular progenitor cells carry several markers similar to receptors expressed on their membranes. [bib_ref] Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells..., Deregibus [/bib_ref] In various disease models, these MVs were shown to enhance expression of angiogenic miRs (miR-126 and 296), and promote neovascularization of pancreatic islets 92 and ischaemic hind limb. [bib_ref] Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb..., Ranghino [/bib_ref] ## Evs from fibroblasts, smooth muscle cells, and mesenchymal stromal cells Ischaemia, pressure, and volume overload induce hypertrophic cellular responses mediated by cross-talk among fibroblast cardiomyocytes, endothelial cells, and inflammatory cells via EVs. In response to angiotensin II, cardiac fibroblasts secreted exosomes that stimulated angiotensin II production and its receptor expression in cardiomyocytes, and stimulated myocyte hypertrophy. [bib_ref] A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system..., Lyu [/bib_ref] Exosomes released from cardiac fibroblasts contained high levels of miR-21-3p/miR-21, which induced cardiomyocyte hypertrophy. [bib_ref] A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system..., Lyu [/bib_ref] Smooth muscle cells also release exosomes and are implicated in vessel calcification and atherosclerosis. [bib_ref] Vascular smooth muscle cell calcification is mediated by regulated exosome secretion, Kapustin [/bib_ref] [bib_ref] Emerging roles for vascular smooth muscle cell exosomes in calcification and coagulation, Kapustin [/bib_ref] Mesenchymal stromal/stem cells (MSCs) are resident in almost all tissues, including the heart, and play a major role in tissue repair and regeneration. [bib_ref] Mesenchymal stromal cells and fibroblasts: a case of mistaken identity?, Hematti [/bib_ref] Characterization of the MSC exosome proteome has revealed many cytokines, growth factors, inflammatory molecules, components of the extracellular matrix, and proteases. Analysis of protein content revealed >400 different proteins. [bib_ref] Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery..., Lai [/bib_ref] Many signalling molecules related to MSC self-renewal, differentiation, and signalling pathways were found to be enriched in MSC exosomes, potentially affecting a diverse range of cellular processes, including cell cycle, proliferation, cell adhesion, cell migration, and cell morphogenesis. Similarly, miRNAs shuttle within MSC exosomes but mostly in precursor form, driving downstream signalling pathways. Additionally, MSC exosomes possess immunologic properties, including secretion of anti-inflammatory cytokines, such as interleukin-10, tumour growth factor (TGF)-b, and promote inhibition of lymphocyte proliferation. [bib_ref] Mesenchymal stem cells secrete immunologically active exosomes, Zhang [/bib_ref] ## Immune cell-derived evs Immune system cells, such as B cells and dendritic cells, mediate MHCdependent immune responses upon EV secretion. [bib_ref] T cell-induced secretion of MHC class IIpeptide complexes on B cell exosomes, Muntasell [/bib_ref] [bib_ref] The immunogenicity of dendritic cell-derived exosomes, Quah [/bib_ref] For this purpose, vesicles express particular adhesion molecules for specific targeting of recipient cells. [bib_ref] Exosomes: proteomic insights and diagnostic potential, Simpson [/bib_ref] Other immune cells release MVs with immune functions, for example, NK-derived exosomes enclose perforin and granzyme B and mediate anti-tumour activities either in vitro or in vivo. [bib_ref] Immune surveillance properties of human NK cell-derived exosomes, Lugini [/bib_ref] Furthermore, peptides expressed in exosomes released by mast cells are presented by DCs and induce specific immune responses in vivo. [bib_ref] Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and..., Skokos [/bib_ref] It has also been reported that macrophages release IL-1b on inflammasome activation, suggesting that these MVs play a role in proinflammatory activity and innate immune response. [bib_ref] Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome..., Qu [/bib_ref] ## Platelet-derived evs Platelets release both exosomes and MVs, [bib_ref] Activated platelets release two types of membrane vesicles: microvesicles by surface shedding..., Heijnen [/bib_ref] and release is strikingly enhanced by many stimuli, including physicochemical stresses and apoptosis. [bib_ref] Platelet microparticles: detection and assessment of their paradoxical functional roles in disease..., Burnouf [/bib_ref] Platelet-derived exosomes are able to regulate the coagulation response, [bib_ref] Activated platelets release two types of membrane vesicles: microvesicles by surface shedding..., Heijnen [/bib_ref] and mediate platelet atherogenic interactions with endothelial cells and monocytes. [bib_ref] Human plasma platelet-derived exosomes: effects of aspirin, Goetzl [/bib_ref] [bib_ref] Role of platelet-derived microvesicles as crosstalk mediators in atherothrombosis and future pharmacology..., Badimon [/bib_ref] Platelet MV stimulate angiogenesis and intramyocardial injection improved post-ischaemic revascularization. [bib_ref] Platelet-derived microparticles induce angiogenesis and stimulate post-ischemic revascularization, Brill [/bib_ref] Platelet exosomal cargoes include diverse cytokines, chemokines, growth factors, coagulation factors, lipoproteins, and other lipids, as well as several types of RNA. [bib_ref] Activated platelets release two types of membrane vesicles: microvesicles by surface shedding..., Heijnen [/bib_ref] [bib_ref] Platelet microparticles: detection and assessment of their paradoxical functional roles in disease..., Burnouf [/bib_ref] [bib_ref] Platelet-derived microvesicles: multitalented participants in intercellular communication, Aatonen [/bib_ref] [bib_ref] Isolation and characterization of platelet-derived extracellular vesicles, Aatonen [/bib_ref] Platelet exosomal membrane proteins also reflect their platelet source, including the constitutively expressed glycoprotein GPIb, as well as GPVI, aIIbb3, CD40 ligand, and P-selectin from activated platelets. [bib_ref] Activated platelets release two types of membrane vesicles: microvesicles by surface shedding..., Heijnen [/bib_ref] [bib_ref] Platelet microparticles: detection and assessment of their paradoxical functional roles in disease..., Burnouf [/bib_ref] It has been suggested that platelet activation in some vascular diseases will elevate loading of cyto-adhesive, thrombogenic, and inflammatory factors into platelet exosomal cargo to promote their delivery to endothelial cells and macrophages at sites of vascular lesions. Augmented delivery of platelet exosomal atherogenic cargo to lesional endothelial cells and macrophages, may consequently accelerate development of vascular plaques, clots, and atherosclerosis. 107,108,112 ## Technical control experiments for mechanistic studies Given that current methods of purification are imperfect, the inclusion of appropriate control experiments is crucial . First and foremost, any biological effects observed using purified EVs should be absent in 'sham' control samples depleted of EVs. Furthermore, when using EVs isolated from tissue culture medium, inhibition of exosome release may be used to confirm EV involvement in a process (e.g. Rab27a Rab27b silencing). [bib_ref] Rab27a and Rab27b control different steps of the exosome secretion pathway, Ostrowski [/bib_ref] Current chemical inhibitors inhibiting sphingomyelinase (e.g. GW4869) are not specific to exosome release. [bib_ref] Communication by extracellular vesicles: where we are and where we need to..., Tkach [/bib_ref] ## Recommendations for mechanistic studies EVs and exosomes appear to mediate a regulated process of intercellular communication, which could be capitalized on in order to obtain information more easily and less invasively than from in vivo experiments. However, for studies of exosomal communication, advanced cell models are needed that can compare the use of single cell types with multiple cell types in a 2D or 3D structure. Once identified, exosomal signalling molecules could potentially be used as biomarkers that reflect the cellular state during cardiovascular disease. Mechanistic experiments should include 'sham' EV-depleted control groups. A dose-response curve should be performed to relate the mechanism of action to the EV concentration. Because of the hundreds of different bioactive molecular species in any EV preparation it is often difficult to ascribe function to a specific EV component. At minimum, an association between a protein/miRNA and EVs in support of any function ascribed to them, e.g. using immuno-EM, or co-purification on a density gradient should be performed. It is important to consider the likelihood that a single miRNA or EV component mediates all of its effects, as opposed to there being a network effect of multiple miRNAs, and other mediators. [bib_ref] Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes..., Gray [/bib_ref] ## Evs as biomarkers for the ischaemic heart Given their easily-accessible presence in bodily extracellular fluids, EVs have been investigated as potential biomarkers for many diseases, and their presence in blood and pericardial or lymphatic fluid lends promise to their use in ischaemic heart disease. Proteins, lipids, coding and noncoding RNAs, and even DNA specific to their cells of origin are incorporated into EVs and released into bio-fluids. They have therefore been described as a form of 'liquid biopsy' of the cell of origin, and its pathophysiological status, and are attractive sources of biomarkers for clinical diagnostic applications in ischaemic heart disease. [bib_ref] Exosomes: novel biomarkers for clinical diagnosis, Lin [/bib_ref] Their power derives from the enrichment of potential protein markers which otherwise constitute only a very small proportion (less than 0.01%) of the total proteome of body fluids. [bib_ref] Exosomes: the future of biomarkers in medicine, Properzi [/bib_ref] Their sequestration within membranes might also protect the cargo from degradation. Similarly, many miRNAs detectable in serum and saliva are concentrated in exosomes, [bib_ref] The majority of microRNAs detectable in serum and saliva is concentrated in..., Gallo [/bib_ref] where they are protected against RNases. [bib_ref] Circulating microRNAs as stable blood-based markers for cancer detection, Mitchell [/bib_ref] The RNA content of EVs, especially the miRNA, has provoked great interest as diagnostic biomarkers in exosomal RNA research. [bib_ref] Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review, Navickas [/bib_ref] Technical issues related to analysis of EV RNA and proteins contents are described in Section 2.2. [bib_ref] Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society..., Ridger [/bib_ref]. Several potential applications for novel biomarkers can be identified. Blood-borne biomarkers of persistent myocardial ischaemia or vascular injury without concomitant cell death are lacking. Subclinical or silent myocardial ischaemia without infarction, different variants of angina and especially microvascular angina 86 would benefit from additional noninvasive diagnostic options in addition to ECG. [bib_ref] Circulating microRNAs as novel biomarkers for the early diagnosis of acute coronary..., Deddens [/bib_ref] Furthermore, in population studies, biomarkers of persistent low grade myocardial ischaemia without cell death would help to determine the prevalence of such conditions. Similarly, diagnosis of acute coronary syndrome (ACS) need to be improved, especially at early time points after coronary occlusion, [bib_ref] Early assessment of acute coronary syndromes in the emergency department: the potential..., Oerlemans [/bib_ref] for microvascular angina and in the case of non-ST segment elevation ACS. [bib_ref] Prevalence of coronary microvascular dysfunction among patients with chest pain and nonobstructive..., Sara [/bib_ref] Given the wide range of cardiac cell types that are capable of releasing EVs upon exposure towards stress, it is clear that circulating EVs offer great potential for the identification of biomarkers to aid diagnosis. Indeed, circulating MV signature (characterized by e.g. CD66b þ / CD62E þ /CD142 þ , or CD235a þ ) in coronary and/or peripheral has been shown to reflect the formation of coronary thrombotic occlusions in STEMI-patients. [bib_ref] Circulating microparticle signature in coronary and peripheral blood of ST elevation myocardial..., Suades [/bib_ref] Moreover, EVs of lymphatic origin have been recently shown in mice as promising biomarkers for lymphatic dysfunction or inflammatory disease progression in atherosclerosis. [bib_ref] Extracellular vesicles are present in mouse lymph and their level differs in..., Milasan [/bib_ref] ## Ev number as biomarker The number of EVs including exosomes seem to be associated with the presence of cardiac ischaemia and correlates with the severity of cardiac injury. The number of procoagulant EVs, particularly MVs, is elevated in the peripheral blood of patients with ACS and chronic ischaemic heart disease. [bib_ref] Microvesicles and exosomes: new players in metabolic and cardiovascular disease, Lawson [/bib_ref] [bib_ref] Microparticles in cardiovascular diseases, Vanwijk [/bib_ref] The quantity of endothelium-derived MVs even allowed discrimination between patients with stable angina, first time-, and recurring myocardial infarction. [bib_ref] High levels of circulating endothelial microparticles in patients with acute coronary syndromes, Bernal-Mizrachi [/bib_ref] Both systemic and intracoronary endothelial and platelet MV correlated with the degree of thrombosis and ischaemic area at risk. [bib_ref] Intracoronary microparticles and microvascular obstruction in patients with ST elevation myocardial infarction..., Porto [/bib_ref] [bib_ref] Circulating endothelial and platelet derived microparticles reflect the size of myocardium at..., Jung [/bib_ref] MV protein levels are associated with increased risk for future vascular events and mortality in patients with clinically manifest vascular disease. [bib_ref] Microvesicle protein levels are associated with increased risk for future vascular events..., Kanhai [/bib_ref] In atherosclerosis, increases in EVs of various cell origins have been demonstrated, predicting cardiovascular morbidity and mortality. [bib_ref] Extracellular vesicles as new pharmacological targets to treat atherosclerosis, Yin [/bib_ref] However, since reports on both pro-and antiatherosclerotic effects of different EV populations have been published (see for review: Ref. [bib_ref] Exosomes: emerging roles in communication between blood cells and vascular tissues during..., Huber [/bib_ref] , their usefulness as diagnostics needs further exploration. Given the caveats mentioned previously with regards the accuracy of current methods of EV quantification, it is important to establish rigorous guidelines for consistency, and to determine the accuracy and precision (coefficient of variation) of the methods used. ## Ev content as a source of biomarkers Since EV content is altered by pathology, diagnostics based on the analysis of exosomal content of body fluids may provide further benefit for diagnosing ischaemic heart diseases. The concentration of certain miRNAs in the blood, such as miR-208a, miR-133a, and miR-499 is elevated after ACS. [bib_ref] Circulating extracellular vesicles contain miRNAs and are released as early biomarkers for..., Deddens [/bib_ref] [bib_ref] Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease..., Kuwabara [/bib_ref] Circulating miRNA have therefore been proposed as diagnostic biomarkers in cardiovascular diseases. [bib_ref] Identifying circulating microRNAs as biomarkers of cardiovascular disease: a systematic review, Navickas [/bib_ref] [bib_ref] Circulating microRNAs as novel biomarkers for the early diagnosis of acute coronary..., Deddens [/bib_ref] [bib_ref] Circulating microRNAs strongly predict cardiovascular death in patients with coronary artery disease-results..., Karakas [/bib_ref] [bib_ref] Serum levels of microRNAs in patients with heart failure, Goren [/bib_ref] [bib_ref] Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease, Creemers [/bib_ref] Some of these may be transported by EVs, especially under pathological conditions [bib_ref] Circulating extracellular vesicles contain miRNAs and are released as early biomarkers for..., Deddens [/bib_ref] [bib_ref] The majority of microRNAs detectable in serum and saliva is concentrated in..., Gallo [/bib_ref] [bib_ref] Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in..., Arroyo [/bib_ref] [bib_ref] MicroRNAs in heart failure: from biomarker to target for therapy, Vegter [/bib_ref] or after coronary-artery by-pass graft surgery. [bib_ref] Coronary arterybypass-graft surgery increases the plasma concentration of exosomes carrying a cargo..., Emanueli [/bib_ref] MVs containing miR-126 and miR-199a, but not freely circulating miRNA expression, predict the occurrence of CV events in patients with stable coronary artery disease. [bib_ref] MicroRNA expression in circulating microvesicles predicts cardiovascular events in patients with coronary..., Jansen [/bib_ref] Assessing miRNAs carried specifically by exosomes can even improve diagnostic sensitivity and precision: exosomal miR-208a content correlated well with cTn-I levels after CABG surgery, while the whole-blood miR-208a levels did not. [bib_ref] Coronary arterybypass-graft surgery increases the plasma concentration of exosomes carrying a cargo..., Emanueli [/bib_ref] Similar results were recently reported in ACS patients, where sensitivity of exosomal miR-208a measurement was superior to that of the serum, which even showed a certain degree of prognostic value regarding 1-year survival rate. [bib_ref] Correlation between serum exosome derived miR-208a and acute coronary syndrome, Bi [/bib_ref] Exosomal miR-192, miR-194, and miR-34a have been identified as prognostic biomarkers predicting the development of heart failure and pathological remodelling after myocardial infarction. [bib_ref] Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial..., Matsumoto [/bib_ref] The diagnostic value of EV protein content has been little studied. De Hoog et al. found that the proteome of ExoQuick TM -precipitated EVs from ACS patients differed from those from non-ACS patients: elevated vesicular levels of polygenic immunoglobulin receptor, cystatin C, and complement factor C5a was associated with ACS diagnosis. [bib_ref] Serum extracellular vesicle protein levels are associated with acute coronary syndrome, De Hoog [/bib_ref] et al. showed that protein levels in EV sub-fractions are associated with heart failure in dyspnea cohort. [bib_ref] Extracellular vesicle proteins associated with systemic vascular events correlate with heart failure:..., Zhang [/bib_ref] ## The effect of co-morbidities on evs It is well known that cardiovascular risk factors and co-morbidities (especially aging, gender, and metabolic diseases such as hyperlipidaemia and diabetes), and their medications alter the phenotype of the normal and pathological myocardium including its response to ischaemia/reperfusion and cardioprotective or regenerative therapies (see for extensive reviews). [bib_ref] Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection..., Ferdinandy [/bib_ref] [bib_ref] Position paper of the European Society of Cardiology Working Group Cellular Biology..., Madonna [/bib_ref] [bib_ref] Functional genomics of cardioprotection by ischemic conditioning and the influence of comorbid..., Varga [/bib_ref] [bib_ref] Novel targets and future strategies for acute cardioprotection: position paper of the..., Hausenloy [/bib_ref] The presence of these confounding factors may interfere with diagnostic opportunities by means of MVs, however, very little is known in this field. Some recent reviews on the diagnosis of diabetes and dyslipidaemia concluded that since EVs may be involved in these pathologies, analysis of EVs might reveal additional biomarkers. [bib_ref] Blood-based biomarkers for metabolic syndrome, O'neill [/bib_ref] [bib_ref] Emerging concepts on the role of exosomes in lipid metabolic diseases, Record [/bib_ref] [bib_ref] Exosomes in diabetic cardiomyopathy: the next-generation therapeutic targets?, Sahoo [/bib_ref] For example, the quantity of MVs/microparticles is elevated in the blood plasma of patients with metabolic syndrome, [bib_ref] Microparticles from patients with metabolic syndrome induce vascular hyporeactivity via Fas/Fas-ligand pathway..., Agouni [/bib_ref] [bib_ref] Endothelial dysfunction caused by circulating microparticles from patients with metabolic syndrome, Agouni [/bib_ref] and elevated levels of certain miRNAs derived from ExoQuick-precipitated EVs have been shown to be associated with metabolic syndrome or diabetes, [bib_ref] Circulating miRNA profiles in patients with metabolic syndrome, Karolina [/bib_ref] but the practical relevance of these reports is yet to be assessed. Since the cardiac transcriptome including miRNA expression profile has been shown to be dramatically changed in the rat myocardium by hyperlipidemia, [bib_ref] MicroRNA-25-dependent up-regulation of NADPH oxidase 4 (NOX4) mediates hypercholesterolemia-induced oxidative/nitrative stress and..., Varga [/bib_ref] analysis of transcriptome including non-coding RNA content of EVs may provide specific diagnostic markers of the heart affected by this and other co-morbidities. [bib_ref] Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets..., Perrino [/bib_ref] In a study on over 1000 patients, EV-associated cystatin C content was found to be significantly elevated (a marginal, 9% difference), in metabolic syndrome patients with cardiovascular disease, and a proteomics study on EVs derived from adipocytes of obese rats revealed 200 proteins with differential expression. [bib_ref] Proteomic analysis of extracellular vesicles released by adipocytes of otsuka long-evans Tokushima..., Lee [/bib_ref] Moreover, it has been shown that at similar plasma cholesterol levels, patients on statin treatment had a significant lower number of circulating MVs carrying markers of activated cells. [bib_ref] Lipid-lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory..., Suades [/bib_ref] These studies suggest that EVs have the potential to evolve into useful biomarkers of various metabolic diseases in the future, however, a substantial amount of research has to be done before their clinical use might be realized. ## Recommendations for study of evs as biomarkers Since miRNAs are transferred by either protein complexes, HDL, or EVs, [bib_ref] Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease, Creemers [/bib_ref] and since protein contamination of isolated EVs is difficult to control, adequate isolation techniques are of the utmost importance if exosomal miRNAs or proteins are to be assessed as biomarkers. Other recommendations relevant to plasma miRNA biomarker studies in general apply equally to EV miRNA studies. [bib_ref] MicroRNA biomarkers and platelet reactivity: the clot thickens, Sunderland [/bib_ref] It should be noted that although detectable amounts of relatively clean EVs can be isolated, e.g. with size exclusion chromatography, 29 methods for the isolation of EVs need to be improved to allow clinical utilization of EV-based diagnostics. Current technical limitations for EV isolation do not allow definitive guidelines for the use of EVs as biomarkers. Several factors that are lacking include: the lack of standardized pre-analytical and isolation procedures; lack of gold standard for processing, characterization and purity; an unknown influence of comorbidities, co-medication and other confounding factors; lack of disease specificity; lack of tissue-specific markers [fig_ref] Table 2: Current technical limitations for clinical translation of EV biomarker [/fig_ref]. As with any biomarker study, pilot observations from small cohorts should be validated in larger patient datasets, and the reproducibility of isolation procedures, including markers of EVs and normal range levels in the healthy population should be reported. Moreover, evidence should be provided of the additional value of EVs over current goldstandard biomarkers. ## Therapeutic potential of evs for the ischaemic heart EVs purified from defined cell types have been suggested as novel therapeutic options for various cardiac diseases including ischaemic heart disease, myocardial infarction, and heart failure, as well as for pathogen vaccination, immune-modulatory and regenerative therapies and drug delivery. However, the first clinical steps have been made using exosomes as an anti-tumour therapy: an effective way to destroy non-small cell lung cancer (NSCLC) is to activate tumour-specific cytotoxic T cells (CTL), and for this autologous dendritic cell (DC)-derived exosomes (DEX) loaded with tumour antigens have been tested not only in phase I 157 but also in a phase II Trial (ClinicalTrials.gov Identifier: NCT01159288). Although this did not induce detectable effector T cell responses, a positive effect on natural killer (NK) cells could be observed in some patients. [bib_ref] Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC, Besse [/bib_ref] This first exosome Phase I trial highlighted the feasibility of large scale exosomes production and the safety of exosome administration. [bib_ref] Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results..., Escudier [/bib_ref] Several other Phase I studies have been initiated, exploring the use of EVs/exosomes as a therapy, including the effect of MSC-derived exosomes on b-cell mass in Type 1 diabetes mellitus (T1DM) Patients (ClinicalTrials.gov Identifier: NCT02138331). Little is known about whether EVs derived from animals might be feasible for human therapy. However, EV fractions derived from human umbilical cord MSCs and administered to different healthy and diseased animal species (including rats with myocardial infarction) were found to be well tolerated. [bib_ref] Safety evaluation of exosomes derived from human umbilical cord mesenchymal stromal cell, Sun [/bib_ref] After further study, these results demonstrating a lack of adverse immunological reactions may open the possibility of producing therapeutic EVs from non-human sources. To develop the application of exosome-based therapeutics, a clear understanding of (1) Lack of standardized pre-analytical and isolation procedures. (2) Currently no gold standard. (3) Need to establish methods of purifying specific subpopulations of EVs originating from the heart, vasculature, or blood cells, no golden standard for processing, characterization, and purity. (4) Unknown influence of confounding factors of EV quality, including disease specificity and presence of comorbidities and their medications. (5) Small yields of EV subpopulations obtained for content analysis: transcriptomics, lipidomics, and proteomics. (6) Validation of novel biomarkers in large patient cohorts, including normal range levels in the healthy population. [bib_ref] Extracellular vesicles in coronary artery disease, Boulanger [/bib_ref] Determine additional value of EV markers over current golden standard clinical biomarkers, or its use as a combinatory marker. Extracellular vesicles in diagnostics and therapy of the ischaemic heart exosome pharmacokinetics in vivo is of utmost importance. Currently, only limited information is available, but unmodified EVs derived from tumours are rapidly cleared in liver and spleen by the reticuloendothelial system and cells of the innate immune system. [bib_ref] Biodistribution and delivery efficiency of unmodified tumor-derived exosomes, Smyth [/bib_ref] Interestingly, there may be concerns about intravenous injection of high concentrations of EVs since the authors observed rapid asphyxiation of mice when injecting over 400 mg. [bib_ref] Biodistribution and delivery efficiency of unmodified tumor-derived exosomes, Smyth [/bib_ref] To date, most in vivo bio-distribution studies have used small lipophilic fluorescent dyes to label EVs. Although useful for first impressions, the reliability of these analyses might be impaired by the free dye released from EVs. [bib_ref] Extracellular vesicles as natural nanosized delivery systems for small-molecule drugs and genetic..., Kotmakçı [/bib_ref] Bioluminescence imaging of a fusion protein consisting of Gaussia luciferase and lactadherin has been used to demonstrate that EVs quickly disappear from the blood circulation and are mainly distributed to the liver after intravenous injection into mice, with a half-life of approximately 2-4 min. [bib_ref] Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6..., Takahashi [/bib_ref] It is likely that surface molecules such as phospholipids and proteins are important for determining the pharmacokinetics and cellular uptake of EVs. [bib_ref] Pharmacokinetics of exosomes-an important factor for elucidating the biological roles of exosomes..., Morishita [/bib_ref] A further question relates to the ideal route of EV administration. In this regard, a recent study demonstrated that MSC-derived EVs were effective in pigs after intramyocardial but not intracoronary delivery post reperfusion. ## Progenitor and stem cell-derived evs Stem cell therapy has been investigated as a potential approach to prevent cardiac damage and stimulate cardiac repair in ischaemic heart disease. [bib_ref] Position paper of the European Society of Cardiology Working Group Cellular Biology..., Madonna [/bib_ref] Recent developments in regenerative medicine that explore the use of cell-free approaches, hence using the isolated paracrine effectors from cells, focus on EVs that are release by cultured cells. [bib_ref] Exosomes and cardiovascular protection, Davidson [/bib_ref] [bib_ref] Exosomes as critical agents of cardiac regeneration triggered by cell therapy, Ibrahim [/bib_ref] The use of these vesicles provide an alternative strategy for the paracrine effects of cell transplantation and activation of the repair mechanisms of the resident myocardium that captures the complexity of the signalling required to stimulate these regenerative processes. The best studied population of cells for its paracrine effects in the heart are the mesenchymal stromal cells (MSCs). Conditioned medium of these cells reduced infarct size in both murine and porcine animal models, [bib_ref] Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal..., Gnecchi [/bib_ref] [bib_ref] Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium, Timmers [/bib_ref] after which the exosome-containing fraction was demonstrated to be the functional fraction, which decreased oxidative stress and activated the PI3K/Akt pathway in the myocardium. [bib_ref] Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury, Lai [/bib_ref] [bib_ref] Mesenchymal stem cellderived exosomes increase ATP levels, decrease oxidative stress and activate..., Arslan [/bib_ref] As indicated above, several subclasses of EVs might be released by cells. A recent study showed that MSCs produce at least three subtypes of EVs, isolated based on their affinities for membrane lipid-binding ligands, and are likely to have a different biogenesis pathway and possibly different functions. [bib_ref] MSC secretes at least 3 EV types each with a unique permutation..., Lai [/bib_ref] [bib_ref] Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis..., Bian [/bib_ref] In addition to the cardioprotective effects of EVs, pro-angiogenic effects have been observed, 170 not only by MSCs but also by cardiacderived progenitor cells (CPCs), which are at least partly mediated via extracellular matrix metalloproteinase inducer (EMMPRIN). [bib_ref] Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells, Vrijsen [/bib_ref] [bib_ref] Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via..., Vrijsen [/bib_ref] [bib_ref] Cardiac progenitor-derived Exosomes protect ischemic myocardium from acute ischemia/reperfusion injury, Chen [/bib_ref] In the EVs of CPCs, several miRNA clusters are enriched and important for their therapeutic effects. [bib_ref] Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve..., Barile [/bib_ref] [bib_ref] Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes..., Gray [/bib_ref] EVs derived from blood-outgrowth endothelial cells [bib_ref] Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells..., Deregibus [/bib_ref] [bib_ref] Human endothelial colony-forming cells protect against acute kidney injury: role of exosomes, Burger [/bib_ref] and especially circulating CD34 þ stem cells [bib_ref] Exosomes from human CD34(þ) stem cells mediate their proangiogenic paracrine activity, Sahoo [/bib_ref] were also shown to exert pro-angiogenic paracrine activity. EVs are now being reported to have anti-inflammatory effects as well, e.g. endothelial cellderived EVs were found to suppress monocyte activation. [bib_ref] Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory..., Njock [/bib_ref] EVs harvested from T reg cells have been found to exert an immune-suppressive function by the suppression of monocyte activation, [bib_ref] Regulatory T cells: exosomes deliver tolerance, Chatila [/bib_ref] and EVs from MSCs can suppress T-Lymphocyte proliferation. [bib_ref] The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated..., Budoni [/bib_ref] [bib_ref] Recent advances in mesenchymal stem cell immunomodulation: the role of microvesicles, Fierabracci [/bib_ref] Mouse embryonic stem cells secrete exosomes which can also augment neovascularization, myocyte proliferation, and survival after MI. [bib_ref] Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function..., Khan [/bib_ref] Importantly, they were shown to augment the survival, retention, and proliferation of CPCs in ischaemic myocardium by delivery of miR-294. [bib_ref] Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function..., Khan [/bib_ref] Exosomes have also been identified as key mediators of regeneration induced by cardiosphere-derived cells (CDCs), which they achieved partly by the transfer of miR-146a. [bib_ref] Exosomes as critical agents of cardiac regeneration triggered by cell therapy, Ibrahim [/bib_ref] Recently, CDC exosomes isolated by filtration and precipitation were injected into the myocardium of pigs following ischaemia and reperfusion, which reduced infarct size and improved cardiac function 4 weeks later.Recent studies described the isolation of EVs from iPSCs, with healing ability in in vivo model of myocardial ischaemia. [bib_ref] Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte..., Wang [/bib_ref] Finally, plasma EVs themselves have been shown to be able to protect the myocardium from ischaemia and reperfusion injury [bib_ref] Plasma exosomes protect the myocardium from ischemia-reperfusion injury, Vicencio [/bib_ref] and EVs have been shown to be necessary for endogenous cardioprotective mechanisms such as remote ischaemic conditioning. [bib_ref] Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by..., Giricz [/bib_ref] ## Hybrid nanomedicine to mimic evs A further approach to the use of EVs as therapeutic tools is to load them with a range of molecules or pharmacological compounds from siRNA to small molecules or proteins, serving as tool for empowering cellderived EVs and for targeted-drug delivery. [bib_ref] Delivery materials for siRNA therapeutics, Kanasty [/bib_ref] For example, liposomes with a phospholipid bilayer can carry a variety of proteins and nucleic acids as well as pharmaceutically active substances to the injured heart. [bib_ref] Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair, Harel-Adar [/bib_ref] Such exosome-mimetic structures can also include specific targeting molecules that enhance their targeting. Currently, liposomal transport of drug molecules are in clinical practice and under clinical trial. [bib_ref] Clinical activity and cardiac tolerability of non-pegylated liposomal doxorubicin in breast cancer:..., Airoldi [/bib_ref] [bib_ref] IMD-0354 targets breast cancer stem cells: a novel approach for an adjuvant..., Gomez-Cabrero [/bib_ref] Exosome-mimetic delivery systems offer the advantage of being more controllable and scalable for clinical settings. [bib_ref] Exosomes as a nanodelivery system: a key to the future of neuromedicine?, Aryani [/bib_ref] [bib_ref] Exosome mimetics: a novel class of drug delivery systems, Kooijmans [/bib_ref] Conversely, the advantage of using EVs in targeted drug delivery over the existing synthetic delivery systems (such as liposomes) includes their potentially increased circulation time, bio-distribution, decreased immunogenicity and toxicity, loading of complex cargo, cellular interactions and the different methods for therapeutic cargo loading (both postloading and pre-loading) and administration. ## Important limitations to overcome in the development of ev therapeutics The use of EVs provides several advantages over the use of cells for therapeutic application. These include the absence of tumourigenicity, conservation of activity between species, lower immunogenic potential, and theoretically improved tissue-targeting potential. However, before EVs can enter the clinic as medicinal products several important steps have to be taken [fig_ref] Table 3: Current limitations for cardiac therapeutic use of EVs [/fig_ref] (1) Therapeutic differences from independent cell preparations have been observed among comparable EV fractions, which might be caused by variability between donors or heterogeneity of EVs harvested. [bib_ref] MSC secretes at least 3 EV types each with a unique permutation..., Lai [/bib_ref] Since cellular growth status varies between cell cultures, as it does for embryonic stem cells or MSCs, 186 these differences might also be reflected in their secreted EVs. (2) Upon EV isolation and usage, contamination by co-purified and bound molecules might affect functional assays. [bib_ref] Low-density lipoprotein mimics blood plasma-derived exosomes and microvesicles during isolation and detection, Só Dar [/bib_ref] (3) Since isolated EVs might be heterogeneous by nature, only a proportion of produced EVs might be responsible for observed therapeutic effects. (4) The EV pharmacokinetics are largely unknown and need detailed followup in patients to understand their bio-distributions. ## 6. Consensus statement on the steps required to take EVs forward to clinical applications as biomarkers or therapeutics Biomarkers: As indicated in Section 4. [bib_ref] Roles of exosomes in cardioprotection, Barile [/bib_ref]., the current technical limitations for EV isolation do not allow specific recommendations for the use of EVs as biomarkers, though guidelines for biomarkers in general are applicable. In the coming years, standardized pre-analytic and isolation procedures need to be further defined and simplified, including the definition of gold standards for processing, characterization, and identification of EV purity . By exploring these areas, the influence of confounding factors, including co-morbidities, co-medication and whether identified EV markers are disease specific will be evaluated. The typically small yields of isolated EVs will hamper a clear full EV characterization, but technical developments that allow, for example, single cell sequencing will lower input needs for these techniques. Most important is the validation of pilot observation from small cohorts in larger dataset of patients, thereby improving the reproducibility of isolation procedures, and to provide evidence of additional value of EVs over current golden standard biomarkers. To strengthen the process of identification of EVs or EVcomponents as biomarkers, experiments may also be designed to identify the tissue source of the biomarker, combined with the functional validation of the identified molecule (protein and/or RNA) in the target tissues. Therapy: The translation of EVs into clinical therapies will require categorization of EV-based therapeutics in compliance with existing regulatory frameworks. Since EVs will probably be considered as biological medicinal products more specifically advanced therapy medicinal products (ATMPs), new rules explicitly regulating EV-based therapies are probably not needed. However, although existing European guidance on biological active substances covers the manufacturing and clinical evaluation of novel EV-based therapeutics, special guidelines addressing EV-based therapeutics may be needed. [bib_ref] Applying extracellular vesicles based therapeutics in clinical trials-an ISEV position paper, Lener [/bib_ref] The regulatory classification of most biological medicinal products, including ATMPs depends on a pharmaceutically active substance that does not require a molecular definition, but could mean the cells themselves in case of cellular therapeutics. [bib_ref] Randomized controlled trial of the effects of remote ischemic preconditioning on children..., Cheung [/bib_ref] Here, one needs to identify, quantify, and characterize the main effector that is causing the biologic effect and define the mode or mechanism of action. Similar to human cell-based products, [bib_ref] Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac..., Candilio [/bib_ref] preclinical safety testing might be needed as well as a risk-analysis approach for the transition from preclinical to clinical development, thereby taking into account the heterogeneity among independent cell donors and different preparations, as well as the EV heterogeneity in obtained donor cell samples. A test for biological activity should be included unless otherwise justified. However, since many cell products are composed of a heterogeneous mixture of cells, identification of the cellular component(s) responsible for a proposed biological activity will be a major challenge. General clinical requirements and developments have been recently reviewed for cardiac cellular therapeutics. [bib_ref] Position paper of the European Society of Cardiology Working Group Cellular Biology..., Madonna [/bib_ref] Based on the legislation for ATMPs including tissues, cells, a set of minimal criteria for the characterization of such products needs to be considered before use in clinical trials. One needs to define whether a product is (i) of autologous, allogeneic or xenogeneic origin; (ii) extensively or minimally manipulated in vitro; and (iii) immunologically active or neutral, (iv) is the proliferative capacity of cells and tissue-like organization, as well as defining (v) the dynamic interaction between these elements, (vi) the intended use. [bib_ref] Applying extracellular vesicles based therapeutics in clinical trials-an ISEV position paper, Lener [/bib_ref] ,189 Future perspectives: Developments required to take EVs forward to clinical applications as biomarkers or therapeutics -Improvement of flow cytometric methods and standardization of analytical procedures. (Until this is achieved, bead-based bulk detection of EVs may provide a feasible flow cytometric detection approach irrespective of the instrument used). -Development of novel high-resolution methodologies for EV isolation and visualizations. -Understand mechanism of inter-cell or inter-organ communication. -Potential source for cardiac tissue and disease specific biomarkers. -Potential packages for cardiac specific therapies. -Potential multi-targeting effects of EVs for the complex mechanisms of ischaemic heart disease. -Potential advantage for EV therapeutic application over cells, including absence of tumourigenicity and cross species efficacy. (2) Scalable production and stability of EVs. (3) Purification problem, including potential heterogeneity of EVs and presence of co-purified molecules. (4) Lack for standardized quality control methods for EV production. [bib_ref] Microparticles in cardiovascular diseases, Vanwijk [/bib_ref] Determine which proportion of EVs mediates therapeutic effects, including unknown mode of action, including potential retention issues. (6) Unknown pharmacokinetics of EVs as a therapeutic. (7) Unknown safety and toxicity, including immunogenicity. [bib_ref] Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society..., Ridger [/bib_ref] Difficulty for freedom to operate due to regulatory protection issues. Extracellular vesicles in diagnostics and therapy of the ischaemic heart In summary, to advance towards first-in-man-clinical trials approval of the technical requirements and quality risk management is needed, donor safety, recipient safety, and release criteria for EV-based therapeutics should be defined and quality control should be in place, including molecular and physical EV characterization, and in vitro potency assays. Moreover, the identified recommendation criteria for the characterization of isolated EV are critical for both their therapeutic use and for biomarker discovery. [fig] Figure 3: Standard techniques used for isolating exosomes fromother EVs, protein, and lipoproteins present in blood and cell-culture medium. [/fig] [fig] Figure 4: Standard methods of characterizing EVs. (A) Transmission electron microscopy (TEM) of negative-stained EVs reveals the 'cup-shaped' appearance of exosomes (E) and MVs once they have been dried for TEM (they are spherical in solution). (B) The spherical appearance of lipoprotein particles by TEM is quite distinct (image courtesy of Robert L. Hamilton and the Arteriosclerosis Specialized Center of Research, University of California, San Francisco). (C) Nanoparticle tracking analysis (NTA) provides a size distribution of particles based on calculating their size by their random Brownian motion. (D, E)Tuneable resistance pulse sensing (TRP) determines size distribution by the change in resistance as the particle crosses a small pore in a membrane (which is selected according to the size range examined). Extracellular vesicles in diagnostics and therapy of the ischaemic heart [/fig] [fig] Funding: JS is supported by Horizon2020 ERC-2016-COG EVICARE (725229), the Project SMARTCARE-II of the BioMedicalMaterials Institute, cofunded by the ZonMw-TAS program (#116002016), the Dutch Ministry of Economic Affairs, Agriculture and Innovation and the Netherlands CardioVascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federations of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences. SD is supported by Project grant PG/16/85/32471 from the British Heart Foundation. PF and RS were supported by the European Cooperation in Science and Technology (COST EU-ROS BM1203). DH is the chair, PF is the vice chair, and SD and RS are working group leaders of COST Action EU-Cardioprotection (CA16225). PF holds grants from the Hungarian National Research, Development, and Innovation Office (OTKA K 109737, OTKA ANN 107803, NVKP 16-1-2016-0017, and VEKOP-2.3.2-16-2016-00002). EIB is supported by NVKP 16-1-2016-0017, OTKA 20237, OTKA 111958, and VEKOP-2.3.3-15-2017-00016. RK is supported by National Institutes of Health Grants HL091983, HL126186 and HL134608. CP is supported by the Italian Ministry of University, Research and Technology (RBFR124FEN and 2015583WMV grants) and by Programme STAR, financially supported by Compagnia di San Paolo and Federico II University, Naples (Italy). SL holds grant from the South African National Research Foundation. FBE is supported by the German Research Foundation (DFG Research Unit FOR2149). DdK is supported by Queen of Hearts Program Dutch Heart Foundation 2013T084; BMRC CS-IRG, ATTRaCT SPF grant. CMB is supported by Insitut National de la Santé et de la Recherche Medicale, Université Paris Descartes and ANR-16-CE92-0032-02. DH was supported by the British Heart Foundation (FS/10/039/28270), Duke-National University Singapore Medical School, the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Singapore Ministry of Health's National Medical Research Council under its Clinician Scientist-Senior Investigator scheme (NMRC/CSA-SI/0011/ 2017) and Collaborative Centre Grant scheme (NMRC/ CGAug16C006), the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2016-T2-2-021), and the National Research Foundation (NRF) Singapore (NRF-CRP13-2014-05). [/fig] [table] Table 2: Current technical limitations for clinical translation of EV biomarker [/table] [table] Table 3: Current limitations for cardiac therapeutic use of EVs(1) Unestablished regulatory aspects. [/table]	None	https://academic.oup.com/cardiovascres/article-pdf/114/1/19/30033827/cvx211.pdf	Abstract Extracellular vesicles (EVs)—particularly exosomes and microvesicles (MVs)—are attracting considerable interest in the cardiovascular field as the wide range of their functions is recognized. These capabilities include transporting regulatory molecules including different RNA species, lipids, and proteins through the extracellular space including blood and delivering these cargos to recipient cells to modify cellular activity. EVs powerfully stimulate angiogenesis, and can protect the heart against myocardial infarction. They also appear to mediate some of the paracrine effects of cells, and have therefore been proposed as a potential alternative to cell-based regenerative therapies. Moreover, EVs of different sources may be useful biomarkers of cardiovascular disease identities. However, the methods used for the detection and isolation of EVs have several limitations and vary widely between studies, leading to uncertainties regarding the exact population of EVs studied and how to interpret the data. The number of publications in the exosome and MV field has been increasing exponentially in recent years and, therefore, in this ESC Working Group Position Paper, the overall objective is to provide a set of recommendations for the analysis and translational application of EVs focussing on the diagnosis and therapy of the ischaemic heart. This should help to ensure that the data from emerging studies are robust and repeatable, and optimize the pathway towards the diagnostic and therapeutic use of EVs in clinical studies for patient benefit.
3e27955af43a1bbe6951911a3adcea64ebffe7cb	pubmed	Guidelines on the management of abnormal liver blood tests	Guidelines on the management of abnormal liver blood tests [bib_ref] Addressing liver disease in the UK: a blueprint for attaining excellence in..., Williams [/bib_ref] [bib_ref] Addressing liver disease in the UK: a blueprint for attaining excellence in..., Williams [/bib_ref] [bib_ref] Presence and severity of nonalcoholic fatty liver disease in a large prospective..., Armstrong [/bib_ref] [bib_ref] Severe asymptomatic non-alcoholic fatty liver disease in routine diabetes care; a multi-disciplinary..., Armstrong [/bib_ref] ## Guidelines of perinatal transmission, and its chronicity contributes to the disease burden seen in adults. Other causes of liver disease, such as biliary atresia or metabolic disorders, 6 present almost exclusively in infancy or childhood, but progressive liver disease continues to evolve throughout childhood and into adulthood. There are concerted efforts to deal with this rising tide of liver disease such as the Lancet Commission on Liver Disease, 7 the Alcohol Health Alliance and the Obesity Health Alliance. Liver disease develops silently; there may be no signs or symptoms until the complications of liver failure or portal hypertension develop. At this late, often pre-terminal stage, the tests of liver function-bilirubin, albumin, international normalised ratio (INR) and platelet count-may be abnormal. In necro-inflammatory hepatitic diseases liver enzymes are frequently elevated, whereas in apoptotic diseases including fatty liver disease (alcohol and non-alcohol related), liver enzymes may be normal or elevated, but the degree of abnormality is not related to the stage of progression from simple fatty liver, through progressive fibrosis to cirrhosis. [bib_ref] Addressing liver disease in the UK: a blueprint for attaining excellence in..., Williams [/bib_ref] Since the current liver blood tests were developed in the 1950s, they have been the mainstay of liver disease identification, with the result that many patients with liver disease are not identified until they have developed significant liver fibrosis. [bib_ref] Addressing liver disease in the UK: a blueprint for attaining excellence in..., Williams [/bib_ref] Liver blood or function tests (LFTs), which are perceived to be inexpensive, are checked ever more frequently in both primary [bib_ref] How are abnormal results for liver function tests dealt with in primary..., Sherwood [/bib_ref] and secondary care in an attempt to exclude liver disease, for the monitoring of potential adverse effects of drugs on the liver such as statins, and for the investigation of the generally unwell patient. These tests often produce an abnormal result, the clinical significance of which is unclear. In many cases though they are requested in response to non-specific symptoms where there is little potential link between symptoms and likelihood of liver disease, or the blood tests are performed for unrelated reasons such as chronic disease monitoring. [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] This commonly presages a cycle of additional liver blood test testing in an otherwise asymptomatic individual, and notably, most patients referred to hospital with abnormal liver tests do not have any evidence of significant liver disease. [bib_ref] Development of a decision support tool for primary care management of patients..., Donnan [/bib_ref] For example, University Hospital Birmingham Foundation Trust received 130 849 requests for liver blood tests in 2016, from 82 general practices and of these, 38 636 (30%) contained at least one abnormal result, defined as being outside the stated reference range. The Abnormal Liver Function Investigations Evaluation (ALFIE) study from Tayside in Scotland showed that over a 10-year period 25% of the community population aged over 16 had liver blood tests, with about a third having at least one abnormal value. Although an abnormal aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level was predictive of liver disease (HR=4.2), the rate of detection was remarkably low, with only 3.9% of those with an abnormal value being diagnosed with significant liver disease Non-alcoholic fatty liver fibrosis algorithm. For those patients with NAFLD or liver disease of unknown aetiology, the next step is to determine the likelihood of liver fibrosis. Initial assessment includes calculation of a FIB4 or NAFLD fibrosis score with values <1.3 and ≤1.455, respectively, signifying a low risk of advanced fibrosis. Higher cut-off points, <2.0 and <0.12, should be used for patients aged over 65 years. Second-line tests that should be considered include serum markers such as ELF and imaging modalities such as ARFI elastography/FibroScan. For children, the text should be consulted for modification of recommendation. Cut-off points for ARFI vary according to manufacturer and thus should be tailored to the device used. ARFI, acoustic radiation force impulse; ELF, enhanced liver fibrosis; FIB-4, fibrosis-4; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD Fibrosis Score. within 5 years of the test. [bib_ref] Development of a decision support tool for primary care management of patients..., Donnan [/bib_ref] Thus, used in isolation, liver blood tests are neither specific diagnostic tools nor specific exclusion tools, [bib_ref] Diagnosing liver disease in asymptomatic patients, Chatwin [/bib_ref] whereas they can be more effectively used to assess the extent of liver fibrosis if incorporated into algorithms [bib_ref] Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients..., Mcpherson [/bib_ref] or used in conjunction with other modalities. [bib_ref] Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic..., Parkes [/bib_ref] [bib_ref] Serum markers detect the presence of liver fibrosis: a cohort study, Rosenberg [/bib_ref] [bib_ref] Feasibility of liver transient elastography with FibroScan using a new probe for..., De Lédinghen [/bib_ref] [bib_ref] Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty..., Wong [/bib_ref] ## Guideline development These guidelines were drafted after discussions within the liver section of the British Society of Gastroenterology (BSG) and acceptance of the proposal by the Clinical Services and Standards Committee (CSSC). There followed division of sections to be researched by designated authors and a literature review. The NICE guidelines were closely followed and guideline quality was assessed using the AGREE tool [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref] (section 'Assessing the quality of guidelines: the AGREE II instrument'). A preliminary guideline document was drafted by the authors following discussion and, where necessary, voting by members of the Guidelines Development Group. The draft guidelines were submitted for review by the CSSC, then BSG council members. Finally, full peer review was undertaken by reviewers selected by the editor of Gut. Assessing the quality of guidelines: the AGREE II instrument is an accepted method for appraising clinical guidelines. [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref] Six domains are listed: ## Scope and purpose These guidelines are intended to be of use for all healthcare professionals, although with a major focus on the asymptomatic patient with abnormal liver blood tests. Nonetheless, the guideline will review the role/utility of liver blood tests in both symptomatic and asymptomatic patients and explore their possible role in case finding in high-risk groups or following a clinical concern. They include recommendations for both adults and children, although the evidence for children is often lacking. No meta-analyses or randomised controlled trials concerning the management of abnormal LFTs in asymptomatic people have been carried out and therefore no grade A evidence exists in these guidelines to support the recommendations made. These guidelines are not intended to serve as rigid protocols or to replace clinical judgement. ## Guideline development group membership and stakeholder involvement Membership of the group includes patient/patient group representation, adult and paediatric hepatologists, clinical biochemists, general practitioners, internal medicine specialists, public health specialists and radiologists. ## Rigour of development The published literature was searched using PubMed, Medline, Web of Knowledge and the Cochrane database between October 2014 and February 2016. The Guidelines Development Group met through a series of meetings and teleconferences during that time. The level of supporting evidence (graded levels 1 to 5) is assessed by the Oxford Centre For Evidence Based Medicine . The recommendation grade is determined on the level of evidence as follows: A. consistent level 1 studies; B. consistent level 2 or 3 studies or extrapolations from level 1 studies; C. level 4 studies or extrapolations from level 2 or 3 studies; D. level 5 evidence or troublingly inconsistent or inconclusive studies of any level. Areas of disagreement about the recommendation grade were subjected to discussion and, if necessary, voting by members of the guidelines group. Where possible, the health benefits, side effects and risks of recommendations were discussed. The guidelines were subject to peer review after submission for consideration for publication in Gut. ## Clarity and presentation Recommendations are intended to be specific to particular situations and patient groups; where necessary, different options are listed. Where the evidence and recommendation is restricted to adults, this will be stated. The term 'patients' implies all ages. Key recommendations are linked to discussion threads on a discussion forum hosted on the BSG website. ## Applicability We have discussed organisational changes that may be needed in order to implement these recommendations with the British Liver Trust, the British Association for the Study of the Liver, the British Society of Gastroenterology, the Royal College of General Practice, the Specialist Advisory Committee in Clinical Biochemistry/Royal College of Pathology and Association for Clinical Biochemistry, the British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), Public Health England, the British Society of Gastrointestinal and Abdominal Radiologists (BSGAR) and the Society of Acute Medicine. We have attempted to identify key criteria for monitoring and audit purposes. ## Editorial independence and conflict of interest Guideline group members have declared any conflicts of interest. There is full editorial independence from the BSG, which commissioned the guideline. The guideline was subsequently peer reviewed by the CSSC, who provided comments and suggestions. ## Scheduled review of guidelines The proposed time for review of the guidelines is 5 years to take into account new developments. To ensure that there is a facility for feedback after publication, links to the BSG discussion forums corresponding to the particular section of these guidelines are included with this document. Feedback from general practitioners will also be incorporated-for example, via the newly established British Liver Trust/Royal College of General Practitioners (RCGP) clinical priority programme. In accordance with the AGREE II tool the BSG forum will provide feedback. ## What constitutes a liver blood test? Liver blood tests are readily available biochemical laboratory tests, with the standard panel varying from hospital to hospital. [bib_ref] AGA technical review on the evaluation of liver chemistry tests, Green [/bib_ref] They have historically been referred to as LFTs, yet the predominant abnormality relates not to liver dysfunction, but to elevations of hepatobiliary liver enzymes. For this reason this guideline will refer to liver blood tests and not LFTs as it more accurately captures their usage in clinical practice. Hepatobiliary enzymes, when interpreted in isolation convey information on the level of ongoing injury, whereas bilirubin, albumin and INR convey information on liver function, with platelets conveying information on the level of fibrosis. In this guideline an abnormal liver blood test is defined as being a value outside the standard reference interval, although there is an emerging literature suggesting that the current reference intervals for ALT may be too high. [bib_ref] Spectrum of NAFLD and diagnostic implications of the proposed new normal range..., Prati [/bib_ref] and not all worrisome heterogeneity need be statistically significant. †CDR, clinical decision rule (algorithms or scoring systems which lead to a prognostic estimation or a diagnostic category). ‡Validating studies test the quality of a specific diagnostic test based on prior evidence. An exploratory study collects information and trawls the data (eg, using a regression analysis) to find which factors are 'significant'. §Good reference standards are independent of the test, and applied blindly or objectively to all patients. Poor reference standards are haphazardly applied, but still independent of the test. Use of a non-independent reference standard (where the 'test' is included in the 'reference', or where the 'testing' affects the 'reference') implies a level 4 study. ¶Good follow-up in a differential diagnosis study is >80%, with adequate time for alternative diagnoses to emerge (eg, 1-6 months acute, 1-5 years chronic). **Met when all patients died before the treatment became available but some now survive while receiving it; or when some patients died before the treatment became available but none now die while receiving it. † †An 'absolute SpPin': a diagnostic finding whose Specificity is so high that a Positive result rules in the diagnosis. An 'absolute SnNout': a diagnostic finding whose Sensitivity is so high that a Negative result rules out the diagnosis. ‡ ‡Split-sample validation is achieved by collecting all the information in a single tranche, then artificially dividing this into 'derivation' and 'validation' samples. § §Poor-quality cohort study: one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded) objective way in both exposed and non-exposed individuals and/or failed to identify or appropriately control known confounders and/or failed to carry out a sufficiently long and complete follow-up of patients. Poor-quality case-control study: one that failed to clearly define comparison groups and/or failed to measure exposures and outcomes in the same (preferably blinded) objective way in both cases and controls and/or failed to identify or appropriately control known confounders. ¶ ¶Poor-quality prognostic cohort study: one in which sampling was biased in favour of patients who already had the target outcome, or the measurement of outcomes was accomplished in <80% of study patients, or outcomes were determined in an unblinded non-objective way, or there was no correction for confounding factors. Bilirubin is predominantly the by-product of the breakdown of the haem component of haemoglobin by the reticuloendothelial system. [bib_ref] A novel perspective on the biology of bilirubin in health and disease, Gazzin [/bib_ref] It exists in two forms, unconjugated and conjugated. Bilirubin is transported to the liver in its insoluble unconjugated form, where it is converted into soluble conjugated bilirubin in order to be excreted. Unconjugated hyperbilirubinaemia is usually due to haemolysis or impaired conjugation whereas conjugated hyperbilirubinaemia is typically due to parenchymal liver disease or obstruction of the biliary system. Most laboratories will routinely report total bilirubin, which comprises unconjugated and conjugated fractions. Elevations of either fraction will therefore lead to a rise in the measured bilirubin concentration. The most common cause of an isolated elevated bilirubin concentration is Gilbert's syndrome, which is an inherited disorder of metabolism and leads to impaired conjugation via reduced activity of the enzyme glucuronyltransferase. [bib_ref] Genetic variation in bilirubin UPDglucuronosyltransferase gene promoter and Gilbert's syndrome, Monaghan [/bib_ref] Except in the neonatal period, the majority of measurable bilirubin should be conjugated, even in individuals with significant liver disease. Hence if the majority of the elevated bilirubin comprises the unconjugated fraction then the cause, in the absence of haemolysis, is virtually always Gilbert's syndrome. As Gilbert's syndrome is not associated with liver disease or ill health, any such individuals should be fully reassured. [bib_ref] Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection..., Kundur [/bib_ref] In the neonatal period, there may be a physiological increase in total bilirubin, which is unconjugated. This may be pathological if high or prolonged. [bib_ref] Neonatal cholestasis -differential diagnoses, current diagnostic procedures, and treatment, Götze [/bib_ref] In neonates and infants in whom the conjugated bilirubin is >25 μmol/L, referral to a paediatrician for urgent assessment of possible liver disease is essential. Albumin is a protein that is produced only in the liver and has multiple biological actions, including maintenance of oncotic pressure, binding of other substances (such as fatty acids, bilirubin, thyroid hormone and drugs), metabolism of compounds, including lipids, and antioxidant properties. As albumin is only produced by the liver, the serum albumin concentration is often considered as a marker of the synthetic function of the liver. However, overinterpretation of the measured concentrations of albumin as a marker of the severity of liver disease is not always merited. Albumin concentrations are reduced in many clinical situations, including sepsis, systemic inflammatory disorders, nephrotic syndrome, malabsorption and gastrointestinal protein loss. Prothrombin time (PT) and INR are assessments of blood clotting, which are used to measure liver function, as the underlying protein clotting factors (II, V, VII, IX and X) are made in the liver. If there is significant liver injury (usually loss of >70% of synthetic function), this results in a reduction in clotting factor production and subsequent coagulopathy, as confirmed by a prolonged PT or INR. While a prolonged PT/INR can indicate either acute or chronic liver dysfunction it can also be caused by vitamin K deficiency as seen in fat malabsorption and chronic cholestasis. A reduction in platelets, termed thrombocytopenia, is the most common haematological abnormality found in patients with chronic liver disease and is an indicator of advanced disease. Multiple factors culminate in a low platelet count: decreased production, splenic sequestration and increased destruction. Decreased production is a consequence of bone marrow suppression, as caused by alcohol, iron overload, drugs and viridae, and also by a reduction in thrombopoietin levels in chronic liver injury. Splenic sequestration results from hypersplenism, which is a consequence of portal hypertension seen in advanced liver fibrosis. Platelet destruction is also increased non-specifically in liver cirrhosis owing to shear stress, fibrinolysis and bacterial translocation, whereas in specific causes of autoimmune liver disease, immunologically mediated destruction of platelets occurs owing to antiplatelet immunoglobulin. Alkaline phosphatase (ALP) is produced mainly in the liver (from the biliary epithelium) but is also found in abundance in bone and in smaller quantities in the intestines, kidneys and white blood cells. Levels are physiologically higher in childhood, associated with bone growth, and in pregnancy due to placental production. Pathologically increased levels occur mainly in bone disease (eg, metastatic bone disease and bone fractures) and cholestatic liver disease-for example, primary biliary cholangitis, primary sclerosing cholangitis, common bile duct obstruction, intrahepatic duct obstruction (metastases) and drug-induced cholestasis. Furthermore, hepatic congestion secondary to right-sided heart failure can also lead to cholestasis (elevated ALP levels and/or bilirubin). When ALP is elevated in isolation, the measurement of γ-glutamyltransferase can indicate whether the ALP is of hepatic or non-hepatic origin. [bib_ref] The measurement of serum alkaline phosphatase in clinical medicine, Posen [/bib_ref] While there are no data on the most likely causes of an isolated raised ALP in an asymptomatic population, the the most common cause is likely to be vitamin D deficiency, or normal increase seen in childhood due to rapid growth. Other causes include Paget's disease and bony metastases. If doubt still exists, the use of electrophoresis to separate the isoenzymes of ALP can differentiate hepatic from non-hepatic causes of increased ALP. AST and ALT are enzymes present in hepatocytes and are released into the blood stream in response to hepatocyte injury or death (hepatitis). Elevations in either of these enzymes are the the most common abnormality seen on liver blood test profiles. Both enzymes are present in many differing types of tissue, but ALT is considered more liver-specific since it is present in low concentrations in non-hepatic tissue, and non-liver related elevations are uncommon. However, AST is abundantly present in skeletal, cardiac and smooth muscle and so may be elevated in patients with myocardial infarction or myositis. Although ALT is considered a more specific indicator of liver disease, the concentration of AST may be a more sensitive indicator of liver injury in conditions such as alcohol-related liver disease and in some cases of autoimmune hepatitis (AIH). In children, creatine kinase measurement may help to determine whether an isolated rise in ALT or AST is due to an underlying skeletal muscle disorder, such as muscular dystrophy. γ-Glutamyltransferase (GGT) is abundant in the liver and also present in the kidney, intestine, prostate and pancreas but not in bone; therefore it can be useful in confirming that an elevated ALP is of liver and not bony origin. [bib_ref] Serum -glytamyl transpeptidase activity in liver disease, Whitfield [/bib_ref] GGT is most commonly elevated as a result of obesity, excess alcohol consumption or may be induced by drugs. Although an elevated GGT has a low specificity for liver disease, it is one of the best predictors of liver mortality. [bib_ref] Development of a decision support tool for primary care management of patients..., Donnan [/bib_ref] It is particularly useful in children to establish the likelihood of biliary disease when ALP is not a reliable indicator. Predominant causes of cholestasis in children include congenital abnormalities of the biliary tract and genetic disorders affecting bile synthesis and excretion. ## What constitutes a standard liver blood test panel? There are remarkably few data to determine what an optimal liver blood test panel should include, although this would be influenced by the clinical setting. [bib_ref] Evaluation of abnormal liver-enzyme results in asymptomatic patients, Pratt [/bib_ref] The Health Technology Assessment commissioned Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS) study reported that ALT and ALP identified the vast majority of adults with Guidelines necro-inflammatory liver disease. The routine addition of GGT led to a marginal increase in sensitivity but at the cost of a loss of specificity and a higher false-positive rate. [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] But the analysis did not include adults with NAFLD or alcohol-related liver disease (ARLD), which account for 90% of liver mortality, 1 in whom liver blood tests and the follow-on liver aetiology screen are seldom diagnostic. In this setting GGT and AST would aid the sensitivity of detecting such patients. Addition of GGT to a liver blood test panel increases the likelihood of an adult having abnormal liver blood tests from around 15% to 30% [bib_ref] Nonalcoholic fatty liver disease, Paredes [/bib_ref] and, notably, a raised GGT is associated with increased liver as well as all-cause (including cancer) mortality, with the greatest risk being observed in those with the most significant elevations of GGT. [bib_ref] Development of a decision support tool for primary care management of patients..., Donnan [/bib_ref] In addition, the routine addition of AST to the initial panel did not improve the detection of specific disease. [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] The analysis from the BALLETS study was predicated on the identification of adults with established causes of liver disease such as autoimmune liver disease, viral hepatitis or metal storage disorders, which were found in just 5% of those with abnormal liver blood tests. [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] Thus, these data would support a strategy of a streamlined panel with high sensitivity without generating large numbers of false positives, which have the potential to lead to greater patient anxiety, overinvestigation and considerably increased costs. Recommendation 1: Initial investigation for potential liver disease should include bilirubin, albumin, ALT, ALP and GGT, together with a full blood count if not already performed within the previous 12 months. ## Level 2b, grade b) If there is clear indication of a specific clinical risk-for example, in high-risk groups such as injecting drug users, migrants from high prevalence areas or prisoners, then some aspects of second-line testing can be undertaken simultaneously. In many patients with liver damage an assessment of liver fibrosis is critical in making decisions about referral and management. In adults, clues to the level of liver fibrosis can be gleaned from the use of non-invasive algorithms such as the AST to ALT ratio. [bib_ref] Development of a decision support tool for primary care management of patients..., Donnan [/bib_ref] An AST:ALT ratio of >1 indicates advanced fibrosis/cirrhosis, [bib_ref] Prediction of liver disease in patients whose liver function tests have been..., Mclernon [/bib_ref] hence the inclusion of this ratio in algorithms has the potential to assess the risk of significant fibrosis in adults with abnormal liver blood tests. However, non-invasive markers have not been sufficiently validated in children to be routinely applied in clinical practice. An important consideration when evaluating the risk of hepatic fibrosis is that both AST and ALT can be normal even in the setting of cirrhosis, and the utility of the AST:ALT ratio in adults persists even if both values are within the normal reference interval. [bib_ref] Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis..., Verma [/bib_ref] While it is hard to justify the routine analysis of both AST and ALT together on every liver blood test request, a strategy not supported by the data from the BALLETS study, subsequent testing of AST (or ALT depending which one is undertaken first) to calculate the AST:ALT ratio is clearly desirable. From a patient and cost perspective this is likely to be more cost-effective if performed by 'reflex' on the same sera following the detection of an abnormal ALT or GGT. To date there is no firm evidence that this is a cost-effective approach, although the results of a pilot study of such 'reflex' testing and additional up-front aetiology screen testing from Wales and Scotland are awaited. ## When should liver blood tests be checked? There are a range of settings where requesting liver blood tests should be considered to determine the presence, or severity, of liver disease: ## Non-specific symptoms Liver disease tends to develop silently with no signs or symptoms, and there is evidence that the majority of people with late-stage liver disease are undiagnosed. [bib_ref] Pediatric liver diseases: current challenges and future perspectives, Della Corte [/bib_ref] However, inflammatory liver diseases including autoimmune liver disease and viral hepatitis can be associated with symptoms. For example, 75% of patients with AIH have one or more non-specific symptoms, such as fatigue, nausea or anorexia. [bib_ref] Implementation of the Lancet Standing Commission on Liver Disease in the UK, Williams [/bib_ref] These diseases can be effectively treated, and are often diagnosed late, so the presence of these non-specific symptoms would be an indication to check routine liver blood tests, accepting that there are many other causes for these symptoms. ## Evidence of chronic liver disease Patients with symptoms or signs of cirrhosis, portal hypertension or liver failure, including ascites, peripheral oedema, spider naevi and hepatosplenomegaly, need liver blood tests to monitor their function. In that regard the inclusion of INR is important to fully define their synthetic function. ## Conditions which are associated with a high risk of developing liver disease Autoimmune liver disease is more common in patients with pre-existing autoimmune diseases, and liver blood tests may be appropriate if clinical symptoms change to suggest development of liver disease-for example, pruritus in primary biliary cholangitis. Patients with inflammatory bowel disease (including ulcerative colitis and Crohn's disease) have a particular notable risk of developing the autoimmune cholestatic liver disease, primary sclerosing cholangitis; disease prevalence is estimated at just under 10%. [bib_ref] Prevalence of sclerosing cholangitis detected by magnetic resonance cholangiography in patients with..., Lunder [/bib_ref] Primary sclerosing cholangitis-inflammatory bowel disease is associated with increased complications relating to liver disease, as well as increased colorectal cancer risk. [bib_ref] Patient age, sex, and inflammatory bowel disease phenotype associated with course of..., Weismüller [/bib_ref] Periodic monitoring of liver blood tests is therefore common practice, with a low clinical threshold for investigation of cholestatic liver blood tests by MRI. In the absence of currently approved medical therapy ongoing efforts clinically focus on early recognition of disease with subsequent risk stratification, in order to facilitate timely consideration of trial-based intervention. ## Use of hepatotoxic drugs A wide variety of drugs are associated with liver disease, and a requirement for the monitoring of liver functions may be documented. [bib_ref] Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory..., Dufour [/bib_ref] In this systematic review the drugs most commonly implicated included: carbamazepine, methyldopa, minocycline, macrolide antibiotics, nitrofurantoin, statins, sulfonamides, terbinafine, chlorpromazine and methotrexate. In addition, drugs can cause fatty liver and steatohepatitis and vascular injury. Methotrexate treatment requires special care, to prevent dose-dependent liver fibrosis, and non-invasive markers of fibrosis should be monitored. [bib_ref] Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests, Dufour [/bib_ref] [bib_ref] How are abnormal results for liver function tests dealt with in primary..., Sherwood [/bib_ref] [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] Although statins can lead to drug-induced liver injury, this is very rare, with studies demonstrating they are safe in patients with pre-existing abnormal liver enzymes. [bib_ref] Patients with elevated liver enzymes are not at higher risk for statin..., Chalasani [/bib_ref] On occasions it can be difficult to establish the relative contribution of a drug or drugs alongside possible concomitant liver disease. In this situation clinical judgement needs to be exercised to determine what is the major contributor and the need to discontinue medication. This will be influenced by the pattern of liver blood tests, the timing of medication use with respect to the liver blood abnormality developing and the clinical setting. ## Family history of liver diseases Investigating the relatives of patients with familial diseases, including haemochromatosis or Wilson's disease, would be an indication for the specific relevant tests: ferritin and transferrin saturation, haemochromatosis genotype, caeruloplasmin and urinary copper. Liver enzymes are a poor guide to the development of progressive liver fibrosis in alcohol-related liver disease, but elevated enzymes, of which GGT is the best predictor of mortality, [bib_ref] Development of a decision support tool for primary care management of patients..., Donnan [/bib_ref] can be useful aids to behaviour change. [bib_ref] Diagnosing liver disease in asymptomatic patients, Chatwin [/bib_ref] The current NICE recommendation is to screen for advanced liver disease using Fibroscan in patients drinking at harmful levels (50 units/week in men and 35 units/week in women), and there is emerging evidence that a diagnosis of liver fibrosis can be an effective stimulus for behaviour change. 14 viral hepatitis Viral hepatitis may be associated with non-specific symptoms, including fatigue, which may be severe, [bib_ref] Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic..., Parkes [/bib_ref] but the majority of patients are symptom free and identified as a result of risk factors, including country of origin or parental exposure. While liver blood tests can give an indication of necro-inflammation or of advanced fibrosis, a key early test is serology for viral hepatitis in high-risk groups, such as people who inject drugs, migrants from high-prevalence areas, prisoners, as liver blood tests can be normal in this setting [fig_ref] table 2: Liver aetiology table for patients with non-acute abnormal liver blood tests [/fig_ref]. ## Presence of lifestyle risk factors associated with the development of nafld: obesity/type 2 diabetes Commonly, the question about non-alcoholic fatty liver arises in response to the incidental observation of abnormal liver blood tests or an echobright liver on an ultrasound scan (USS). Case finding or screening to identify patients with NAFLD remains controversial, with conflicting advice from American [bib_ref] The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by..., Chalasani [/bib_ref] and European 44 guidelines. Indeed recent NICE guidance does not advocate this at present, although the advent of new diagnostics and treatments allied with cost-effectiveness analyses may affect this in the future. Research Recommendation 1: Further evidence is required to establish the cost-effectiveness of case finding for NAFLD in high-risk groups before it can be recommended. (level 5, grade D) ## Does the extent and duration of abnormal liver blood tests determine subsequent investigation? Many previous guidelines have stipulated minimum criteria for the extent and duration of any liver blood test abnormality before further investigation is considered, which in the main has been influenced by workload considerations given the large numbers of liver blood tests outside the standard reference intervals. However, over 50% of patients presenting with end-stage liver disease, without a previous diagnosis of chronic liver disease, were previously noted to have abnormal liver blood tests in their health records, indicating inadequate investigation. [bib_ref] Development of a decision support tool for primary care management of patients..., Donnan [/bib_ref] The Epidemiology of Liver Disease in Tayside (ELDIT) project used electronic case record linkage to diagnose liver disease and demonstrated that 20% of all liver blood tests measured were found to be abnormal, with <10% of these explained by existing liver disease. Thus, GPs and practice nurses who request liver blood tests have the problem of managing the 20% patients who have test results reported as 'abnormal' and outside the laboratory reference intervals. GP management strategies can vary from ignoring some results (potentially unsafe), repeating them (inconvenient to the patient), requesting more tests (expensive) or referring patients to a gastroenterologist (incurring NHS costs). The NHS faces the potential for a significant rise in the costs and consequences of the uncertainty GPs have in managing liver blood test results, necessitating clear guidance on how to respond to these tests. ## Importance of context Interpretation of abnormal liver blood tests requires an understanding of the context in which they arise. This can be illustrated in the extreme by a patient receiving statin therapy who has an ALT of 80 U/L, who is well and requires continued treatment with the statin compared with a patient with end-stage alcohol-related liver disease with an ALT in the normal reference interval at 30 U/L and who may have a life expectancy of weeks. A common assumption is that the detected abnormality represents the first presentation of abnormal LFTs, when it should be standard practice to review previous blood test records and past/ current medical history before requesting additional investigations and referrals. Another setting in which liver bloods are commonly abnormal but not necessarily of clinical concern is pregnancy where the alkaline phosphatase and serum albumin are often elevated and reduced, respectively. Other changes in liver bloods in this setting may indicate worsening of pre-existing disease or the development of pregnancy-related disease, which would warrant prompt investigation. [bib_ref] Liver abnormalities in pregnancy, Than [/bib_ref] Recommendation 2: Abnormal liver blood test results should only be interpreted after review of the previous results, past medical history and current medical condition. (level 5, grade D) ## Extent of abnormality It is assumed that the magnitude of derangement of a liver blood test panel correlates with prognosis, and for this reason threshold values above the upper limit of the reference interval are commonly used when directing the need for further Guidelines investigation. However, this assumption is not supported by the literature, and prognosis is more clearly determined by diagnosis and context within which the tests are requested. To illustrate this consider two patients; a patient with an acute hepatitis A infection can have ALT values >1000 U/L, whereas a patient with hepatitis C can have an ALT within the normal reference interval, yet 10 years later the patient with hepatitis A is likely to be alive and well irrespective of how they are managed, whereas the patient with hepatitis C if not investigated and diagnosed is at substantial risk of progressing to end-stage liver disease. Indeed, the the most common causes of abnormal liver blood tests leading to chronic liver disease-namely non-alcoholic fatty liver disease, alcohol-related liver disease and hepatitis C, are frequently associated with only mild or moderate liver blood test abnormalities. Therefore, despite the increasing use of liver blood tests, patients continue to present with undiagnosed end-stage liver disease, which might have been preventable by earlier diagnosis. Moreover, the current upper limit of normal for many of the liver enzymes (for example ALT) may be too high, which is probably a consequence of patients with occult NAFLD being included in the generation of normal serum ALT ranges. [bib_ref] Spectrum of NAFLD and diagnostic implications of the proposed new normal range..., Prati [/bib_ref] This is perhaps best appreciated in patients with chronic hepatitis B, where treatment guidelines recommend an ALT of >30 U/L as being significant in males and >19 U/L significant for females. Further, indirect evidence for this comes from the recognition that in some patients with autoimmune hepatitis their fibrosis stage progresses despite apparent control of their inflammatory process via perceived normal aminotransferase levels. This is compounded by the knowledge that many patients with significant liver fibrosis may have liver enzymes in the normal reference range and normal synthetic function, increasing the difficulty of their early identification. Thus, the clinical assessment of such individuals is critical in determining what the question is (do they have fibrosis?), which tests should be ordered and how should they be interpreted. Recommendation 3: The extent of liver blood test abnormality is not necessarily a guide to clinical significance. This is determined by the specific analyte which is abnormal (outside the reference range) and the clinical context. (level 5, grade D) ## Duration of abnormality and retesting As with extent of liver blood test derangement, there are also assumptions that the duration is a reflection of clinical significance, thus necessitating routine repeat testing for patients with mildly abnormal liver blood tests. This is predicated on the belief that many liver blood test abnormalities may be transient and incidental and will normalise thus precluding any significant liver disease. While this may be true of some acute liver diseases, it is manifestly not the case for many chronic liver diseases such as HCV and NAFLD where even normalised liver blood tests do not necessarily imply absence or resolution of disease. Moreover, as demonstrated by the BALLETS study, 84% of adults still had abnormal tests when repeated 1 month later. [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] When repeating blood tests (to see if they have normalised) the whole cost of the investigation must be borne in mind, which includes recalling the patient as well as obtaining and transporting the blood sample to the laboratory and the cost of the laboratory analysis. Therefore, a strategy of simply repeating abnormal tests can only be justified where there is a high degree of certainty that the abnormality will resolve in response to an identified acute insult. In other cases, detection of the first abnormality should trigger investigation of the aetiology, or repeat testing to assess progression or disease severity where there is a suspicion that the underlying cause may require urgent referral/admission. The Health Technology Assessment-commissioned ALFIE study, which was a retrospective study of outcomes following abnormal liver blood tests in patients over 16 years of age seen in primary care, demonstrated that just 50% of abnormal liver blood tests were ever followed up. [bib_ref] Development of a decision support tool for primary care management of patients..., Donnan [/bib_ref] This highlights the challenges in identifying/capturing significant liver disease early and emphasises the importance of assessing such patients expediently without adding unnecessary delays. Recommendation 4: Patients with abnormal liver blood tests should be considered for investigation with a liver aetiology screen irrespective of level and duration of abnormality. Abnormal refers to an analyte which is outside the laboratory reference range. [fig_ref] Figure 2: Non-alcoholic fatty liver fibrosis algorithm [/fig_ref] ## Clinical pattern recognition for liver blood tests There are three common patterns of abnormal liver test results whose recognition can aid diagnosis: 1. Isolated raised bilirubin-most commonly caused by Gilbert's syndrome (affects 5-8% of the population). [bib_ref] Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms..., Erlinger [/bib_ref] Consider haemolysis in patients with anaemia. Repeat liver blood tests on a fasting sample with a full blood count and a direct and indirect bilirubin; the total bilirubin should rise further, owing to the indirect component, and there should be no evidence of anaemia. If the patient is anaemic, haemolysis needs to be excluded by requesting reticulocyte count/lactate dehydrogenase/haptoglobin. If the unconjugated bilirubin is more markedly elevated (>40 μmol/L) then rarer causes such as Crigler-Najjar syndrome [bib_ref] Inherited disorders of bilirubin transport and conjugation: new insights into molecular mechanisms..., Erlinger [/bib_ref] should be considered and genetic testing undertaken. 2. Cholestatic-predominantly raised ALP and GGT indicate cholestasis. Common causes include primary biliary cholangitis, PSC, biliary obstruction (stones, strictures, neoplasia, etc), hepatic congestion and drug-induced liver injury. In children, additional disorders that may present with cholestasis include biliary tract abnormalities and genetic disorders of bile synthesis and excretion. However, an isolated raised ALP may be caused by vitamin D deficiency and not be liver related, or it may relate to raised values during periods of rapid growth in childhood, and thus the presence of a concomitantly elevated GGT can help confirm the cause of liver disease. In children with specific inherited disorders of bile acid synthesis and transport, however, GGT is characteristically low or normal. In these disorders, cholestasis occurs without GGT elevation. 3. Hepatitic-predominantly raised ALT and AST indicate hepatocellular liver injury (hepatitis). Common causes include viral hepatitis, NAFLD, ARLD, AIH and druginduced liver injury. Details of the approach to these liver blood test abnormalities are given in the subsequent section on outcomes and pathways. ## Response to abnormal liver blood tests: outcomes and pathways As indicated in the presence of unexplained clinical jaundice or suspicion of possible hepatic or biliary malignancy should lead to an immediate referral. In all other adults with incidentally raised liver enzymes it is important to take a careful history and perform a targeted clinical examination to look for the cause. Liver enzymes can occasionally be raised owing to intercurrent illness, although when liver blood tests were repeated, 84% of tests remained abnormal on retesting after 1 month, and even at 2 years 75% remained abnormal. [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] Thus, in a patient with abnormal liver blood tests it is not recommended to simply repeat the same panel of tests but to determine the cause unless there is a high index of clinical suspicion that it is a transient finding. In children, there should be a low threshold for referral to a paediatrician for further investigation, as the most common causes of liver dysfunction in adults are less common in children, and there is a wider differential diagnosis. Therefore, the response to the finding of abnormal liver blood tests should be to obtain a thorough clinical history, including age; ethnicity/country of birth (to explore possible risk of hepatitis B or C); specific symptoms (jaundice, abdominal pain, weight loss, pruritus, etc); comorbidity; drug history (prescribed, over the counter, herbal, injecting drug use, illicit); travel history; occupational exposure; tick bites; muscle injury; alcohol history (current and past intake in average units per week, consider AUDIT C); features of the metabolic syndrome (central obesity, hypertension, diabetes/insulin resistance and dyslipidaemia); family history; other symptoms, and, additionally, in children a maternal, neonatal, nutritional and developmental history. For patients with more marked elevations in ALT (>1000 U/L) other possible causes of viral hepatitis should be considered, including hepatitis A and E and cytomegalovirus. Examinations should include: body mass index and an abdominal examination looking for hepatosplenomegaly, ascites and other signs of chronic liver disease. PSC should be considered for patients with raised cholestatic liver enzymes and a personal or family history of autoimmune disease or personal history of inflammatory bowel disease. No diagnostic or serological markers exist for PSC and MRI may be required at the outset. Investigations should include a standard liver aetiology screen or core panel (table 2) to identify the cause of damage and exclude additional pathologies. There is uncertainty as to whether the entire extended liver aetiology screen should be undertaken in response to abnormal liver blood tests, but in most situations only the core panel should be performed with the extended panel (table 2) reserved for patients with no clear cause. The choice of blood tests in the core panel is influenced by prevalence (BALLETS) in the UK and the identification of treatable causes of liver disease. Patients with evidence of hepatitis B (HBsAg positive), HCV (antibody positive then PCR positive), autoimmune hepatitis (raised IgG ± positive autoantibodies), primary biliary cholangitis (cholestatic liver enzymes+positive anti-mitochondrial antibody), PSC (cholestatic liver enzymes ± history of inflammatory bowel disease) or haemochromatosis (raised ferritin and transferrin saturation >45%) should be referred to a specialist clinic in accordance with locally agreed guidance. An isolated elevated serum ferritin result is commonly seen in dysmetabolic iron overload syndrome as found in the setting of alcohol excess, NAFLD and other chronic liver diseases and does not reflect haemochromatosis. The presence of dilated bile ducts requires further assessment and consideration of urgent hospital referral depending on the clinical setting. In the BALLETS study, [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] in a cohort of 1290 adults in primary care, fully characterised and followed up for 2 years, <5% of people with abnormal liver blood test results had a specific disease affecting the liver. In only 1.3% was a specific liver disease identified requiring immediate treatment (13 with viral hepatitis and four genetic haemochromatosis). Notably, the country of origin (not ethnic group) was the strongest predictor of viral hepatitis. [bib_ref] Should patients with abnormal liver function tests in primary care be tested..., Arnold [/bib_ref] The condition of infants with neonatal cholestasis (conjugated bilirubin >25 μmol/L) should be discussed urgently with the local paediatrician. Recommendation 5: In adults a standard liver aetiology screen should include abdominal USS, hepatitis B surface antigen, hepatitis C antibody (with follow-on polymerase chain reaction if positive), anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, serum immunoglobulins, simultaneous serum ferritin and transferrin saturation. (level 2b, grade C) Recommendation 6: In children, ferritin and transferrin saturation may not be indicated, but autoantibody panel should include anti-liver kidney microsomal antibody and coeliac antibodies. Alpha-1-antitrypsin level and caeruloplasmin (age >3 years) should be included, and abnormalities discussed with an appropriate inherited metabolic disease specialist. (level 2b, grade C) Nearly 4 in 10 adults had a 'fatty liver' on ultrasound in the BALLETS study, and an abnormal ALT concentration was the strongest laboratory predictor of this finding. [bib_ref] Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study, Lilford [/bib_ref] Obesity was more strongly associated with 'fatty liver' than with alcohol excess, but one-quarter of adults with 'fatty liver' were neither overweight nor excessive alcohol drinkers. The majority of adults with abnormal liver blood tests will be identified as having NAFLD or ARLD and most will not need referral to a specialist, but will require reinforcement of lifestyle advice and ongoing assessment in primary care. For such patients, together with those with other aetiologies, it is important to establish if there is significant liver fibrosis and risk of progression of cirrhosis, [bib_ref] Increased liver echogenicity at ultrasound examination reflects degree of steatosis but not..., Mathiesen [/bib_ref] as early recognition of liver disease and appropriate treatment can prevent progression to end-stage liver disease. As illustrated in figures 1 and 2, this can be achieved in adults by use of algorithms and non-invasive fibrosis markers, with recourse to specialist clinics and liver biopsy as needed. A range of non-invasive algorithms has been examined in NAFLD [bib_ref] Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients..., Mcpherson [/bib_ref] and ARLD but in this guideline we will focus on those with the greatest evidence base. ## Approach to common conditions nafld NAFLD is diagnosed by the presence of an echobright liver on ultrasound in the absence of excessive alcohol consumption. For adults with NAFLD it is recommended that a first-line, non-invasive assessment, such as Fibrosis-4 (FIB-4) [bib_ref] The predictive value of FIB-4 versus FibroTest, APRI, FibroIndex and Forns index..., Adler [/bib_ref] or NAFLD Fibrosis Score (NFS), 50 is undertaken to identify patients with advanced fibrosis [fig_ref] table 3: Non-invasive algorithms for gauging liver fibrosis in patients with NAFLD ALT, alanine... [/fig_ref]. Patients with a low FIB-4 (<1.3 for those aged <65 years or <2.0 for those >65 years) or low NFS (<−1.455 for those aged <65 years or <0.12 for those >65 years) can be managed in primary care. [bib_ref] Age as a confounding factor for the accurate non-invasive diagnosis of advanced..., Mcpherson [/bib_ref] Presently, the mainstay of treatment for NAFLD is to reduce calorie intake and increase physical activity with the aim of inducing gradual and long-term weight loss (see figures 1 and 2). Those patients with indeterminate FIB-4 (1.3-3.25) or NFS scores (−1.455 to 0.675) should undergo further testing with a second-line test such as serum enhanced liver fibrosis (ELF) [bib_ref] Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic..., Parkes [/bib_ref] ## Guidelines or Fibroscan/acoustic radiation force impulse (ARFI) elastography. The decision to use Fibroscan or ARFI should be based on local expertise and availability of respective devices. Consider referral to a specialist clinic for patients with serum ELF measurements >9.5 or Fibroscan >7.8 kPa. Cut-off points for ARFI vary according to the manufacturer 57-61 and thus should be tailored to the device used.Finally, those patients with elevated FIB-4 (>3.25) or NFS (>0.675) should be considered for referral to a specialist clinic irrespective of second-line tests. Non-invasive markers of fibrosis have not been sufficiently validated in children to recommend routine use in clinical practice. Of note, recent guidance by NICE on NAFLD proposed single testing with serum ELF measurements without recourse to algorithms or other diagnostic modalities,on the basis of cost-effectiveness analyses. This recommendation was noted and carefully considered during the drafting of this guideline. On balance, however, it was felt that the evidence for diagnostic tests, and their use in combination in NAFLD, was still evolving and thus this guidance took a broader view setting out a pathway structure with a range of options. This view is endorsed by the EASL-ALEH guidelines for the non-invasive assessment of liver disease.Recommendation 7: Adults with NAFLD should undergo risk stratification to determine their extent of liver fibrosis. ► First-line testing should use either FIB-4 or NAFLD Fibrosis Score -see ## Arld Alcohol-related cirrhosis is the the most common cause of liver-related mortality in Western populations. The majority Alcohol-related liver disease algorithm. In patients in whom alcohol is suspected to be the main injurious factor, the extent of consumption influences early decision-making. For those drinking at harmful levels, ≥35 units/week women and ≥50 units/week men, an assessment of liver fibrosis is the critical next step. For other patients, administration of the AUDIT C questionnaire alongside brief intervention is recommended initially. For patients who continue to drink at hazardous levels consideration should be given to assessment as for the higher-risk category according to liver fibrosis evaluation. This is particularly important for those with a GGT of >100 U/L. Cut-off points for ARFI vary according to manufacturer and thus should be tailored to the device used. ARFI, acoustic radiation force impulse; ELF, enhanced liver fibrosis; GGT, γ-glutamyltransferase; HCC, hepatocellular carcinoma. of patients with this condition are heavy daily drinkers, with a median alcohol consumption of around 120 units/week. [bib_ref] UK health performance: findings of the Global Burden of Disease Study, Murray [/bib_ref] Notably, 25% of the population drink more than recommended guidelines (≤14 units/week), with 10% drinking twice as much and 1.4% drinking more than 75 units/week.The relationship between alcohol consumption and liver cirrhosis is exponential; at 20 units/week the relative risk is approximately 3, whereas at 80 units/week it is 30. [bib_ref] Addressing liver disease in the UK: a blueprint for attaining excellence in..., Williams [/bib_ref] There is also a synergy between alcohol intake and obesity; when body mass index (BMI) is >35, the risk of liver disease doubles for any given alcohol intake (see . The aim of treatment in ARLD is for the patient to stop drinking harmfully, and this usually means complete abstinence. [bib_ref] Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory..., Dufour [/bib_ref] Referral to alcohol services should be undertaken for those patients with alcohol dependency as defined by an AUDIT score of >19, and kept in mind for those patients with an AUDIT score of ≥8. Importantly, a liver diagnosis in itself can be a highly effective intervention to change behaviour, and may be all that is required in many cases. [bib_ref] Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests, Dufour [/bib_ref] However, current provision of such brief interventions in primary care is inconsistent and should be given greater priority.Recommendation 8: Consider referral to alcohol services for all adults with ARLD with evidence of alcohol dependency as defined by an AUDIT score of >19. (level 3b, grade C) Normal liver blood tests do not rule out advanced liver fibrosis and cirrhosis, and so different approaches have been adopted/ recommended for the identification of the at-risk patient. The Lancet Commission recommended the use of AUDIT-C as a first-line screening tool in high-risk groups followed by the full 10-item AUDIT to determine when to look for liver disease. [bib_ref] Addressing liver disease in the UK: a blueprint for attaining excellence in..., Williams [/bib_ref] The recent NICE guideline (NG50)on cirrhosis recommended a cut-off point of 50 units/week for men and 35 units/week for women, above which Fibroscan/ARFI elastography is recommended to detect cirrhosis and advanced fibrosis. Patients with cirrhosis require screening for oesophageal varices and hepatocellular carcinoma. Recommendation 9: Harmful drinkers should undergo risk stratification with clinical assessment and Fibroscan/ARFI elastography. Adults should be referred to secondary care if there is evidence of advanced liver disease (features of cirrhosis or portal hypertension on imaging or from blood tests) and/or Fibroscan reading is >16 kPa (if available). (level 2b, grade B) Patients flagged up with the AUDIT-C but drinking <35 units/ week (women) and <50 units/week (men), respectively, should proceed to the full AUDIT questionnaire as detailed in figure 3. If GGT is elevated (>100 U/L) then consideration should be given to an assessment of liver fibrosis, as for the higher-risk group. Research Recommendation 2: Further evidence is required to establish the most cost-effective approach to identify patients with ARLD and NAFLD at risk of having advanced liver fibrosis. ## Approach to a patient with abnormal liver blood tests and a negative extended liver aetiology screen When the extended liver aetiology screen is negative [fig_ref] table 2: Liver aetiology table for patients with non-acute abnormal liver blood tests [/fig_ref] , including an abdominal USS, it is important to re-examine the history to exclude potential drug-induced aetiologies, including over-the-counter preparations and any potential recreational/ herbal drug use. In a UK primary care study of 1118 adults no cause was found in 45%, although many of these adults had metabolic risk factors and were likely to have NAFLD, [bib_ref] Presence and severity of nonalcoholic fatty liver disease in a large prospective..., Armstrong [/bib_ref] and it is important to recognise that ultrasound is only sensitive for steatosis when hepatocytes are more than 30% steatotic so patients with milder steatosis might have a normal USS. [bib_ref] The utility of radiological imaging in nonalcoholic fatty liver disease, Saadeh [/bib_ref] Therefore patients with raised ALT and/or GGT levels who are obese and/or have metabolic risk factors may still have NAFLD despite a normal USS. Such patients should be assessed in accordance with the NAFLD fibrosis algorithm. To further risk stratify this group of patients offer a second-line test for fibrosis such as Fibroscan/ARFI elastography or ELF test as shown in figures 1 and 2. Those patients with no NAFLD risk factors (eg, type 2 diabetes mellitus (T2DM), BMI >25, dyslipidaemia and hypertension) and with persistently elevated liver enzymes should be considered for referral to a local specialist for further evaluation. For example, in autoimmune liver disease there may be no autoantibodies detected, and in some cases immunoglobulins may also be normal-as a result, some entirely treatable conditions may be overlooked. For children, assessment of fibrosis will be performed after referral to secondary care, and may include Fibroscan/ARFI elastography or biopsy depending on local practice and guidelines. Recommendation 10: Adults with abnormal liver blood tests, even with a negative extended liver aetiology screen and no risk factors for NAFLD, should be referred/discussed to a gastroenterologist with an interest in liver disease/hepatologist for further evaluation (figure 1). (level 4, grade C) ## Applicability This guideline has provided advice on the pathways and tools to be used to best manage patients with abnormal liver blood tests. The pathways will be freely disseminated and incorporated into primary care IT systems to allow automatic calculation of risk scores when appropriate, to ensure recommendations can be put into practice. Facilitators of the guideline will include specialist societiesin particular, the Royal College of General Practitioners, the British Liver Trust and the British Society of Gastroenterology. Barriers to use include access to the guideline and its potential complexity. This has been addressed by inclusion of all relevant stakeholders, a simplified set of pathway figures and a comprehensive dissemination plan. The potential resource implications of applying the recommendations have been considered, and will be formally evaluated after adoption. At present, investigation and referral of patients with abnormal liver blood tests is variable, resulting in both unnecessary referral of patients and missing of significant liver disease. This pathway may rationalise the approach to abnormal liver blood tests and reduce healthcare expenses. An example of this is in Lambeth, where such a pathway has been successfully introduced, reducing referral of patients with NAFLD and minimal fibrosis. monitorinG And/or AuditinG criteriA 1. Formal adoption of this referral pathway for abnormal liver blood tests within each Clinical Commissioning Group (CCG) and updated annually. Data to be expressed as number of CCGs having adopted the pathway as a percentage of all CCGs. 2. Review number of referrals for abnormal liver blood tests from each CCG per year and audit the number that had followed the pathway. Data to be expressed as a percentage of referrals. 3. Proportion of patients with NAFLD or ARLD who have an assessment of liver fibrosis, as evaluated by FIB-4, NFS, ELF, Fibroscan and/or ARFI, in their records. Data to be expressed as a percentage of patients coded with NAFLD or ARLD on GP list. [fig] ►: Recommendation 1: Initial investigation for potential liver disease should include bilirubin, albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT), together with a full blood count if not already performed within the previous 12 months. (level 2b, grade B) Research Recommendation 1: Further evidence is required to establish the cost-effectiveness of case finding for non-alcoholic fatty liver disease (NAFLD) in high-risk groups before it can be recommended. (level 5, grade D) Recommendation 2: Abnormal liver blood test results should only be interpreted after review of the previous results, past medical history and current medical condition. (level 5, grade D) Recommendation 3: The extent of liver blood [/fig] [fig] Figure 2: Non-alcoholic fatty liver fibrosis algorithm. For those patients with NAFLD or liver disease of unknown aetiology, the next step is to determine the likelihood of liver fibrosis. Initial assessment includes calculation of a FIB4 or NAFLD fibrosis score with values <1.3 and ≤1.455, respectively, signifying a low risk of advanced fibrosis. Higher cut-off points, <2.0 and <0.12, should be used for patients aged over 65 years. Second-line tests that should be considered include serum markers such as ELF and imaging modalities such as ARFI elastography/FibroScan. For children, the text should be consulted for modification of recommendation. Cut-off points for ARFI vary according to manufacturer and thus should be tailored to the device used. ARFI, acoustic radiation force impulse; ELF, enhanced liver fibrosis; FIB-4, fibrosis-4; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD Fibrosis Score. [/fig] [table] table 2: Liver aetiology table for patients with non-acute abnormal liver blood tests [/table] [table] table 3: Non-invasive algorithms for gauging liver fibrosis in patients with NAFLD ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; IFG, impaired fasting glucose; NAFLD, non-alcoholic fatty liver disease. [/table]	None	https://gut.bmj.com/content/gutjnl/67/1/6.full.pdf	These updated guidelines on the management of abnormal liver blood tests have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines, which this document supersedes, were written in 2000 and have undergone extensive revision by members of the Guidelines Development Group (GDG). The GDG comprises representatives from patient/carer groups (British Liver Trust, Liver4life, PBC Foundation and PSC Support), elected members of the BSG liver section (including representatives from Scotland and Wales), British Association for the Study of the Liver (BASL), Specialist Advisory Committee in Clinical Biochemistry/Royal College of Pathology and Association for Clinical Biochemistry, British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), Public Health England (implementation and screening), Royal College of General Practice, British Society of Gastrointestinal and Abdominal Radiologists (BSGAR) and Society of Acute Medicine. The quality of evidence and grading of recommendations was appraised using the AGREE II tool. These guidelines deal specifically with the management of abnormal liver blood tests in children and adults in both primary and secondary care under the following subheadings: (1) What constitutes an abnormal liver blood test? (2) What constitutes a standard liver blood test panel? (3) When should liver blood tests be checked? (4) Does the extent and duration of abnormal liver blood tests determine subsequent investigation? (5) Response to abnormal liver blood tests. They are not designed to deal with the management of the underlying liver disease.
72e19b52b20be6450bcbbfdb79fe6a46650f2282	pubmed	Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19)	Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19) As the coronavirus disease 19 global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the "off-label" repurposing of drugs such as hydroxychloroquine and lopinavir/ritonavir, which have the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death. With the possibility that a considerable proportion of the world's population soon could receive COVID-19 pharmacotherapies with torsadogenic potential for therapy or postexposure prophylaxis, this document serves to help health care professionals mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk of COVID-19 exposure to personnel and conserving the limited supply of personal protective equipment. Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus S ince its emergence from Wuhan, China, in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID- [bib_ref] Inhibition of hERG Kþ currents by antimalarial drugs in stably transfected HEK293..., Traebert [/bib_ref] , has already claimed the lives of more than 70,000 individuals worldwide.With the number of COVID-19 cases and deaths increasing with each passing day, there is perhaps no more pressing need in medicine than to identify safe and efficacious therapies to prevent SARS-CoV-2 infections as well as to attenuate the severity of the resulting COVID-19 illness.Although there are no proven US Food and Drug Administration (FDA)eapproved drugs to prevent or treat COVID-19, a number of promising novel (eg, remdesivir) and repurposed (eg, hydroxychloroquine, potentially together with azithromycin) pharmacological agents, reported to inhibit the growth of SARS-CoV-2 in vitro, [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] are being evaluated in randomized clinical trials. In advance of more definitive evidence, clinicians on the front lines of the pandemic have begun to use these medications under the auspices of "off-label," "compassionate-use," or FDA-approved Emergency Use Authorization (for chloroquine and hydroxychloroquine) with anecdotal success.In light of (1) the need for this practice to continue in the absence of viable, evidence-based therapies and (2) the proclivity of many promising COVID-19 pharmacotherapiesdspecifically antimalarial agents such as hydroxychloroquinedto prolong the QTc, thereby increasing the risk of drug-induced torsades de pointes (DI-TdP) and drug induced-sudden cardiac death (DI-SCD), this document was assembled to help health care professionals safely use these medications and minimize concomitant risks. PHARMACODYNAMICS AND QTC-PROLONGING/TORSADOGENIC POTENTIAL OF THE ANTIMALARIAL MEDICATIONS CHLOROQUINE AND HYDROXYCHLOROQUINE Chloroquine and its analogue hydroxychloroquine have been used for nearly 80 years as prophylactic pharmacotherapies for malaria. Although still used as antimalarial agents in parts of the world with chloroquinesensitive Plasmodium falciparum protozoa, hydroxychloroquine has found new life as a disease-modifying antirheumatic drug for the management of conditions such as systemic lupus erythematosus and rheumatoid arthritis. At the cellular level, these antimalarial drugs accumulate in intracellular vesicles such as endosomes and lysosomes where they are protonated, leading to increased vesicular pH. [bib_ref] Effects of chloroquine on viral infections: an old drug against today's diseases?, Savarino [/bib_ref] This process in turn inhibits the activity of the pH-dependent proteases involved in the intracellular processing of secretory proteins with a number of immunologic and nonimmunologic effects, including tumor necrosis factor a and interleukin 6. 7 Collectively, a reduction in these secretory proteins is believed to result in (1) the accumulation of cytotoxic heme that poisons P falciparum protozoa and (2) modulation of immune cell behavior in a manner that attenuates inflammatory processes. [bib_ref] Effects of chloroquine on viral infections: an old drug against today's diseases?, Savarino [/bib_ref] In addition, chloroquine and hydroxychloroquine possess antiviral properties in vitro. [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] [bib_ref] Effects of chloroquine on viral infections: an old drug against today's diseases?, Savarino [/bib_ref] [bib_ref] Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Vincent [/bib_ref] Both chloroquine and hydroxychloroquine are believed to act on the entry and postentry stages of severe acute respiratory syndrome coronavirus and SARS-CoV-2 infection, likely via effects on endosomal pH and the resulting underglycosylation of angiotensin-converting enzyme 2 receptors that are required for viral entry. [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] [bib_ref] Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Vincent [/bib_ref] Based on this in vitro data, it has been hypothesized that hydroxychloroquine, more so than chloroquine, may have therapeutic efficacy in the COVID-19 pandemic by (1) preventing SARS-CoV-2 infection by inhibiting angiotensin-converting enzyme 2emediated viral entry (ie, preinfection prophylaxis) and (2) attenuating the postviral cytokine storm observed in severe COVID-19 cases via a multitude of immunomodulatory mechanisms (ie, treatment of active infection/postviral sequelae). Promising in vitro data [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] as well as anecdotal in vivo evidence of therapeutic benefit 5 have led many institutions, including Mayo Clinic, to consider the use of hydroxychloroquine as a first-line COVID-19 pharmacotherapy for the time being and spurred an array of clinical trials designed to assess the efficacy of repurposed hydroxychloroquine in both the prevention and treatment of COVID-19. Although the collective safety profiles of chloroquine and hydroxychloroquine are relatively favorable, both drugs block the KCNH2-encoded HERG/K v 11.1 potassium channel and potentially can prolong the QTc. In at-risk individuals, these so-called HERG blockers can precipitate DI-TdP or, worse, DI-SCD, especially with long-term use [fig_ref] TABLE 1: Torsadogenic Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed Pharmacotherapies... [/fig_ref]. As a result, the number of DI-SCDs attributable to hydroxychloroquine in particular is not trivial [fig_ref] TABLE 1: Torsadogenic Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed Pharmacotherapies... [/fig_ref]. With the theoretical possibility that a substantial proportion of the world population could receive hydroxychloroquine as first-line prophylaxis or treatment, including an estimated 3 million individuals with congenital long QT syndrome (LQTS), the number of hydroxychloroquine-mediated DI-SCDs could increase precipitously unless appropriate QTc monitoring algorithms are instituted. This risk of DI-SCD could be further amplified if multiple medications, each with their own QTc-prolonging/ torsadogenic potential (eg, chloroquine/ hydroxychloroquine plus azithromycin and/ or lopinavir/ritonavir), are used in combination [fig_ref] TABLE 1: Torsadogenic Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed Pharmacotherapies... [/fig_ref]. ## Mitigating the potential risk of di-tdp and di-scd associated with widespread use of chloroquine/ hydroxychloroquine in the covid-19 pandemic Although some might argue that DI-SCDs in the setting of widespread chloroquine/ hydroxychloroquine use represents acceptable "friendly fire" in the war on SARS-CoV-2/COVID-19, we believe that with the institution of a few simple and safe precautions, the risk of DI-TdP and DI-SCD can be mitigated. Ultimately, it comes down to identifying the small subset of individuals who, either secondary to an underlying genetic predisposition (such as congenital LQTS, which is present in 1 in 2000 people) and/or by virtue of the presence of multiple modifiable and nonmodifiable QTc risk factors [fig_ref] TABLE 2: Modifiable and Nonmodifiable Risk Factors for Drug-Induced Long QT Syndrome/ Torsades de... [/fig_ref] , [bib_ref] Institution-wide QT alert system identifies patients with a high risk of mortality, Haugaa [/bib_ref] have excessive baseline QTc prolongation (QTc !500 ms) and/or have an inherent tendency for development of an exaggerated QTc response (ie, DQTc !60 ms) following exposure to medications with the adverse effect of potential QTc prolongation [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref]. Although the percentage of individuals at risk is small, given the pandemic nature of COVID-19, in absolute terms the number of individuals potentially at risk for lethal adverse drug effects is large (at least 10,000 individuals of the >1,000,000 COVID-19epositive patients worldwide are expected to be at increased risk for DI-TdP/DI-SCD if treated with these medications). This issue would be especially true if these medications are adopted for postexposure prophylaxis. Traditionally, the QTc is calculated from either lead II or V 5 of the 12-lead electrocardiogram (ECG) and corrected for heart rate using the Bazett or Fridericia formula before any intraindividual or interindividual QTc comparisons are made. Unfortunately, in the context of the COVID-19 pandemic, acquisition of the patient's QTc by the 12-lead ECG, which requires additional personnel exposure (ie, ECG technician), and a necessity for serial ECGs, which requires exposure of complex equipment (multiple ECG wires), could further strain the already limited supply of personal protective equipment (PPE) in many countries. Alternatively, some FDAapproved consumer mobile ECG devices are capable of generating accurate QTc measurements. [bib_ref] Comparison of QT interval readings in normal sinus rhythm between a smartphone..., Garabelli [/bib_ref] To this end, AliveCor, Inc, just received emergency clearance from the FDA for use of the KardiaMobile 6L device (FDAapproved for atrial fibrillation detection) for QTc monitoring of patients with COVID-19 treated with QT-prolonging medications such as chloroquine/hydroxychloroquine (March 20, 2020, 1:15 PM CST). Similarly, many telemetry systems are equipped with real-time QTc monitoring features that could be used for hospitalized patients. For patients with COVID-19 about to be treated with medications with the increased potential for DI-TdP/DI-SCD [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref] , baseline QTc status should be obtained either by a traditional 12-lead ECG or perhaps preferably with the use of a smartphoneenabled mobile QTc meter using the simple infection control measures outlined in to limit personnel exposures and conserve critical PPE. On average, the QTc values for otherwise healthy postpubertal males and females are around 410 ms and 420 ms, respectively. In contrast, a QTc value that exceeds the 99th percentile value for otherwise healthy individuals (ie, 460 ms in both sexes before puberty, 470 ms in postpubertal males, and 480 ms in postpubertal females), in the absence of any exogenous QTc-aggravating factors, may signal an individual at increased risk for QT-related ventricular arrhythmias. [bib_ref] International recommendations for electrocardiographic interpretation in athletes, Sharma [/bib_ref] [bib_ref] Determination and interpretation of the QT interval, Vink [/bib_ref] In contrast and as a frame of reference, the average QTc value was 470 ms for the more than 1400 patients with congenital LQTS who have been cared for in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Furthermore, with very few exceptions (amiodarone being one), patients with a resting QTc of 500 ms or more, whether secondary to congenital LQTS or acquired (QTc-prolonging drugs, QTc-prolonging electrolyte abnormalities such as hypokalemia, or QTc-prolonging disease states as detailed in [fig_ref] TABLE 2: Modifiable and Nonmodifiable Risk Factors for Drug-Induced Long QT Syndrome/ Torsades de... [/fig_ref] , have a considerably greater risk for both DI-TdP and DI-SCD. 14e16 Accordingly, the baseline QTc value can be used to roughly approximate the patient's risk of DI-TdP/DI-SCD following initiation of a medication with QTc-prolonging potential. For patients with QTc values less than the 99th percentile for age/sex (ie, 460 ms in prepubertal males/females, 470 ms in postpubertal males, and 480 ms in postpubertal females [ [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref] "green light" status]), the risk of DI-TdP/DI-LQTS is low, and chloroquine/ hydroxychloroquine (or other QTcprolonging COVID-19 pharmacotherapies) should be initiated without delay as outlined in the QTc monitoring algorithm. Remember, whether by 12-lead ECG, telemetry, or smartphone-enabled acquisition of the ECG, if the noted QT interval is less than one-half the preceding RR interval, then the calculated QTc will always be less than 460 ms and the patient can be "green light go" for COVID-19 treatments that may have QTc-prolonging potential. - High-risk comorbid condition(s) (CKD, COPD, CHF, cystic fibrosis, or pulmonary fibrosis). - Obtain pretreatment Q Tc using standard 12-lead ECG, telemetry, or mobile ECG device (see for details). - Obtain baseline expanded electrolytes (Ca 2+ , Mg 2+ , and K + ). - Determine if any home QTcprolonging medications can be discontinued (www.qtdrugs.org). - Document high-risk CV and comorbid conditions (see [fig_ref] TABLE 2: Modifiable and Nonmodifiable Risk Factors for Drug-Induced Long QT Syndrome/ Torsades de... [/fig_ref]. ## Yes ## 90% QTc ≥460 ms (prepuberty), ≥470 ms (postpubertal males), and ≥480 ms (postpubertal females), but <500 ms. ## 9% - Repeat QTc using standard 12-lead ECG, telemetry, or mobile ECG device (see for details). - Obtain baseline expanded electrolytes (Ca 2+ , Mg 2+ , and K + ). ## Post-treatment checklist ## Enroll Monitoring per trial protocol. QTc-prolonging drug(s) under consideration? (eg. chloroquine, hydroxychloroquine ± azithromycin, and/or lopinavir/ritonavir). ## Or Consider alternative non-QTc-prolonging therapies with in vitro activity against SARS-CoV-2 ¥ or no therapy. ) treated following a hypothetical treatment algorithm with "off-label" hydroxychloroquine alone or in combination with azithromycin. Both medications are known HERG blockers with both QTc-prolonging and torsadogenic potential. The estimated 99th percentile QTc values (derived from otherwise healthy individuals), which places a patient in the "green light" category, are less than 460 ms before puberty, less than 470 ms in men, and less than 480 ms in women. We estimate that the baseline QTc assessment will place 90% of patients in green light, 9% in yellow light, and 1% in red light status. Severe COVID-19 cases are defined as a respiratory rate of greater than 30 breaths/min (adults) or 40 breaths/min (children), oxygen saturation of 93% or less, PaO 2 to fraction of inspired oxygen ratio less than 300, or lung infiltrates involving more than 50% of the lung field after 24 to 48 hours. U Repurposed antiviral alternatives such as lopinavir/ritonavir also have QTc-prolonging effects. CHF ¼ congestive heart failure; CKD ¼ chronic kidney disease; COPD ¼ chronic obstructive pulmonary disease; CV ¼ cardiovascular; ECG ¼ electrocardiography; ICU ¼ intensive care unit; NIAID ¼ National Institute of Allergy and Infectious Diseases. ## Covid-19 pharmacotherapies and qtc/tdp susceptibility In contrast, those patients with a baseline QTc of 500 ms or greater are at increased risk for DI-TdP/DI-SCD [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref] "red light" status) and every effort should be made to (1) assess and correct for contributing electrolyte abnormalities (eg, replete potassium and magnesium to levels > 4 mmol/L and > 2 mg/dl, respectively), (2) review and discontinue other unnecessary QTc-prolonging medications if present or transition to alternatives with less QTc liability, and/or (3) proceed with closer monitoring (telemetry) or even consideration of more advanced countermeasures such as equipping the patient with a wearable defibrillator (eg, LifeVest [ZOLL Medical Corporation]) if the decision is made to commence therapy. In the setting of a QTc value of 500 ms or greater, navigating and circumventing this QTc liability depends greatly on the riskbenefit calculus, and the decision rests with the treating clinician and patient. For example, in younger patients with COVID-19 (ie, <40 years) who have only mild symptoms and a QTc of 500 ms or greater, it may be reasonable to avoid treatment altogether because the arrhythmia risk may outweigh the risk of developing COVID-19erelated acute respiratory distress syndrome. However, in patients with a QTc of 500 ms or greater presenting with progressively worsening respiratory symptoms or at greater risk (eg, >65 years of age, immunosuppressed, and/or high-risk comorbid conditions) for respiratory complications, the potential benefit of QTc-prolonging COVID-19 pharmacotherapies may exceed the arrhythmia risk. Importantly, if the decision has been made to proceed with such therapies for the patient with a "red light" QTc value (ie, QTc >¼ 500 ms), it may be reasonable to give magnesium prophylactically, regardless of their magnesium level, as an anti-torsadogenic counter measure. Therefore, the ultimate goal of QTc surveillance in the COVID-19 pandemic should NOT be to identify those who cannot receive these medications but to identify those with FIGURE 2. Protocols for the possible inpatient and outpatient use of a smartphone-enabled mobile electrocardiogram (ECG) to assess and monitor QTc values in patients with coronavirus disease 19. A, Inpatient protocol using dedicated institutional smartphone/ tablet and mobile ECG device. Whenever possible, we strongly recommend the use of a dedicated institutional Bluetooth-enabled smartphone or tablet device that is not used for personal use (ie, phone calls or other activities) to limit the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). B, Inpatient or outpatient protocol using personal (or institutionally loaned) smartphone/tablet and mobile ECG device. Currently, the only smartphone-enabled mobile ECG with US Food and Drug Administration approval for QTc monitoring is the AliveCor KardiaMobile 6L device. PPE ¼ personal protective equipment. compromised or reduced "repolarization reserve" in whom increased QTc countermeasures can and should be taken to mitigate the risk of drug-related death from DI-TdP/DI-SCD. [bib_ref] Long QT syndrome: reduced repolarization reserve and the genetic link, Roden [/bib_ref] Ultimately, much of the risk-benefit calculus awaits determination of the therapeutic efficacy of hydroxychloroquine, with or without concomitant azithromycin. Until such information is available, if the decision has been made to treat a patient with a red light designation [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref] based on their baseline QTc of 500 ms or greater, it seems prudent to start with hydroxychloroquine alone, rather than combination drug therapy with azithromycin. In addition, if combination drug therapy, with hydroxychloroquine and azithromycin, was initiated in a patient with an initial green light/yellow light QTc status and the individual transitions to red light status after self-identification as a "QTc reactor" with a DQTc of 60 ms or greater, then consideration should be given to discontinuing azithromycin, optimizing electrolyte status, or intensifying countermeasures further (placing on telemetry for continuous rhythm assessment). ## Frequency of qtc surveillance and adjustments in the setting of wide qrs complex Ideally, following a baseline QTc assessment, therapy may be initiated with either QTc reassurance (low risk for the vast majority [90%] of patients) or varying QTc countermeasures in place for those flagged as at increased risk. The timing of on-therapy QTc surveillance will be dictated not only by the pharmacokinetics of the COVID-19 therapies used but also by the practical logistics of an institution's method of QTc monitoring. For the 12-lead ECG approach, if QTc surveillance is deemed important, then one machine should be designated for acquisition of the data and a limited number of ECG technicians/personnel should be used to minimize PPE utilization and personnel exposure. Also, the number of on-therapy QTc assessments should be constrained to minimize personnel exposure risk and PPE consumption. In this scenario, for those placed in red light status because their baseline QTc is 500 ms or greater, an initial on-therapy QTc should be obtained around 2 to 4 hours after the first dose and then again at 48 hours and 96 hours following treatment initiation. Patients receiving either green light or yellow light status can probably forego the early QTc assessment and wait until 48 hours and 96 hours for their on-drug QTc determination. If the ontherapy QTc is 500 ms or greater or the patient self-identified as a QTc reactor with a DQTc of 60 ms or greater, then the QTc countermeasures need to be reexamined or the medications stopped in an effort to neutralize the increased potential for DI-TdP and DI-SCD [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref]. In contrast, for medical centers able to implement the FDA emergency-approved, smartphone-enabled approach or to determine the QTc from the telemetry strips, ECG technician exposure risk and consumption of PPE by those individuals would be eliminated and the patient's QTc could be obtained by the health care team already present, for example, with the QTc obtained per shift as another vital sign. [bib_ref] The QT interval, Giudicessi [/bib_ref] Such increased QTc surveillance would enable discovery of the QTc reactor and implementation of countermeasures sooner and hopefully would thereby circumvent the potentially preventable tragedy of DI-SCD [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref]. Finally, for patients with a wide QRS complex from either ventricular pacing or right/left bundle branch block, a wide QRS complex QTc adjustment will need to be made. Otherwise, patients will receive a red light signal inappropriately, resulting in therapy delay, discontinuation, or avoidance altogether. In this setting, the simplest approach is to maintain the previously indicated QTc green, yellow, and red light thresholds and apply a simple formula to account for the wide QRS complex (wide QRS complexeadjusted QTc ¼ QTc e [QRS À 120 ms]). For example, if a patient's left bundle branch block has yielded a QRS complex of 200 ms and a QTc of 520 ms, this scenario would appear to activate the red light pathway [fig_ref] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes [/fig_ref]. However, the wide QRS complexeadjusted QTc would be 520 ms e (200 À 120 ms) ¼ 520 À 80 ¼ 440 ms, which is not red light status at all but rather "green light go" status with much QTc reassurance that the patient is at low risk for DI-SCD. # Conclusion As this coronavirus pandemic continues to spread and wreak havoc, economic loss, and more importantly, the tragic deaths of thousands throughout the world, we must all do our part in this war on COVID-19. Washing hands and physical distancing are core components of containment efforts to "flatten the curve." Development of a coronavirus vaccine is progressing at unprecedented speed but is still at least 12 to 18 months away. In the meantime, there is hope that a long-ago discovered antimalarial drug, hydroxychloroquine, may have lifesaving therapeutic efficacy against COVID-19. And if it does, we hope that this simple QTc surveillance strategy, enabled by innovation and the FDA's emergency approval, will help prevent altogether or at least substantially reduce the number of druginduced ventricular arrhythmias and sudden cardiac deaths, particularly if there is widespread adoption and utilization of these medications for COVID-19. Potential Competing Interests: Dr Ackerman is a consultant for Abbott, Audentes Therapeutics, BIOTRONIK SE & Co. KG, Boston Scientific Corporation, Invitae Corporation, LQT Therapeutics Inc, Medtronic, and MyoKardia. Drs Noseworthy, Friedman, and Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Inc (not involved in this study). Dr Giudicessi reports no competing interests. [fig] FIGURE 1: Approach to mitigating the risk of drug-induced torsades de pointes (TdP)/drug-induced sudden cardiac death in patients with coronavirus disease 19 (COVID-19 [/fig] [table] TABLE 1: Torsadogenic Potential and Postmarketing Adverse Events Associated With Possible COVID-19 Repurposed Pharmacotherapies a COVID-19 ¼ coronavirus disease 2019; FAERS ¼ US Food and Drug Administration Adverse Event Reporting System; LQTS ¼ long QT syndrome; SARS-CoV-2 ¼ severe acute respiratory syndrome coronavirus 2; TdP ¼ torsades de pointes; VF ¼ ventricular fibrillation; VT ¼ ventricular tachycardia.Adverse event reporting from postmarketing surveillance does not account for prescription volume and is often subjected to substantial bias from confounding variables, quality of reported data, duplication, and underreporting of events.Lopinavir/ritonavir has been found to inhibit other severe acute respiratory syndrome viruses in vitro. However, a recent randomized trial found no benefit in COVID-19. [/table] [table] TABLE 2: Modifiable and Nonmodifiable Risk Factors for Drug-Induced Long QT Syndrome/ Torsades de Pointes a,b [/table]	None	http://www.mayoclinicproceedings.org/article/S002561962030313X/pdf	None
8273d1aae9de07206437e9c72293fb250fe32987	pubmed	Meditation and Cardiovascular Risk Reduction	Meditation and Cardiovascular Risk Reduction Despite numerous advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains a leading cause of morbidity and mortality. Novel and inexpensive interventions that can contribute to the primary and secondary prevention of cardiovascular disease are of interest. Numerous studies have reported on the benefits of meditation. Meditation instruction and practice is widely accessible and inexpensive and may thus be a potential attractive cost-effective adjunct to more traditional medical therapies. Accordingly, this American Heart Association scientific statement systematically reviewed the data on the potential benefits of meditation on cardiovascular risk. Neurophysiological and neuroanatomical studies demonstrate that meditation can have long-standing effects on the brain, which provide some biological plausibility for beneficial consequences on the physiological basal state and on cardiovascular risk. Studies of the effects of meditation on cardiovascular risk have included those investigating physiological response to stress, smoking cessation, blood pressure reduction, insulin resistance and metabolic syndrome, endothelial function, inducible myocardial ischemia, and primary and secondary prevention of cardiovascular disease. Overall, studies of meditation suggest a possible benefit on cardiovascular risk, although the overall quality and, in some cases, quantity of study data are modest. Given the low costs and low risks of this intervention, meditation may be considered as an adjunct to guideline-directed cardiovascular risk reduction by those interested in this lifestyle modification, with the understanding that the benefits of such intervention remain to be better established. Further research on meditation and cardiovascular risk is warranted. Such studies, to the degree possible, should utilize randomized study design, be adequately powered to meet the primary study outcome, strive to achieve low drop-out rates, include long-term follow-up, and be performed by those without inherent bias in outcome. ( J Am Heart Assoc. 2017;6:e002218. inexpensive interventions that are of benefit to patients and can contribute to the primary and secondary prevention of CVD are of interest. Dozens of studies have reported on the health benefits of meditation. According to the National Health Interview Survey, 8% of US adults practice some form of meditation. [bib_ref] Web-Based Mindfulness Intervention in Heart Disease: A Randomized Controlled Trial, Younge [/bib_ref] Up to 14% to 24% of patients with CVD have been reported to use or to have used some form of mind-body therapy, and 2% to 3% use or have used some form of meditation. [bib_ref] Heart rate variability is enhanced in controls but not maladaptive perfectionists during..., Azam [/bib_ref] [bib_ref] Decrease in blood pressure and improved psychological aspects through meditation training in..., De Fatima Rosas [/bib_ref] [bib_ref] Randomized controlled trial of Mindfulness-based cancer recovery versus supportive expressive group therapy..., Carlson [/bib_ref] [bib_ref] Mindfulness meditation alleviates fibromyalgia symptoms in women: results of a randomized clinical..., Cash [/bib_ref] In addition, half of CVD patients are interested in participating in a clinical trial of alternative therapies, and 17% are interested in participating in a clinical trial of meditation. [bib_ref] Heart rate variability is enhanced in controls but not maladaptive perfectionists during..., Azam [/bib_ref] [bib_ref] Decrease in blood pressure and improved psychological aspects through meditation training in..., De Fatima Rosas [/bib_ref] [bib_ref] Randomized controlled trial of Mindfulness-based cancer recovery versus supportive expressive group therapy..., Carlson [/bib_ref] [bib_ref] Mindfulness meditation alleviates fibromyalgia symptoms in women: results of a randomized clinical..., Cash [/bib_ref] Many forms of meditation can be learned from publications, the internet, and audio media. Many meditation courses are available for a modest fee or voluntary contribution. Hence, meditation may be an attractive costeffective adjunct to more traditional medical therapies. Accordingly, the American Heart Association commissioned this scientific statement to systematically and scientifically review the data on the potential benefits of meditation related to CVD. # Methodology Studies on meditation and cardiovascular risk reduction were searched for on PubMed using search terms including meditation, stress, blood pressure, hypertension, smoking, tobacco use, insulin resistance, metabolic syndrome, atherosclerosis, endothelial function, myocardial ischemia, primary prevention, and secondary prevention. Additional searches were performed on Google and Google Scholar, because some articles on meditation are not listed in PubMed. Practices such as tai chi, qigong, and yoga, although involving inner focus and a concentration on breathing, consist of both mental and physical practices. Regular physical activity and exercise has itself been associated with cardiovascular risk reduction, [bib_ref] Mindfulness-Based Stress Reduction training reduces loneliness and pro-inflammatory gene expression in older..., Creswell [/bib_ref] [bib_ref] Self-compassion training modulates alpha-amylase, heart rate variability, and subjective responses to social..., Arch [/bib_ref] and thus findings from such studies would be confounded. Therefore, this review was restricted to practices of sitting meditation. For all sections examining the effects of meditation on aspects of cardiovascular risk, a primary author without relationships with industry and a secondary reviewer drafted the initial text and conclusions. All sections, tables, and conclusions were then reviewed by all writing group members and the manuscript revised based on this review. The manuscript was then reviewed by 4 external reviewers and revised accordingly. The finalized manuscript was approved by all writing group members. ## Meditation The practice of meditation dates as far back as 5000 BC. [bib_ref] Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators, Kaliman [/bib_ref] Although associated with Eastern philosophies and religion, including Buddhism and Hinduism, references or inferences regarding meditation and the meditative process can be found in Christianity, Judaism, and Islam. [bib_ref] Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators, Kaliman [/bib_ref] Over the past several decades, meditation is increasingly practiced as a secular and therapeutic activity. In the traditional context, meditation refers to a family of mental practices that are designed to improve concentration, increase awareness of the present moment, and familiarize a person with the nature of their own mind. [bib_ref] Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators, Kaliman [/bib_ref] In a more general and contemporary context, meditation can be categorized as primarily focused attention, mindfulness, loving kindness and compassion, or mantra repetition, although there is usually overlap between the focuses. [bib_ref] Influence of mindfulness-based stress reduction (MBSR) on telomerase activity in women with..., Lengacher [/bib_ref] [bib_ref] Reduction in salivary alpha-amylase levels following a mind-body intervention in cancer survivors--an..., Lipschitz [/bib_ref] [bib_ref] Workplace based mindfulness practice and inflammation: a randomized trial, Malarkey [/bib_ref] With focused attention ("samatha" meditation), the practitioner may focus on the breath or on an object, sound, sensation, visualization, thought, or repeated word or phrase ("mantra"). When the mind wanders, the meditator notices the mind wandering and learns to bring the mind back to the present moment or the object of meditation. In mindful meditation, the individual strives to be in the present moment and aware of internal sensations, thoughts, and external stimuli, without becoming engrossed in or distracted by them. Mindfulness-based stress reduction is a program based primarily on mindful meditation, as well as yoga; other mindfulness-based programs are similarly based on mindful meditation. Insight ("vipassana") meditation can be considered a form of mindful meditation. In loving kindness and compassion, the meditator cultivates a feeling of benevolence toward oneself and others. In Vedic or transcendental meditation, repeated thought of a word is used to relax and clear the mind. The "relaxation response" technique similarly uses focused silent repetition of a word, sound, or phase. These practices may be used to: (1) increase concentration, insight, or awareness of the present moment; (2) promote relaxation; (3) reduce stress; (4) settle the mind; (5) achieve a state of increased consciousness; and (6) reduce perceived suffering and increase happiness. [fig_ref] Table 1: Common Types of Meditation [/fig_ref] provides a summary of common types of meditation. Most forms of meditation are practiced ≥20 minutes or once or twice daily. Although meditation was first practiced millennia ago as part of Buddhist and Hindu religions, it has recently been introduced in the West as a stand-alone secular activity. ## Neurophysiology and neuroanatomy of meditation Almost 2 decades of scientific studies, conducted at ≥20 universities, have identified the effects of meditation on the brain. [bib_ref] Reduction in salivary alpha-amylase levels following a mind-body intervention in cancer survivors--an..., Lipschitz [/bib_ref] Most forms of meditation engage regions in the brain that regulate attention and emotion. [bib_ref] Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to..., Pace [/bib_ref] The adult brain can undergo changes through a process called neuroplasticity, which may include development of new circuits ("rewiring") and/or neurons. [bib_ref] Effect of mindfulness based stress reduction on immune function, quality of life..., Witek-Janusek [/bib_ref] The different psychological targets of meditation are instantiated in distributed neural circuits that include different sectors of the prefrontal cortex and anterior cingulate cortex, the insula, and the midline regions that are important in default mode function. [bib_ref] One year pre-post intervention follow-up of psychological, immune, endocrine and blood pressure..., Carlson [/bib_ref] In addition, studies of loving-kindness and/or compassion meditation practices often lead to alterations in subcortical circuits directly implicated in emotional processing, such as the amygdala and ventral striatum. [bib_ref] Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to..., Pace [/bib_ref] [bib_ref] Short-term meditation training improves attention and self-regulation, Tang [/bib_ref] [bib_ref] A randomized controlled trial of mindfulness meditation versus relaxation training: effects on..., Jain [/bib_ref] Studies of the effects on meditation on the brain include those using electroencephalography, magnetic resonance imaging, and functional magnetic resonance imaging. Whereas numerous studies have reported on the acute neurophysiological effects of meditation, more relevant to this scientific statement are long-term neurophysiological and neuroanatomical changes. In 1 of the first reports on the longterm effects of meditation on the brain, a 2-month mindfulness meditation program resulted in increased left-sided anterior brain electrical activation, a pattern associated with positive affect and emotion, whereas no such changes occurred in a wait-listed control group. [bib_ref] A pilot study to examine the effects of a mindfulness-based stress-reduction and..., Mccomb [/bib_ref] A study of long- ## Samatha meditation Samatha is translated to mean "calm" and samatha meditation is often referred to as calm, abiding meditation. Samatha meditation is the practice of calming the mind by practicing single-pointed meditation through mindful concentration focusing on the breath, image, or object. Buddhist practice, dating to the time of the Buddha or even before ## Vipassana meditation (insight meditation) Vipassana is translated to mean, "to see things as they really are." Vipassana emphasizes awareness of the breath, tuning into the air passing in and out through the nose. Vipassana teaches one to label thoughts and experiences as they arise, taking mental notes as one identifies objects that grab one's attention. Vipassana meditation is often taught at 10-day retreats. Traditional Buddhist and Indian meditation. Well-known teachers include Mahasi Sayadaw, S.N. Goenka, Sharon Salzberg, Joseph Goldestein, Jack Kornfield, and Michael Stone Mindful meditation An umbrella term for the category of techniques used to create awareness and insight by practicing focused attention, observing, and accepting all that arises without judgment. This type of meditation is also referred to as "open monitoring," in which one allows one's attention to flow freely without judgment or attachment. Origins come from Buddhist teaching. Well-known Western teachers include Jon-Kabat Zinn, Tara Brach, Sharon Salzberg, Joseph Goldestein, Jack Kornfield, and Pema Chodron ## Zen meditation (zazen) A type of meditation where one focuses one's awareness on one's breath and observes thoughts and experiences as they pass through the mind and environment. In some senses similar to Vipassana meditation, but with an emphasis on a focus of the breath at the level of the belly and on posture while sitting. Buddhist meditation from Japan. Well-known teachers include Thich Nhat Hanh and Joan Halifax Roshi Raja yoga meditation Referred to also as "mental yoga," "yoga of the mind," or Kriya yoga. A practice of concentration to calm the mind and bring it to one point of focus. Includes a combination of mantra, breathing techniques, and meditation on the chakras/spinal cord focus points. Hindu practice dating back thousands of years. Introduced to the West in 1893 by Swami Vivekananda. Further clarified and taught by Paramhansa Yogananda for the Western audience Loving-kindness (metta) meditation Loving-kindness meditation involves sending loving kindness to oneself, then continuing to send it to a friend or loved one, to someone who is neutral in your life, to a difficult person, and then out to the universe. Through this practice, the meditator cultivates a feeling of benevolence toward oneself and others. Originates from Buddhist teachings, mainly Tibetan Buddhism. Well-known instructors include Sharon Saltzberg and Pema Chodron ## Transcendental meditation Mantra-based meditation technique in which each practitioner is given a personal mantra that is used to help settle the mind inward. Transcendental meditation is taught by certified teachers through a standard 4-day course of instruction. Transcendental meditation is practiced for 20 minutes twice daily. standing Buddhist meditation practitioners demonstrated durable electroencephalographic changes, suggesting that the resting state of the brain may be altered by long-term meditative practices. [bib_ref] A randomized, wait-list controlled clinical trial: the effect of a mindfulness meditation-based..., Speca [/bib_ref] A brain magnetic resonance imaging study of experienced meditators found, when compared with age-matched controls, higher gray matter density in lower brainstem regions involved in the autonomic system and cardiorespiratory control. [bib_ref] Mindfulness training for smoking cessation: A meta-analysis of randomized-controlled trials, Oikonomou [/bib_ref] Some, though not all, longitudinal studies of 1 to 3 months of mindful meditation have demonstrated changes in brain structure and function not observed in control participants. [bib_ref] Effect of Brief Mindfulness Practice on Self-Reported Affect, Craving, and Smoking: A..., Ruscio [/bib_ref] A meta-analysis of 21 neuroimaging studies examining 300 meditation practitioners found 8 brain regions consistently altered in meditators, including areas key to meta-awareness, body awareness, and self-and emotion regulation. [bib_ref] Mindfulness training for smokers via web-based video instruction with phone support: a..., Davis [/bib_ref] Anatomical changes have been reported in the cerebral cortex, subcortical gray and white matter, brainstem, and cerebellum of meditators. [bib_ref] Effect of Brief Mindfulness Practice on Self-Reported Affect, Craving, and Smoking: A..., Ruscio [/bib_ref] Neurophysiological and neuroanatomical studies suggest that meditation can have long-standing effects on the brain, which may have beneficial consequences on the physiological basal state, physiological responses, and cardiovascular risk. However, these studies generally were nonrandomized and involved modest numbers of participants, some of whom were highly experienced (>10 000 hours) meditators. Additionally, different forms of meditation (eg, focused attention, mindfulness, and loving kindness) will have different psychological and neurological effects. Thus, the neurophysiological and neuroanatomical findings associated with 1 type of meditation cannot be extrapolated to all forms. Extrapolation of the findings in the aforementioned studies to the general population who engage in meditation must be done with caution. ## Meditation and cardiovascular risk reduction A summary of the findings on meditation and cardiovascular risk reduction is provided in [fig_ref] Table 2: Summary of Findings on Studies of Meditations and Cardiovascular Risk Reduction* [/fig_ref]. Summaries of the individual studies, as well as their limitations, evaluated in this scientific statement are provided in Tables S1 through S9. These summary tables are not all-inclusive but summarize the findings of those studies deemed most relevant to this scientific statement. Findings on the effects of meditation on specific aspects of cardiovascular health are given in the following sections. ## Effects of meditation on psychological, psychosocial, and physiological responses to stress Numerous studies, across both healthy and disease-based populations, have explored the effects of meditation on psychological and psychosocial outcomes. Most published studies report some improvements in levels of perceived stress, mood, anxiety, depression, quality of sleep, or overall wellbeing [bib_ref] Randomized trial comparing mindfulness training for smokers to a matched control, Davis [/bib_ref] [bib_ref] Randomized trial on mindfulness training for smokers targeted to a disadvantaged population, Davis [/bib_ref] [bib_ref] Brief meditation training induces smoking reduction, Tang [/bib_ref] [bib_ref] Mindfulness training for smoking cessation: results from a randomized controlled trial, Brewer [/bib_ref] [bib_ref] A pilot study on mindfulness based stress reduction for smokers, Davis [/bib_ref] [bib_ref] Effects of a randomized controlled trial of transcendental meditation on components of..., Paul-Labrador [/bib_ref] [bib_ref] Effects of yoga and meditation on clinical and biochemical parameters of metabolic..., Khatri [/bib_ref] [fig_ref] Table 1: Common Types of Meditation [/fig_ref]. A review by the Agency for Healthcare Research and Quality restricted to randomized, controlled trials with an active control concluded-with low strength of evidence-that mindfulness meditation programs show modest improvements in stress/distress and negative affect. [bib_ref] Effect of meditation on endothelial function in Black Americans with metabolic syndrome:..., Vaccarino [/bib_ref] Few studies have focused on patients with CVD. In a study of 60 patients recruited from a private cardiology clinic, those randomized to 8 weeks of mindfulness-based stress reduction (primarily using meditation techniques) had significantly lower perceived stress and anger 47 than a comparison control group. Similarly, a study of 59 elderly participants with stage I hypertension randomized to Zen meditation (20 minutes twice daily for 3 months) or a wait list found that meditation significantly improved psychological facets of and overall quality of life. [bib_ref] The effect of a six-week program of yoga and meditation on brachial..., Sivasankaran [/bib_ref] A growing body of research has examined the mechanisms by which meditation alters the physiological response to stress, with salivary cortisol the most commonly studied biomarker and a few exploring salivary amylase, [bib_ref] Association Between Mind-Body Practice and Cardiometabolic Risk Factors: The Rotterdam Study, Younge [/bib_ref] proinflammatory cytokines (ie, interleukin-6), or telomerase activity. Overall, findings from these studies have been mixed, with some demonstrating improvements in physiological parameters with meditation and others finding no changes. [bib_ref] Randomized trial comparing mindfulness training for smokers to a matched control, Davis [/bib_ref] [bib_ref] A pilot study on mindfulness based stress reduction for smokers, Davis [/bib_ref] [bib_ref] Effects of a randomized controlled trial of transcendental meditation on components of..., Paul-Labrador [/bib_ref] [bib_ref] Effects of combined traditional Chinese exercises on blood pressure and arterial function..., Zhang [/bib_ref] [bib_ref] Regression of coronary atherosclerosis through healthy lifestyle in coronary artery disease patients--Mount..., Gupta [/bib_ref] [bib_ref] Effect of a multimodality natural medicine program on carotid atherosclerosis in older..., Fields [/bib_ref] [bib_ref] Effects of stress reduction on carotid atherosclerosis in hypertensive African Americans, Castillo-Richmond [/bib_ref] [bib_ref] Can lifestyle changes reverse coronary heart disease? The Lifestyle Heart Trial, Ornish [/bib_ref] [bib_ref] Intensive lifestyle changes for reversal of coronary heart disease, Ornish [/bib_ref] [bib_ref] Effects of transcendental meditation on symptoms and electrocardiographic changes in patients with..., Cunningham [/bib_ref] Several recent studies have focused on the impact of meditation on proteomic and genomic regulators of the physiological stress response. [bib_ref] Regression of coronary atherosclerosis through healthy lifestyle in coronary artery disease patients--Mount..., Gupta [/bib_ref] [bib_ref] Usefulness of the transcendental meditation program in the treatment of patients with..., Zamarra [/bib_ref] [bib_ref] Effects of stress management training and dietary changes in treating ischemic heart..., Ornish [/bib_ref] Although unique gene expression profiles have been noted with meditation, their association with established physiological parameters is unknown. [bib_ref] Impact of transcendental meditation on mortality in older African Americans with hypertension..., Barnes [/bib_ref] One study of 40 patients reported that mindfulness-based stress reduction downregulated proinflammatory nuclear factor kappa B gene expression profile compared to wait-list control, with a trend-but no statistically significant reduction-in C-reactive protein levels. [bib_ref] Usefulness of the transcendental meditation program in the treatment of patients with..., Zamarra [/bib_ref] Overall, many, though not all, studies have reported that meditation is associated with improved psychological and psychosocial indices. Differences in study populations, control of potential confounders, and type and length of meditation evaluated may account for discrepant findings. Furthermore, small sample sizes and lack of randomization are common study limitations. Further study is needed on how meditation influences physiological processes associated with stress. ## Effects of meditation on blood pressure Few high-quality, randomized trials of meditation and lowering of blood pressure have been published [fig_ref] Table 2: Summary of Findings on Studies of Meditations and Cardiovascular Risk Reduction* [/fig_ref]. The efficacy of mindfulness meditation for blood pressure reduction has been evaluated in a few studies. [bib_ref] The effect of a six-week program of yoga and meditation on brachial..., Sivasankaran [/bib_ref] [bib_ref] Long-term effects of stress reduction on mortality in persons > or =..., Schneider [/bib_ref] [bib_ref] Transcendental meditation, mindfulness, and longevity: an experimental study with the elderly, Alexander [/bib_ref] [bib_ref] A Prospective Trial of Ayurveda for Coronary Heart Disease: A Pilot Study, Dubroff [/bib_ref] The HARMONY (Hypertension Analysis of Stress Reduction Using Mindfulness Meditation and Yoga) trial assessed 24-hour ambulatory blood pressure measurements in patients with stage I hypertension randomized to an 8-week mindfulness-based stress reduction program or wait-list control and found no benefit of meditation. [bib_ref] Mind-body practices for patients with cardiac disease: a systematic review and meta-analysis, Younge [/bib_ref] In contrast, in a pilot study of 83 predominantly hypertensive blacks randomized to a mindful meditation program or control social support group, an 11/4 mm Hg decrease in systolic/diastolic blood pressure was observed in those randomized to 8 weeks of treatment and an analysisadjusted 22/17 mm Hg difference in blood pressure between the 2 groups at follow-up. [bib_ref] Mindfulness-based stress reduction program in coronary heart disease: A randomized control trial, Parswani [/bib_ref] Of note, this trial had 100% data ascertainment, over 80% compliance at each clinic visit, and measured blood pressure with an unattended manual device (a rigorous protocol with measurements 7-15 mm Hg lower than typical office readings). Other mind-body interventions that ## Neurophysiology and neuroanatomy - Neurophysiological and neuroanatomical studies suggest that meditation can have long-standing effects on brain physiology and anatomy - Studies generally are nonrandomized and involve modest numbers of participants, sometimes performed under the direction of extremely experienced (>10 000 hours) meditators - Different forms of meditation have different psychological and neurological effects, and thus the neurophysiological and neuroanatomic findings of 1 type of meditation cannot be extrapolated to other forms of meditation Psychological, psychosocial, and physiological response to stress - Many, although not all, studies report that meditation is associated with improved psychological and psychosocial indices - Differences in populations, control of potential confounders, and type and length of meditation evaluated may account for discrepant findings. Small sample sizes and lack of randomization are common study limitations - Further study is needed on how meditation influences physiological processes associated with the stress response Blood pressure - Magnitude of reductions of systolic blood pressure varies widely - Study limitations including the methods of blood pressure measurements and bias in data ascertainment, high dropout rates, and different populations studied Smoking and tobacco use - Some randomized data show that mindful meditation instruction improves smoking cessation rates Insulin resistance and metabolic syndrome - Limited data on the effects of meditation on insulin resistance and metabolic syndrome Subclinical atherosclerosis - A few suboptimal studies of meditation and lifestyle intervention suggest the potential for benefit on atherosclerosis regression - Studies limited by multimodality approach, attrition, and incomplete follow-up - No firm conclusions can be drawn on the effects of meditation on atherosclerosis ## Endothelial function - Three studies showed no benefit of meditation on brachial reactivity in the overall cohorts, although 1 study suggested a benefit in a subgroup of patients with coronary artery disease - No conclusions can be drawn on the effects of meditation on endothelial function ## Inducible myocardial ischemia - Limited older studies suggest that meditation can lead to improvement in exercise duration and decreased myocardial ischemia - No contemporary studies have evaluated effects of meditation on myocardial blood flow or ischemia with advanced imaging techniques Primary prevention of CVD - Two studies of short-term intervention report surprising mortality reductions, and thus these findings need to be reproduced in larger, multicenter studies - Overall, because of the limited evidence to date, no conclusions can be drawn as to the effectiveness of meditation for the primary prevention of CVD Secondary prevention of CVD - Data on the potential benefits of meditation in patients with established coronary artery disease can best be characterized as generally of modest quality and as suggesting, but not definitely establishing, benefit - Because of generally limited follow-up time, there are more data on reduction of cardiac risk factors and psychological indices than on hard end points (eg, death, myocardial infarction) involve both a physical and mental component have been associated with significant reductions in blood pressure, [bib_ref] Comparison of cardiac rehabilitation programs combined with relaxation and meditation techniques on..., Delui [/bib_ref] [bib_ref] Stress reduction in the secondary prevention of cardiovascular disease: randomized, controlled trial..., Schneider [/bib_ref] [bib_ref] Mindfulness meditation, anxiety reduction, and heart disease: a pilot study, Tacon [/bib_ref] [bib_ref] The Support, Education, and Research in Chronic Heart Failure Study (SEARCH): a..., Sullivan [/bib_ref] but the specific contribution of meditation and meditation-like practices of inner focus and a concentration on the breath cannot be determined. The effects of transcendental meditation on blood pressure have also been reported. 70-73 A study of 298 university students randomized to transcendental meditation or wait-list control found at 3-month follow-up no significant changes in systolic or diastolic blood pressure, although significant reductions in blood pressure (5/3 mm Hg, respectively) did occur in those at high risk of the development of hypertension. In a randomized study of stress reduction in 201 black men and women with angiographically documented coronary artery disease randomized to transcendental meditation or health education, 5.4-year follow-up found a 4.9 mm Hg lower systolic blood pressure, 1 of numerous secondary study end points, in those randomized to transcendental meditation than in those randomized to health education, primarily because of an increase in blood pressure in the health education group. Numerous systematic reviews have been conducted on the effects of meditation on blood pressure. One 2007 systematic review assessed several methods of stress reduction in patients with hypertension and found modest benefit (ie, 5/ 3 mm Hg systolic/diastolic blood pressure reduction) with transcendental meditation; other popular types of meditation were not assessed. 74 Numerous meta-analyses in a 2007 Agency for Healthcare Research and Quality report on meditation and health generally found modest to no significant benefit with different meditation techniques when compared with active control groups (eg, health education), though the report also stated that meta-analyses based on low-quality studies and small numbers of hypertensive participants showed that transcendental meditation and Zen Buddhist meditation significantly reduced blood pressure. 75 A 2013 American Heart Association scientific statement on alternate approaches to lowering blood pressure concluded that transcendental meditation modestly lowers blood pressure and that its use may be considered. The writing group also concluded at that time that there were insufficient highquality studies assessing the benefit of other forms of meditative techniques to recommend them for blood pressure lowering. A 2015 analysis of 12 randomized, clinical trials of transcendental meditation involving a total of 996 predominantly black patients with or without hypertension found a mean reduction in blood pressure of 4/2 mm Hg (systolic/ diastolic) over the study duration of 2 to 60 months (mean 4 months) when compared with control participants. 72 Benefit in systolic blood pressure reduction seemed to persist up to 12 months. Of note, the completion rate (percentage of patients who completed all training and post-test) in these studies was a modest 63%. The mechanism(s) whereby meditation lowers blood pressure when it occurs has not been fully elucidated. 77 Possibly, the long-term neurophysiological changes that occur with meditation [bib_ref] A randomized, wait-list controlled clinical trial: the effect of a mindfulness meditation-based..., Speca [/bib_ref] [bib_ref] Mindfulness training for smoking cessation: A meta-analysis of randomized-controlled trials, Oikonomou [/bib_ref] [bib_ref] Effect of Brief Mindfulness Practice on Self-Reported Affect, Craving, and Smoking: A..., Ruscio [/bib_ref] may lead to autonomic nervous systemmediated changes in blood pressure. One study of 15 participants with hypertension and chronic kidney disease reported a decrease in muscle sympathetic nerve activity and blood pressure during mindfulness meditation, 79 but no such long-term data exist. The impact of stress reduction on blood pressure remains to be better defined. Reported reductions of systolic blood pressure with meditation vary widely. The heterogeneity in results reflects the various study populations, study designs, data ascertainment protocols, study duration, baseline blood pressure, and blood pressure measurement techniques used. Limitations to clinical interpretation include high drop-out rates, bias in data ascertainment, and lack of attention to statistical power, control participants, and methods of blood pressure measurements. [bib_ref] Effect of meditation on endothelial function in Black Americans with metabolic syndrome:..., Vaccarino [/bib_ref] The ability to generalize the findings is limited by the lack of reproducibility of results. ## Effects of meditation on smoking and tobacco use Cigarette smoking is the leading cause of preventable disease and deaths in the United States, accounting for >480 000 deaths every year, or 1 of every 5 deaths. 81,82 Two thirds of American adults want to quit smoking, and yet only 6% achieve this goal annually. 83 Several types of meditation have been studied as interventions to facilitate smoking cessation [fig_ref] Table 3: Summary of Findings and Suggestions on Meditation and Cardiovascular Risk Reduction [/fig_ref]. Small studies 84-89 have shown that mindfulness training, a form of meditation, increases abstinence rates when compared with more traditional intervention programs. In 1 study of volunteers wishing to reduce stress, half of whom were smokers, who were randomized to either a 2week program of integrative body-mind technique-a form of mindfulness meditation-or relaxation training, a 60% reduction in smoking was observed among those instructed in integrative body-mind technique, with no reduction in those instructed in relaxation training. In this study, resting-state brain scans before and after intervention showed increased activity in the anterior cingulate and prefrontal cortex-areas of the brain that are related to self-control-for the meditation group, but not the relaxation training group. 90 A metaanalysis of 4 randomized, controlled trials of mindfulness training involving a total of 474 patients found that it was more effective than group counseling, with 25% of mindfulness training participants remaining abstinent from smoking for >4 months, compared with 14% of those receiving moretraditional cessation instruction. One study of transcendental meditation in 295 college students found no significant reduction in cigarette smoking at 3-month follow-up between those randomized to transcendental meditation and those in a wait-list control group. Thus, some randomized data show that mindful meditation instruction improves smoking cessation rates. Potential mechanisms include management of cravings and decreasing negative effect, which has been shown to be a potent stimulus for drug-seeking behavior and smoking relapse. Meditation may also affect smoking behavior through changes in urge intensity 87 and improved self-control. 90 ## Effects of meditation on insulin resistance and metabolic syndrome Metabolic syndrome, a cluster of conditions including hypertension, dyslipidemia, elevated fasting blood glucose, and abdominal obesity, is a risk factor for diabetes mellitus and CVD. 93-95 Data on the effects of meditation on insulin resistance and metabolic syndrome are sparse . In a study of 103 patients with coronary artery disease randomized to transcendental meditation or active control (health education), transcendental meditation improved insulin resistance. A study of the effects of meditation, yoga, and a vegetarian diet on parameters of metabolic syndrome 97 was too confounded by the multimodality approach to draw meaningful conclusions. The relaxation response-the counterpart of the stress response-can be evoked by meditation. In 1 novel study, 98 20 minutes of listening to a relaxation response instructional CD reduced expression of genes linked to inflammatory response and the stress-related pathway-mechanisms that contribute to metabolic syndrome 99,100 -and enhanced expression of genes associated with energy metabolism, mitochondrial function, and insulin secretion. Changes in gene expression were more pronounced in experienced practitioners of relaxation techniques than in novices who had recently undergone 8 weeks of relaxation response training. The clinical effects of these changes in gene expression, if any, remain unknown. A comprehensive review of metabolic syndrome and mindbody therapies identified only 3 relevant clinical trials, 2 of which are discussed above and the third of which involved restorative yoga as the primary intervention. In summary, data on the effects of meditation on insulin resistance and metabolic syndrome are limited. ## Effects of meditation on subclinical atherosclerosis Limited evidence exists for the effects of meditation on subclinical atherosclerosis . Only 1 randomized, controlled trial was identified that studied the effects of a meditation intervention on atherosclerosis progression. In this study, carotid intimal thickness was assessed in 138 hypertensive blacks randomized to a transcendental meditation or control health education program and followed for a mean of 7 months. Attrition was high, with 57% of participants not completing follow-up. Among completers of the study, carotid intimal thickness regression was noted in the meditation group, whereas progression occurred in controls, with the difference between the 2 groups being statistically significant. In another randomized study, 57 healthy adults aged ≥65 years were randomized to 1 of 3 interventions: a transcendental meditation program that also included diet, exercise, and vitamin treatment; a diet/exercise/ vitamin arm without the meditation component; or a usual care arm. At 1 year, the meditation intervention group showed reduction in carotid intimal thickness that was not observed in the other groups. Other studies on subclinical atherosclerosis evaluated more comprehensive multimodality lifestyle interventions that generally included components of dietary changes, exercise, and stress management (including components of meditative practice). 104-107 Study end points included changes in coronary artery atherosclerosis as assessed by quantitative coronary angiography 104-106 and ankle-brachial indices. Although these studies showed favorable effects of lifestyle intervention on atherosclerosis regression, given the multimodality approach, it is difficult to discern the effects of the meditation component alone. Study result interpretation is also limited by attrition and incomplete follow-up. In summary, although a few studies of meditation and lifestyle intervention suggest the potential for benefit on atherosclerosis progression, no firm conclusions can be made on the effects of meditation alone on atherosclerosis. ## Effects of meditation on endothelial function Endothelial function can be indirectly assessed by evaluating brachial artery endothelial vasomotor response. In a pilot study of 41 participants (33 of whom completed the study), a 6-week combined yoga and meditation intervention failed to significantly improve endothelial function, although there was improvement in the cohort of 10 patients with coronary artery disease. 108 In a trial of 103 patients with coronary artery disease (84 of whom completed follow-up) randomized to 16 weeks of transcendental meditation or control health education, meditation had no significant effect on brachial artery reactivity testing. In a trial of 68 black Americans with metabolic syndrome risk factors, consciously resting meditation improved flow-mediated dilation at 12month follow-up, but compared with changes in the control health-education group, this improvement was not significantly different. 109 Only 38 participants (56%) completed the 12-month follow-up. Limitations of these studies variably include modest sample size, relatively short durations of intervention, high attrition rates, and incomplete follow-up . Given these factors, as well as the different patient populations studied and variable findings in those with established coronary artery disease, no definitive conclusions on the effects of meditation on endothelial function can be made. ## Effects of meditation on inducible myocardial ischemia A paucity of studies has examined the effects of meditation on inducible myocardial ischemia . In a 1996 study of 21 participants with coronary artery disease, 7.6 months of transcendental meditation led to significant increases in exercise duration (15%) and maximal workload (12%) compared with wait-listed controls, as well as lower rate-pressure products at given workloads and significantly delayed onset of ST depression. In a 1983 study of 46 patients with ischemic heart disease that combined stress management (meditation and stretching/relaxation exercises) and a veganbased diet, after 24 days those randomized to the lifestyleintervention group had a 44% increase in exercise duration, 55% increase in total work, and improved exercise ejection fraction and regional wall motion, whereas no significant changes occurred in those randomized to the control group. No contemporary studies have evaluated the impact of meditation on myocardial blood flow or ischemia with techniques such as stress echocardiography, single-photon emission computed tomography, cardiac positron emission tomography, or cardiac magnetic resonance imaging. Larger, randomized, clinical studies that evaluate the impact of meditation-based interventions on inducible myocardial ischemia, ideally using more sophisticated modalities to assess and quantify ischemia, are needed. ## Meditation and primary prevention of cvd Although studies have assessed the effect of meditation on cardiovascular risk factors, recent Cochrane reviews have concluded that no properly conducted randomized, controlled trials have assessed its role in the primary prevention of cardiovascular mortality or nonfatal primary end points. This is largely because the relevant studies are small, with short-term follow-up and carried out in predominantly healthy participants. One study 116 measured survival rate in 73 elderly participants randomly assigned to 3 months of transcendental meditation, mindfulness training, mental relaxation, or a no-treatment control group. The survival rate after 3 years for the transcendental meditation group was significantly better; 100% compared with 65% to 87% for other groups. In a second study, mortality and cause of death were assessed from vital statistics over 8 years of follow-up in 109 older black patients who had participated in a hypertension study. Participants were randomly assigned to 2 stress reduction approaches-either transcendental meditation or progressive muscle relaxation-or to a health education (ie, control) group for 3 months. The adjusted relative risk for CVD mortality was significantly reduced by 81% in the transcendental meditation group when compared with the control group. In both studies, mortality was assessed 3 to 8 years after the intervention period, so the results may not be attributed to transcendental meditation. This and other methodological issues raise concerns about the validity of their findings. When patient data from the abovementioned 2 randomized, controlled trials were combined in a post-hoc analysis, [bib_ref] A meta-analytic review of the effects of mindfulness meditation on telomerase activity, Schutte [/bib_ref] the transcendental meditation group reportedly showed a 23% reduction in all-cause mortality compared with the control patients, a 30% reduction in cardiovascular mortality, and a nonstatistically significant 51% reduction in rate of cancer mortality . These studies of shortterm intervention applied to a limited number of participants report surprising mortality reductions that are on par with, or greater than, those observed in long-term intervention, large-scale, primary prevention studies of cholesterol therapy 118 and of blood pressure reduction. 119,120 Accordingly, these findings need to be reproduced in larger, multicenter studies. In summary, data regarding the effectiveness of meditation for primary prevention of CVD are lacking, and because of the limited evidence to date, no conclusions can be drawn as to the effectiveness of meditation for the primary prevention of CVD. ## Meditation and secondary prevention of cvd Limited and limited-quality data are available from studies of meditation for secondary prevention of CVD . Such studies, which generally have enrolled patients with stable coronary artery disease, have variably reported reductions in systolic blood pressure, insulin resistance, serum lipids, clinical symptoms, and anxiety and stress. 70,96,106,110,121-127 Most, although not all, studies randomized patients to either meditation or some type of "usual care." These studies are generally limited by modest sample size and limited duration follow-up, and a few assessed multifactorial interventions that combined meditation with other interventions (ie, yoga, diet). A systematic review and meta-analysis of randomized, controlled trials of mind-body practices, including meditation but other interventions as well, found that such interventions were associated with improvements in physical and mental quality of life, depression and anxiety, and systolic and diastolic blood pressure, but rated the overall quality of the studies as low. One commonly cited study involves 201 patients with angiographically documented coronary artery disease randomized to transcendental meditation or health education. After a mean of 5.4 years, the primary composite end point of all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke was significantly lower in the meditation group (adjusted hazard ratio, 0.52). Post-hoc analysis found greater benefit (hazard ratio, 0.34) in those with high adherence. There was a nonsignificant 24% reduction in the broader secondary composite endpoint, which also included coronary revascularization or hospitalization for cardiac causes. The study, though, was conducted in 2 phases after a 1-year hiatus with 58 patients not participating in phase 2 of the study, and some concerns about analysis of the data have been raised. Overall, data on the potential benefits of meditation in patients with established coronary artery disease can best be characterized as of modest quality and suggesting, but not definitely establishing, benefit in secondary prevention. Because of the generally limited follow-up time, more data on reduction of cardiac risk factors and psychological indices (eg, stress, anxiety, and depression) exist than on hard end points (eg, death or myocardial infarction). ## Summary Studies of meditation to date suggest a possible, though not definitively established, benefit of meditation on cardiovascular risk reduction. A 2008 review of >400 trials of meditation and health care rated the methodological quality of clinical trials as poor, but noted that the quality of these trials had significantly improved over time. Methodological issues in research to date include modest study size, limited and often incomplete followup, high drop-out rates, lack of randomization and/or appropriate control group, and unavoidable patient nonblinded study design. As with many other novel interventions, there is the possibility of publication bias toward positive studies of the beneficial effects of meditation. [bib_ref] Effect of Brief Mindfulness Practice on Self-Reported Affect, Craving, and Smoking: A..., Ruscio [/bib_ref] [bib_ref] Mindfulness training for smokers via web-based video instruction with phone support: a..., Davis [/bib_ref] Many investigators who conducted studies of meditation may have a strong belief in the benefits of meditation and may be enthusiastic meditators themselves, [bib_ref] Effect of Brief Mindfulness Practice on Self-Reported Affect, Craving, and Smoking: A..., Ruscio [/bib_ref] thereby introducing the possibility of unintended bias. Many studies of meditation techniques are performed by the same groups of researchers, so there is a need for independent verification of reported positive findings. Whereas these studies are important in that they serve to suggest that meditation may reduce cardiovascular risk, these limitations prevent definitive conclusions regarding efficacy of meditation on cardiovascular risk reduction. Currently, the mainstay for primary and secondary prevention of CVD is American College of Cardiology/American Heart Association guideline-directed interventions. However, considering the generally low costs and risks associated with meditation, meditation may be considered as a reasonable adjunct to guideline-directed cardiovascular risk reduction by those so interested in this lifestyle modification, with the understanding that the benefits of such intervention remain to be better established. Further research on meditation and cardiovascular risk is warranted. Such studies, to the degree possible, should utilize randomized study design, be adequately powered to detect clinically meaningful benefit, include long-term follow-up, and be performed by those without inherent bias in outcome. One such example is the ongoing Yoga-CaRe study for secondary prevention of myocardial infarction. 131 A summary of findings on meditation and cardiovascular risk reduction and on suggested methodology for future research are given in [fig_ref] Table 3: Summary of Findings and Suggestions on Meditation and Cardiovascular Risk Reduction [/fig_ref]. - Studies of meditation suggest a possible benefit on cardiovascular risk, although the overall quality and, in some cases, quantity of study data is modest - The mainstay for primary and secondary prevention of CVD is ACC/AHA guideline-directed interventions - Meditation may be considered as an adjunct to guideline-directed cardiovascular risk reduction by those interested in this lifestyle modification with the understanding that the benefits of such intervention remain to be better established - Further research on meditation and cardiovascular risk is warranted. Such studies, to the degree possible, should meet the following criteria: - This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be "significant" if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person's gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition. Modest. † Significant. # Reviewer disclosures Reviewer Employment This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be "significant" if (a) the person receives $10 000 or more during any 12-month period, or 5% or more of the person's gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10 000 or more of the fair market value of the entity. A relationship is considered to be "modest" if it is less than "significant" under the preceding definition. Significant. - Single-blind randomized controlled trial to that assessed blood pressure, perceived stress, and anger in 60 cardiac patients. - Experimental group (N=30) received 8 weeks MBSR training while those in control group received no psychological training (wait-listed control group N=30). - Systolic blood pressure, perceived stress, and ager were significantly improved (p<.01) in MBSR group as compared to control group. - University employees were randomized to a 6-week mindfulness-based stress release program (SRP) (N=50) or a waitlist control group (N=29) - SRP program is a structured program consisting of "practices using body, breath, and cognitive strategies and reflective activities to enhance professional and personal life" and is considered to be less intensive than MBSR - Perceived stress, workplace well-being, and engagement were measured at baseline and at completion of the program - Randomized trial that examined brief mindfulness-based intervention for younger female breast cancer survivors. - Women diagnosed with early stage breast cancer at or before age 50 who had completed cancer treatment were randomly assigned to a 6-week Mindful Awareness Practices (MAPS) intervention group (n = 39) or to a wait-list control group (n = 32). - Participants completed questionnaires before and after the intervention to assess stress and depressive symptoms (primary outcomes) as well as physical symptoms, cancerrelated distress, and positive outcomes. Blood samples were collected to examine genomic and circulating markers of inflammation. Participants also completed questionnaires at a 3-month follow-up assessment. - Meta-analysis of 4 clinical trials (total N=191) examining telomerase activity in association with meditation. - A meta-analytic effect size of d = 0.46 indicated that mindfulness meditation leads to increased telomerase activity in peripheral blood mononuclear cells. These results - Small number of studies included in analysis. Younge, JO, PLoS One, 2015 - Randomized controlled single-blind trial that examined the physiological and psychological outcomes of a 12 weeks online mindfulness training program (N=215) as compared to usual care (N=109) in patients with cardiac disease - Primary outcome was exercise capacity as measured by a 6 min walk test. Other outcomes included heart rate, blood pressure, respiratory rate, NT-proBNP, subjective health status, perceived stress, psychological well-being, social support, and a composite end-point (all-cause mortality, heart failure, symptomatic arrhythmia, cardiac surgery, and percutaneous cardiac intervention). - Stratified-randomized trial - Following a laboratory cognitive stressor, participants (maladaptive perfectionists -N=21, and controls -N=39, were randomly assigned to a 10 min audio instructed mindfulness meditation condition or a 10 min rest condition with audio description of mindfulness meditation. - Significant elevated heart rate variability (HRV) during meditation for controls but not for maladaptive perfectionists - Findings suggest that mindfulness meditation promotes relaxation following cognitive stress but the maladaptive perfectionist personality hinders relaxation possibly due to decreased cardiac vagal tone - Randomized controlled trial comparing Mindfulness Based Cancer Recovery program to a supportive-expressive group. A one day stress management seminar was used for the control group. - 88 distressed cancer survivors with a diagnosis of stage 1 or stage 11 cancer who completed treatment at least three months prior participated. - No differences were found in regards to telomere length between the mindfulness group and the supportive expressive group -but a trend was observed in the combined intervention group as compared to the control group - Examined the extent to which a brief mindfulness training intervention buffered self-reported psychological and cortisol responses to TSST in 66 young adults. - Participants were randomly assigned to either a 3 day (25 min per day) mindfulness meditation training or an analytic cognitive training control program. - Controlled for treatment expectancies. - Perceived stress was reduced in brief mindfulness training group however demonstrated increased cortisol reactivity to TSST as compared to the control group. - No changes were observed in systolic or diastolic blood pressure between the two groups. - Did not include a validated state mindfulness measure - Since blood pressures were not taken continuously during/after the TSST, BP reactivity may not have been fully captured. - Examined impact of a day of intensive mindfulness meditation in experienced individuals (N=19) on expression of circadian, chromatin modulatory, and inflammatory genes in peripheral blood mononuclear cells compared to a control group (N=21) of individuals with no meditation experience who engaged in leisure activities in the same environment as intervention group - Blood was collected before and after the intervention for analysis of gene expression. In addition, individuals underwent the Trier Social Stress Test (TSST). - Core clock gene expression at baseline was similar between groups and their rhythmicity was not influenced by meditation. - Epigenetic regulatory enzymes and inflammatory genes were similar at baseline for the two groups. - Reduced expression of histone deacetylase genes (HDAC 2, 3, and 9), alterations in global modification of histones , and decreased expression of proinflammatory genes (RIPK2 and COX2 were found in meditators as compared to controls. - Faster recovery of cortisol levels after the TSST was associated with lower gene expression levels of RIPK2 and HDAC2 - Small sample size Lengacher CA, Biol Res Nursing 2014 [bib_ref] Influence of mindfulness-based stress reduction (MBSR) on telomerase activity in women with..., Lengacher [/bib_ref] - 162 breast cancer survivors were randomized or wait-listed. [bib_ref] Mindfulness meditation and improvement in sleep quality and daytime impairment among older..., Black [/bib_ref] week Mindfulness-based stress reduction (MBSR) on telomere length (TL) and telomerase activity (TA) at 6 and 12 weeks. - MBSR led to increased telomerase activity but no increase in telomere length - Small-modest sample size - Mindfulness-based stress reduction influenced telomerase activity in women with breast cancer - Prospective study of 26 healthy subjects who had no prior relaxation response training (RR; diaphragmatic breathing, mantra repetition, and mindfulness meditation)-eliciting experience (Novices, N1) who underwent 8 weeks of RReliciting training (Short-term Practitioners, N2). - Parallel cross-sectional study of another 26 healthy subjects with significant prior RR-practice (4-20 years; Long-Term Practitioners, M) and compared with novices either before or after their 8-week RR training. - Both short-term and long-term practitioners evoked significant temporal gene expression changes with greater significance in the longterm practitioners as compared to novices. RR practice enhanced gene expression related to energy metabolism, mitochondrial function, insulin secretion and telomere maintenance, and reduced expression of genes linked to inflammatory response and stressrelated pathways. - Small sample size - Quasi-experimental design - Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. Some genes were modified only in long-term practitioners, whereas others were modified in both short-and long-term practitioners with a greater intensity in the latter. Rosenkranz, MA, Brain Behav Immun, 2013 [bib_ref] A comparison of mindfulness-based stress reduction and an active control in modulation..., Rosenkranz [/bib_ref] - Randomized controlled trial (N=49) comparing 8 weeks MBSR program to Health Enhancement Program (HEP) - Psychological stress and endocrine response were measured before and after the Trier Social Stress Test. - Inflammation was measured by using capsaicin topical cream to induce inflammation before and after intervention - Cortisol responses to TSST were similar between MBSR and HEP groups. - Reduction in psychological distress and symptoms in response to TSST were similar between groups - Those randomized to MBSR group had significantly smaller post-stress inflammatory response as compare to HEP. - Generalizability to populations with chronic illness - Unable to determine interaction between stress and inflammation because, due to potential participant burden, stress condition was not employed in the absence of inflammation and an inflammation condition was not tested in the absence of stress. Qu S, PLoS ONE 2013 [bib_ref] Rapid gene expression changes in peripheral blood lymphocytes upon practice of a..., Qu [/bib_ref] - Ten health adults did two courses of 4 consecutive days of a comprehensive yoga program, at the same time of the day (6.30 am -8.30 am) or yoga and related practices or nature walk with relaxing music. - Gene expression changes were noted as early as 2 hours. 97 unique genes were affected by yoga and related practices vs. 24 by the control regimen. 36% of the control group genes were also influenced by the yoga regimen, suggesting overlap in effect on biological processes. Nyklicek, L, Health Psychol, 2013 (23) - 88 community-dwelling volunteers reporting elevated levels of perceived stress were randomly assigned to a MBSR program or waitlist control group. - Participants underwent a social stressor consisting of mental math and making a speech before and after the intervention. - Measurements before, during and after the social stressor included heart rate variability, blood pressure, and salivary cortisol. - Controlling for age, body mass index, and beta blockers, participants in the MBSR group demonstrated larger decreases in systolic blood pressure, diastolic blood pressure. - No effect was obtained for other physiological measures. - Absence of critical committee during TSST could have reduced cortisol response to stressor. - Recovery period after social stressor was only 10 minutes which may have limited the ability to capture changes during recovery. Carlson, J Clin Oncol, 2013 [bib_ref] Randomized controlled trial of Mindfulness-based cancer recovery versus supportive expressive group therapy..., Carlson [/bib_ref] - Randomized controlled trial to compare mindfulness -based cancer recovery (MBCR) program to supportive-expressive group therapy (SET) in distressed survivors of stage 1 to III breast cancer (N=271) - 1-day stress management class was used as a control condition - Measures (mood, diurnal salivary cortisol, stress, quality of life, and social support) were collected at baseline and after the intervention by evaluators blinded to the study condition. - Cortisol slopes were maintained in MBCR (p=.011) and SET group (p=.002) participants in comparison to those in the control group whose cortisol slopes became flatter. - Stress symptoms were improved in MBCR group compared to SET (p=.009) and control (p=.024) groups. - Those participating in the MBCR group demonstrated greater improvements in quality of life compared to the control group (p=.005) and social support compared to those in the SET group (p=.012). - Only breast cancer patients in study -findings may not be generalizable. - High attrition (34.5% in MBCR group). Jacobs, TL, Health Psychol, 2013 (24) - Observational study examining self-reported mindfulness and evening cortisol at the beginning and after a 3 month Shamatha meditation retreat (N=57) - The group met 2×/day for 1-hr sessions to engage in guided meditations and dialogue but primarily practiced solitary meditation for much of the day (M = 6.3 hr/day, SD = 1.34). - To allow for acclimatization, cortisol measures were taken 2 weeks after arrival to the retreat site, which meant that participants had already been meditating for up to 9 days before the initial cortisol measure was - Blinded design -48 young, healthy meditation novices were randomly assigned to MBSR, non-MBSR, or inactive control group. - At posttest, those in the inactive control group were randomly split into incentive and non-incentive controls - Attention, self-report of mindfulness, perceived stress, and salivary cortisol were measured at pre and post intervention. - Attentional effects of MBSR, non-MBSR, and the financial incentive were comparable or significantly larger in the incentive group. - 33 women who had completed treatment for breast cancer participated in the study' - MBSR group met weekly for 2.5 hours for 8 consecutive weeks - Cortisol Awakening Response (CAR) was assessed at three days prior to the MBSR program and three days after. - Depressive symptoms, perceived stress, and medical symptoms were measured pre and post intervention. - Cortisol levels demonstrated a prolonged increase after awakening at the post MBSR assessment. This was accompanied by significant improvements in self-reported stress, depressive symptoms, and medical symptoms. - Small sample size - University employees and staff randomized to a low dose MBSR program (N=24 or wait list control group (N=24). - Low dose MBSR program consisted of 1 hour weekly sessions for 6 consecutive weeks with 20 minutes of daily practice. - Perceived stress, sleep quality and mindfulness assessed at baseline and at end of 6 weeks intervention. - Salivary cortisol was collected three times a day for 2 consecutive days every week for the duration of the intervention. - Participants in the low dose MBSR group had significant reduction of perceived stress (p=.0025) and increase in mindfulness (p=.0149). - No changes in average daily salivary cortisol levels over time for participants in both groups and no differences from the pretest to the posttest were found. - Small sample size - Psychological measures (i.e. perceived stress) only measured at baseline and end of intervention. - Wait list control group Pace, TW, Psychoneuroendocrinology, 2009 [bib_ref] Effect of compassion meditation on neuroendocrine, innate immune and behavioral responses to..., Pace [/bib_ref] - Examined the effect of compassion meditation on innate immune, neuroendocrine, and behavioral responses to psychosocial stress and examined the degree to which meditation practice influenced stress reactivity in 61 healthy adults randomized to 6 weeks of training in compassion meditation (N=33) or in a health discussion control group (N=28). - Response to TSST was measured by repeated measures of interleukin -6 (IL-6), cortisol and total distress scores on the Profile of Mood States (POMS). - No main effect of group assignment on TSST responses was found for IL-6, cortisol, or POMS scores. - Increase meditation practice was correlated with decreased TSSTinduced IL-6 (p=.0008) and POMS distress scores (p=.014). - Small sample size - Did not perform TSST prior to intervention -may be possible that individuals who had reduced inflammatory response to social stress may have been more willing or able to engage in meditation practice. - Those randomized to the meditation group may have had higher expectations of outcomes than those randomized to the control group. Witek-Janusek, Brain Behav Immun, 2008 - Non randomized controlled design to evaluate the effect of MBSR on immune function, quality of life, and coping in women recently diagnosed with breast cancer - Participants self-selected into the MBSR group (N=44) or control group (usual care) (N=31). - Data was collected from a cancer free group of women (N=30) for comparison of immune measures. - Over time, women in MBSR group reestablished NKCA and cytokine production levels while women in the usual care group demonstrated continued reductions in NKCA and IFN-gamma. IL4, IL-6, and IL-10 increased. - Women in MBSR group had reduced cortisol levels and improved QOL and coping effectiveness compared to those in the usual care group. - Small sample size - Non-randomization of participants [formula] Carlson, LE, Brain Behav Immun, 2007(31) [/formula] - 49 women with breast cancer and 10 men with prostate cancer were enrolled in an 8 weeks MBSR program. - Health behaviors, quality of life, mood, stress, salivary cortisol levels, immune cell counts, intracellular cytokine production, blood pressure and heart rate were assessed at baseline, post-intervention, and 6 and 12 months post intervention. - Symptoms and stress were significantly improved after the intervention and improvements were maintained at 12 months post intervention. - Cortisol and proinflammatory cytokines decreased over follow up period - Blood pressure significantly decreased from baseline to post intervention. - Randomized controlled trial examining the effects of a 1month mindfulness meditation to a somatic relaxation training to a control group in 83 students. - Both meditation and relaxation groups demonstrated improvements in mood and decreases in distress when controlling for social desirability as compared to the control group (p>.05). - Meditation group demonstrated significant pre-post decreases in distractive and ruminative thoughts compared to control group (p<.04). - Small sample size Robert MacComb, JJ, J Altern Complement Med, 2004 (34) - Women with documented histories of cardiovascular disease were randomly assigned to a MBSR group (N=9) or control group (N=9). - Pre-post hormonal measures and physical functioning were collected - Submaximal exercise responses were measured after the 8 weeks intervention. - No significant main effects or interaction for resting levels of stress hormones or physical functioning, or submaximal exercise responses - Significant differences in breathing patterns (p<.01). - Small sample size [formula] Speca, M. Psychosomatic Medicine, 2000(35) [/formula] - 90 outpatient cancer patients were randomized to a weekly meditation group lasting 1.5 hours or 7 weeks with home meditation practice or a wait-list control group. - Participants completed the Profile of Mood States and the Symptoms of Stress Inventory before and after the intervention - Participants in meditation group reported significantly lower total mood disturbance and fewer overall symptoms of stress (p<.05). - Wait list control group - Prospective Cohort study with 2 cohort of subjects with and without established CAD. - 6 weeks of yoga and meditation on hemodynamic and laboratory parameters as well as on endothelial function were studied. - Significant reductions in blood pressure, heart rate, and BMI in the total cohort with yoga. - Design: RCT - Population: 138 hypertensive African Americans enrolled but only 60 completed post-test carotid ultrasound. - Intervention: Transcendental Meditation vs a Health Education program. TM is a mental technique practiced twice a day for 20 minutes. Initial teaching instructions conducted in both groups within 1 weeks, follow-up meetings 1 weeks later, than every 2 weeks for 2 months, and once a month for 3 months. - Outcome: carotid intimal medial thickness (cIMT) by B-mode U/S. - Follow-up: 6-9 months (mean 6.8±1.3 months) - TM group showed a significant decrease of -0.098 mm (95% CI -0. 198 to 0.003 mm) in cIMT compared with an increase of 0.054 mm (95% CI -0.05 to 0.158 mm) in the control group (P=0.038 for between group difference). - Correlation between attendance rates of meetings and change in cIMT scores was significant for TM group but not health education group - TM group also had statistically significant within-group changes in SBP, DBP, pulse and pulse pressure while health education group improved only SBP and DBP. - - TM reduced carotid atherosclerosis among African American hypertensive adults - High rate of attrition questions the generalizability of these findings. 170 participants were randomized but only 60 had completed posttest interpretable cIMT scans, although attrition was equal in both groups. - Design: RCT - Population: 28 patients with CAD - Intervention: randomized to a lifestyle intervention vs control. Lifestyle intervention included a very low fat vegetarian diet, moderate aerobic exercise, stopping smoking, stress management program (that included stretching, breathing techniques, meditation, progressive relaxation, and imagery) which they were asked to practice at least 1 hour per day, and group therapy - Outcome: Coronary atherosclerosis by quantitative coronary angiography - Follow-up: 1 yr and 5 years - At 1 yr, 82% overall experienced some regression of their CAD. Average % diameter stenosis regressed from 40% to 38% in intervention group, yet progressed from 43% to 46% in controls. - More regression of atherosclerosis occurred at patients in the intervention group at 5 years followup than was seen at the 1 yr followup. There was a 4.5% and 7.9% relative improvement in coronary stenosis in the intervention arm at 1 and 5 years, respectively vs. 5.4% and 28% relative worsening at 1 and 5 years in control. - A multi-modality lifestyle intervention (that includes meditation stress management as one component) confers coronary atherosclerosis regression - Small sample size. And only 20 out of 28 (71%) had 5 yr follow-up data - Intervention not blinded - Multi-modality of the lifestyle intervention limits the ability to discern the effects of mediation vs. the other components such as the extremely low fat vegetarian diet. - Randomized study of 30 male patients with a diagnosis of coronary artery disease treated with either mindfulness based stress reduction (mindfulness meditation) consisting of 8 weekly instructional session and 30 minutes meditation daily at home or "treatment as usual" - Mindfulness based stress reduction including training in different variants of mindfulness meditation including body scan meditation, sitting meditation, mindful walking and mindful eating - All patients in both groups instructed on health behaviors including regular exercise for at least 30 minutes and suggested diet - At the end of the intervention, for the mindfulness based stress reduction group, there were significant within group and between group decreases in anxiety, depression, perceived stress, and systolic blood pressure - At 3 month follow-up, there was a further significant reduction in blood pressure - Specific independent contribution of meditation to study findings cannot be determined [fig] ••: Wait97 Healthy women aged 30-60 entered into 1 week spa retreat: 30 regular meditators and 64 non meditators (31 vacation only and 33 vacation + meditation) with post intervention 1 and 10 month follow up • Regular meditators had lower telomerase at baseline, and a significant increase in peripheral blood cell telomerase activity post treatment not observed in the other two groups. [/fig] [fig] •: Perceived stress reduced (p=.004) post intervention, Decreased pro-inflammatory gene expression (P = .009) and inflammatory signaling (P = .001) at post intervention. Intervention effects on psychological and behavioral measures not maintained at 3 month follow up. Small sample size Use of wait-list control group Levine et al. Meditation and Cardiovascular Risk Reduction: A Scientific Statement From the American Heart Association © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. [/fig] [table] Table 1: Common Types of Meditation [/table] [table] Table 2: Summary of Findings on Studies of Meditations and Cardiovascular Risk Reduction* [/table] [table] Table 3: Summary of Findings and Suggestions on Meditation and Cardiovascular Risk Reduction [/table]	None	https://www.ahajournals.org/doi/pdf/10.1161/JAHA.117.002218	Abstract Despite numerous advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains a leading cause of morbidity and mortality. Novel and inexpensive interventions that can contribute to the primary and secondary prevention of cardiovascular disease are of interest. Numerous studies have reported on the benefits of meditation. Meditation instruction and practice is widely accessible and inexpensive and may thus be a potential attractive cost‐effective adjunct to more traditional medical therapies. Accordingly, this American Heart Association scientific statement systematically reviewed the data on the potential benefits of meditation on cardiovascular risk. Neurophysiological and neuroanatomical studies demonstrate that meditation can have long‐standing effects on the brain, which provide some biological plausibility for beneficial consequences on the physiological basal state and on cardiovascular risk. Studies of the effects of meditation on cardiovascular risk have included those investigating physiological response to stress, smoking cessation, blood pressure reduction, insulin resistance and metabolic syndrome, endothelial function, inducible myocardial ischemia, and primary and secondary prevention of cardiovascular disease. Overall, studies of meditation suggest a possible benefit on cardiovascular risk, although the overall quality and, in some cases, quantity of study data are modest. Given the low costs and low risks of this intervention, meditation may be considered as an adjunct to guideline‐directed cardiovascular risk reduction by those interested in this lifestyle modification, with the understanding that the benefits of such intervention remain to be better established. Further research on meditation and cardiovascular risk is warranted. Such studies, to the degree possible, should utilize randomized study design, be adequately powered to meet the primary study outcome, strive to achieve low drop‐out rates, include long‐term follow‐up, and be performed by those without inherent bias in outcome.
b9eb8d91697acc3837b52018974b6edbadc6a4a5	pubmed	Care of the Patient with IBD Requiring Hospitalization During the COVID-19 Pandemic	Care of the Patient with IBD Requiring Hospitalization During the COVID-19 Pandemic # Introduction The COVID-19 pandemic has led to restriction of hospitalizations and unprecedented redeployment of healthcare resources. The management of IBD has been highly impacted. [bib_ref] Implications of COVID-19 for patients with pre-existing digestive diseases, Mao [/bib_ref] [bib_ref] Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD..., Bezzio [/bib_ref] [bib_ref] Novel Coronavirus Disease (COVID-19) in patients with Inflammatory Bowel Diseases, Taxonera [/bib_ref] [bib_ref] AGA Clinical Practice Update on Management of Inflammatory Bowel Disease During the..., Rubin [/bib_ref] On the one hand, hospital admissions of IBD patients should be limited to reduce the risks of coronavirus transmission between hospitalized patients and to ensure that there is inpatient capacity to look after the many admissions with COVID-19. [bib_ref] Management of IBD during the COVID-19 outbreak: resetting clinical priorities, Danese [/bib_ref] On the other hand, delaying hospitalization of IBD patients with severe or complicated disease may increase the risk of poor outcomes. Surgery is also seriously impacted in the present context. [bib_ref] Medically Necessary, Time-Sensitive Procedures: Scoring System to Ethically and Efficiently Manage Resource..., Prachand [/bib_ref] [bib_ref] Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period..., Lei [/bib_ref] A number of emergencies require surgery in the short term, and delaying surgery in some cases may increase the risk of disease progression, post-operative morbidity and disease complications. Performance of endoscopic procedures is also impacted, with significant delays to routine endoscopy. [bib_ref] Endoscopy in inflammatory bowel diseases during the COVID-19 pandemic and post-pandemic period, Iacucci [/bib_ref] IBD patients do not appear to have an increased risk of being infected with SARS-CoV-2. [bib_ref] Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD..., Bezzio [/bib_ref] [bib_ref] Covid-19 in Immune-Mediated Inflammatory Diseases -Case Series from New York, Haberman [/bib_ref] However, IBD patients who are infected with SARS-CoV-2 may have a higher risk of poor outcomes than the general population.This increased risk may be driven by concomitant medications, especially corticosteroids, but may also be associated with gastrointestinal inflammation, IBD itself or associated comorbidities. Additional risk factors for poor outcomes A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa150 from COVID-19 include older age, pre-existing cardiovascular and respiratory disease, obesity, diabetes and cigarette smoking. [bib_ref] Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients..., Wu [/bib_ref] While the use of immunosuppressing medications such as thiopurines, and biologics has been associated with increased risks of a range of infections in IBD patients, at this point, there is no evidence that IBD patients with COVID have worse outcomes if they receive these drugs. [bib_ref] Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic, D'antiga [/bib_ref] [bib_ref] Are Patients with Inflammatory Bowel Disease at Increased Risk for Covid-19 Infection?, Monteleone [/bib_ref] National and international societies, including IOIBD, have recommended the maintenance of these therapies in the present context. 14 Which IBD drugs should be preferentially used to induce response or remission in patients with active IBD during the COVID-19 pandemic is unclear. There is even less evidence on how IBD patients with active disease should be treated according to their COVID-19 infectious status. Manifestations and outcomes from COVID-19 infection are related to host defense responses. The hyper-inflammatory response may lead to organ failures, associated with a cytokine "storm", characterized by high levels of pro-inflammatory cytokines, such as TNF, several interleukins and chemokines. Immunomodulation of this hyperinflammatory state is currently being explored 15 , and there are several clinical trials in COVID-19 patients of immunomodulators or targeted therapies. [bib_ref] The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R)..., Zhang [/bib_ref] It is possible that even if immunomodulators suppress viral immunity, they may exert a beneficial effect by controlling the hyperinflammatory state. COVID-19 can cause diarrhea and abdominal pain and may mimic an IBD flare. [bib_ref] Covid-19 and the digestive system, Wong [/bib_ref] The virus can infect the gut, as demonstrated by a positive SARS-CoV-2 viral nucleocapsid positive staining in digestive biopsies. [bib_ref] Evidence for Gastrointestinal Infection of SARS-CoV-2, Xiao [/bib_ref] It is currently unknown if SARS-CoV-2 can cause relapse of or de novo IBD. A striking characteristic of severe COVID-19 infections is the predisposition to develop thromboembolic complications. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] [bib_ref] Prominent changes in blood coagulation of patients with SARS-CoV-2 infection, Han [/bib_ref] [bib_ref] Thromboprophylaxis and laboratory monitoring for in-hospital patients with COVID-19 -a Swiss consensus..., Casini [/bib_ref] [bib_ref] Acute Pulmonary Embolism Associated with COVID-19 Pneumonia Detected by Pulmonary CT Angiography, Grillet [/bib_ref] [bib_ref] Acute Pulmonary Embolism in COVID-19 Patients on CT Angiography and Relationship to..., Leonard-Lorant [/bib_ref] Given that IBD patients are already at risk, anticoagulation prophylaxis should be adapted to each situation. e. Depending on institutional policy and availability, testing for SARS-CoV-2 may be required prior to needed inpatient endoscopic, radiologic or surgical procedures, as even asymptomatic patients with SARS-CoV-2 infection may be at risk for postoperative ICU care and mortality [bib_ref] Minimally Invasive Surgery and the Novel Coronavirus Outbreak: Lessons Learned in China..., Zheng [/bib_ref] , and are at risk for infecting others. f. Ideally, and when possible, testing for SARS-CoV-2 should be performed before admission. We recommend to hospitalize the patient in a single room until the result of testing for SARS-CoV-2 is available. ## Evaluation for covid-19 a. Patients suspected of having COVID-19 should be tested for SARS-CoV-19 in the nasopharynx. Serologic antibody testing may also be used, provided that this testing is both accurate and has clinical relevance. Testing for SARS-CoV-2 is evolving and it is currently unclear which test will be best. b. If testing for SARS-CoV-2 is negative, or if the patient is considered as immune, the patient can be admitted to a COVID-free unit. b. Radiologic procedures should be limited to those that are urgently needed or will directly influence management, e.g., AXR, CT or MR to evaluate for abscess or obstruction. In the current environment, CT may be preferred over MR due to faster acquisition time and easier deep cleaning of equipment. c. Endoscopic procedures should be limited to those that are urgently needed or will directly influence management. Serum and stool biomarkers may have a more prominent role to play in this setting. (Refer to IOIBD Endoscopy guidance document.) ## Considerations for treatment of ibd in a patient with sars-cov-2 a. c. In cases of moderate-severe COVID-19, discontinuation of IBD therapies must be discussed case-by-case, according to IBD activity and treatment. Interestingly, some treatments such as steroids and even some biologics are considered and even assessed in ongoing clinical trials in the second phase of COVID-19 (so called cytokine storm). ii. For small perianal abscesses, it is reasonable to try a short course of antibiotic therapy before surgery. However, the role of oral antibiotic therapy alone versus surgical drainage for small abscesses in these patients is unknown. iii. The presence of a large or complex perianal abscess in the CD patient requires surgery and should not be delayed. A c c e p t e d M a n u s c r i p t	None	https://academic.oup.com/ecco-jcc/article-pdf/14/Supplement_3/S774/33977557/jjaa150.pdf	Abstract The management of IBD has been highly impacted in the context of the COVID-19 pandemic, with restriction of hospitalizations and unprecedented redeployment of healthcare resources. Hospital admissions of IBD patients should be limited to reduce the risks of coronavirus transmission. However, delaying hospitalization of IBD patients with severe or complicated disease may increase the risk of poor outcomes. Delaying surgery in some cases may increase the risk of disease progression, post-operative morbidity and disease complications. IBD patients who are infected with SARS-CoV-2 may have a higher risk of poor outcomes than the general population, potentially related to concomitant medications, especially corticosteroids. There is no evidence today that IBD patients with COVID-19 have worse outcomes if they receive immunosuppressant medications including thiopurines, biologics and novel small molecules. This article summarizes recommendations by the international membership of IOIBD regarding hospitalizations of IBD patients, either for active or complicated IBD or severe COVID-19, and for management of IBD patients according to SARS-CoV-2 infectious status.
56df0c753d5bd3bdeb27ea0ec3bb1b9ed4824aeb	pubmed	Renal Association Clinical Practice Guideline on Haemodialysis	Renal Association Clinical Practice Guideline on Haemodialysis This guideline is written primarily for doctors and nurses working in dialysis units and related areas of medicine in the UK, and is an update of a previous version written in 2009. It aims to provide guidance on how to look after patients and how to run dialysis units, and provides standards which units should in general aim to achieve. We would not advise patients to interpret the guideline as a rulebook, but perhaps to answer the question: "what does good quality haemodialysis look like?" The guideline is split into sections: each begins with a few statements which are graded by strength (1 is a firm recommendation, 2 is more like a sensible suggestion), and the type of research available to back up the statement, ranging from A (good quality trials so we are pretty sure this is right) to D (more like the opinion of experts than known for sure). After the statements there is a short summary explaining why we think this, often including a discussion of some of the most helpful research. There is then a list of the most important medical articles so that you can read further if you want tomost of this is freely available online, at least in summary form. A few notes on the individual sections:1. This section is about how much dialysis a patient should have. The effectiveness of dialysis varies between patients because of differences in body size and age etc., so different people need different amounts, and this section gives guidance on what defines "enough" dialysis and how to make sure each person is getting that. Quite a bit of this section is very technical, for example, the term "eKt/V" is often used: this is a calculation based on blood tests before and after dialysis, which measures the effectiveness of a single dialysis session in a particular patient. 2. This section deals with "non-standard" dialysis, which basically means anything other than 3 times per week.For example, a few people need 4 or more sessions per week to keep healthy, and some people are fine with only 2 sessions per weekthis is usually people who are older, or those who have only just started dialysis. Special considerations for children and pregnant patients are also covered here. 3. This section deals with membranes (the type of "filter" used in the dialysis machine) and "HDF" (haemodiafiltration) which is a more complex kind of dialysis which some doctors think is better. Studies are still being done, but at the moment we think it's as good as but not better than regular dialysis.(Continued on next page) # Introduction Haemodialysis continues to expand in the UK with over 25 000 patients now being treated, representing a 10% increase since publication of the previous Renal Association guideline for haemodialysis. In addition the patient group continues to develop: the typical patient is now 67 years old with a median history of 3.2 years on renal replacement therapy. The authors of this guideline aimed principally to update the previous guideline according to the latest research and experience, but also to expand the scope into areas not previously covered but relevant to haemodialysis practice. The guideline was written collaboratively: lead and coauthors for each section conducted literature reviews and wrote first drafts of the statements and rationale. Feedback and discussion were provided by all authors via email exchanges and meetings, revised versions were produced with editorial input from the chair, and these were subsequently agreed by all authors. Two current haemodialysis patients gave advice on tone and readability. Systematic literature searches were undertaken by lead authors to identify all relevant evidence published up until the end of June 2018. Compound search terms were used which included a dialysis identifier (hemodialysis[tiab] OR haemodialysis OR dialysis[tiab]) followed by title/abstract-filtered topic terms ("dialysis dose", Kt/V, augmented, intensive, conservative, incremental, pregnancy, membrane, hydration, "dry weight", "fluid overload", dialysate, potassium, bicarbonate, buffer, phosphate, "dialyser reaction", hypersensitivity, "blood loss", "needle dislodgment", exsanguination, "home haemodialysis", "nocturnal haemodialysis", exercise, "physical training") followed by negative terms (e.g. to exclude animal studies and acute kidney injury) finally with date and language restrictions ("1990/ 01/01"[dp]: "3000"[dp] AND english . Searches were conducted in MEDLINE, PUBMED, Embase, and The Cochrane Library, and supplemented with papers handpicked from the reference lists of review papers. The strengths of the recommendations and the level of supporting evidence are coded as previously using the Modified GRADE system. There are a few changes in scope, for example dialysis water treatment is now covered in another guideline, as are many aspects of dialysis, including: We have removed the section on targets for blood testing since these are better covered in other guidelines, and have not covered infrastructure or workforce since these will be addressed separately by the Renal Association in a different format. However, in most ways the update is broader than previous versions. For example, new sections have been written covering fluid management (surely an essential topic but not really covered previously or elsewhere) and dialysate (often underestimated in importance). In other areas this update seems to make no substantial change to previous guidance (as with dialysis dose, for example, where the literature remains dominated by previous large trials), however whilst key concepts remain valid, their understanding has developed, and the guideline aims to provide greater context, encouraging a more holistic interpretation. Discussions about dialysis often become overly technicalthese concepts are important but hard to fit into a narrative so we have moved a few aspects into the appendix, where we aim to provide simplified summaries. We have tried to maintain a high standard of readability since conceptual understanding is the key goal, and as the guideline is not intended to replace review articles or original papers, it seems correct to favour readability over detail. ## Summary of clinical practice guidelines ## Dialysis dose in thrice weekly dialysis schedules We recommend eKt/V as the most clinically valid smallsolute measure of dialysis dose, and recommend monitoring of dialysis dose on a monthly basis for the majority of centre-based dialysis patients. We recommend targeting dialysis dose to achieve consistently a minimum eKt/V of 1.2 for thrice weekly patients, in the absence of a measured contribution from residual function. We recommend a minimum of 12 hours per week for the majority of thrice weekly patients with minimal residual function. Non-standard schedules (Guidelines 2.1 -2.4) Guideline 2.1 -Augmented schedules We suggest offering an augmented schedule to patients who are unable to achieve adequacy targets or fluid control on a standard thrice weekly schedule. We suggest that relative contraindications to augmented schedules should be considered, such as significant residual function or problematic fistula access. [2C] ## Guideline 2.2 -incremental schedules We suggest that lower haemodialysis dose targets may be optimal in patients with significant residual renal function. We recommend that residual renal function should be quantified intermittently in patients on incremental dialysis schedules. [1D] ## Guideline 2.3 -conservative schedules We suggest that lower haemodialysis dose targets may be optimal when quality of life is the primary goal of treatment, rather than longevity. [2D] ## Guideline 2.4 -paediatric schedules In children and adolescents we recommend an approach to the assessment of dialysis adequacy which goes beyond biochemical targets, incorporating clinical goals such as growth, bone health, cardiac function and quality of life. We recommend targeting dialysis dose to achieve a minimum eKt/V of 1.2 for thrice weekly patients, or a standardized Kt/V of 2.2 for those on augmented schedules. We suggest an augmented schedule for children on predominantly liquid nutrition, and those with ventricular systolic dysfunction. We recommend a blood flow rate of 5-7ml/kg/min for the majority of patients, using consumables appropriate to body size, with extracorporeal volume less than 10% of the patient's blood volume. [1C] ## Guideline 2.5 -schedules during pregnancy We recommend counselling women of reproductive age who are receiving or anticipating dialysis, so that they are aware of the interactions between renal replacement therapies and pregnancy which may impact on family planning and modality decisions. For dialysis patients wishing to continue their pregnancy, we recommend changing as early as possible to an individualised, augmented haemodialysis schedule. For those with minimal residual function this should be at least 20 hours per week, delivered over at least 6 sessions. We recommend an individualised dialysate prescription appropriate to the dialysis schedule and biochemistry results, anticipating the frequent need for a high potassium / low bicarbonate dialysate, supplemented with phosphate. We suggest an individualised fluid management protocol, with low ultrafiltration rates and regular clinical assessment, anticipating the typical change in weight during pregnancy. [2C] ## Membrane flux and haemodiafiltration We recommend that patients with minimal residual function should be treated with high-flux dialysers. We suggest that haemodiafiltration may be considered as a treatment for intra-dialytic hypotension refractory to other measures, and for dialysis patients with favourable prognosis who are unable or unlikely to be transplanted. We suggest a multidisciplinary approach to fluid assessment, with patient involvement and the adoption of patient-friendly terminology such as "target weight", "fluid gain" and "over-hydration". We recommend clinical assessment of fluid status on a monthly basis for the majority of patients. We suggest supplementing clinical assessment of fluid status with a validated objective measurement, such as bioimpedance, at regular intervals, when clinical assessment is unclear, and following an intercurrent illness. We recommend a dialysate temperature not greater than 36'C if standardised. We recommend avoiding excessive ultrafiltration rates by addressing fluid gains, accepting staged achievement of target weight, or using an augmented schedule, as necessary. We recommend prompt nursing intervention to restore haemodynamic stability in symptomatic / severe intradialytic hypotension, with such interventions leading to clinical review. [1C] ## Guideline 4.2 -paediatric fluid considerations In growing children we recommend clinical assessment of fluid status and target weight, and dietetic assessment, at least monthly. We suggest supplementing clinical assessment with a validated objective measure of fluid status such as bioimpedance, on a monthly basis or more frequently during periods of rapid growth or illness. We recommend regular assessment of ultrafiltration tolerance, using extended times to avoid excessive ultrafiltration rates. We recommend an optimal pre-dialysis serum potassium in the range 4.0-6.0mmol/L, remembering to consider measurement errors (e.g. due to haemolysis) when interpreting levels. We suggest choosing dialysate potassium between 1.0 and 3.0mmol/L for the majority of patients, using an individualised approach, in general using the highest dialysate potassium that is sufficient to control pre-dialysis hyperkalaemia. We suggest a combined approach to managing hyperkalaemia, which may include decreasing dialysate potassium and/or other measures, including dietary advice, medication review and increased dialysis frequency. [2D] ## Guideline 5.2 -selection of dialysate buffer We recommend an optimal pre-dialysis serum bicarbonate in the range 18.0-26.0mmo/L, remembering to consider measurement errors (e.g. due to exposure to air) when interpreting levels. We suggest the term 'dialysate buffer' rather than 'dialysate bicarbonate' to avoid confusion arising from differences in manufacturers' terminology. We suggest choosing dialysate buffer below or equal to 37.0mEq/L for the majority of patients, using a standardised or individualised approach. We suggest a combined approach to abnormal predialysis serum bicarbonate, which may include increasing dialysis dose, oral bicarbonate, nutritional support, or individualising dialysate buffer. [2D] ## Guideline 5.3 -supplementation of dialysate with phosphate We suggest considering supplementation of the dialysate with phosphate in patients on augmented dialysis schedules. [2D] ## Guideline 5.4 -paediatric dialysate considerations We recommend individualisation of dialysate electrolyte concentrations, including potassium, buffer and calcium. We suggest an individualised dialysate temperature, between core temperature and 0.5°C below, with monitoring of intradialytic core temperature for neonates and smaller children. [2D] ## Anticoagulation We recommend that patients without increased bleeding risk should be given unfractionated or low-molecularweight heparin during dialysis to reduce clotting of the extracorporeal system. We recommend that systemic anticoagulation should be omitted or minimised in patients with increased bleeding risk. We recommend that patients with heparin allergies should be prescribed a non-heparin form of anticoagulation. We suggest training patients and/or care partners to achieve a defined set of competencies, using an individualised approach to training method and speed. We suggest units form a contract with patients outlining responsibilities, including an agreement to dialyse as per prescription and trained technique, and including a policy for re-imbursement of directly arising patient costs. [2D] We suggest supporting patients with a specific team including nephrologists, technicians, and nurses, with rapid access to dialysis in-centre when required. We suggest an agreed individualised prescription for home haemodialysis, taking into account lifestyle goals, with the same dose and time target considerations as centre-based patients. We recommend enhanced safety measures for patients who dialyse alone or overnight, and an enhanced risk assessment for patients with blood-borne viruses. [1C] ## Guideline 8.2 -shared haemodialysis care We suggest that all centre-based haemodialysis patients should have opportunity and encouragement to learn aspects of their dialysis treatment, and take an active role in their care. [2D] ## Guideline 8.3 -intradialytic exercise We recommend that intradialytic exercise should be available in all units, as a treatment for enhancing physical functioning, in patients without contraindications. We suggest that intradialytic exercise be considered as a method of enhancing quality of life. We suggest that exercise regimes be devised by appropriately trained staff. [2C] ## Guideline 8.4 -dialysis experience for children and adolescents We recommend that haemodialysis for children and adolescents should be delivered in a dedicated paediatric dialysis centre or at home, with the involvement of a paediatric multidisciplinary team. We recommend that adolescents should commence an active transition programme by 14 years, or at the time of presentation in those already over 14. [1D] ## Summary of audit measures Audit Measure 1: Amongst thrice-weekly patients on dialysis for more than a year, the median eKt/V, and proportion achieving eKt/V at least 1.2. Audit Measure 2: Amongst thrice-weekly patients on dialysis for more than a year, the median dialysis time per week, and proportion receiving at least 12 hours. Audit Measure 3: The proportion of patients dialysing 4 or more times per week (either in-centre or at home). Audit Measure 4: The proportion of patients dialysing less than 3 times per week, separated into: (a) patients in their first year of dialysis, and (b) patients on dialysis for more than a year. Audit Measure 5: The median ultrafiltration rate, and proportion of patients with residual kidney function (Kru > 2ml/min, or urine volume > 500ml/d), separated into: (a) patients in their first year of dialysis, and (b) patients on dialysis for more than a year. Audit Measure 6: The proportion of patients receiving haemodiafiltration, and the median convection volume in this group. Audit Measure 7: The most commonly used dialysate sodium level, and proportion of patients using this dialysate sodium level. Audit Measure 8: The availability of an objective tool for fluid state assessment, the type of tool used most commonly, and the proportion of patients assessed with an objective tool during the last year. Audit Measure 9: The median pre-dialysis serum potassium, and proportion of patients arriving with average potassium over 6.0mmol/l, and proportion with average under 4.0mmol/l. Audit Measure 10: The proportion of patients using a dialysate potassium level in the following categories: less than 2.0, 2.0, and more than 2.0mmol/l. Audit Measure 11: The number of disconnection haemorrhage events each year. Audit Measure 12: The proportion of haemodialysis patients having all or most of their dialysis at home. Audit Measure 13: The proportion of in-centre patients recognised as engaging in "Shared Care". Audit Measure 14: The availability of a program for intra-dialytic exercise, the resource available (equipment, physiotherapist time), and the proportion of incentre patients engaging with regular intra-dialytic exercise. ## Rationale for clinical practice guidelines Dialysis dose in thrice weekly dialysis schedules We recommend eKt/V as the most clinically valid smallsolute measure of dialysis dose, and recommend monitoring of dialysis dose on a monthly basis for the majority of centre-based dialysis patients. We recommend targeting dialysis dose to achieve consistently a minimum eKt/V over 1.2 for thrice weekly patients, in the absence of a measured contribution from residual function. We recommend a minimum of 12 hours per week for the majority of thrice weekly patients with minimal residual function. This may lead to higher than minimum eKt/V in smaller adult patients which is appropriate. [1B] ## Rationale Dialysis adequacy encompasses concepts including the clinical assessment of general wellbeing, fluid status, and control of laboratory parameters, along with quantification of the dose of dialysis provided. The purpose of dialysis is to provide enough removal of uraemic solutes and fluid that accumulate in kidney failure to maintain health and quality of life: more specific goals include control of uraemic symptoms, maintenance of safe electrolyte levels, prevention of nutritional decline, and optimum long term mortality. Whilst the earlier items in this list are readily assessed over a short time scale, concepts of dialysis dose are required to define the amount of dialysis likely to achieve longer term goals of treatment. Due to the simplicity and low cost of measurement of urea in blood, measurement of dialysis adequacy has historically focused on clearance of small solutes, represented by urea. Concentration of a range of uraemic toxins of larger size (e.g. β-2 microglobulin) is likely to be important, but their measurement is not commonly performed. Use of thrice weekly haemodialysis schedules emerged from the realisation during the early era of haemodialysis treatment that once or twice-weekly haemodialysis schedules in patients with minimal residual function was insufficient to control the symptoms and complications of severe uraemia. Most research on dialysis dose is therefore based on urea clearance, in patients on a thrice weekly schedule. Urea clearance may be calculated by three methods in common use: Urea Reduction Ratio, and the 'single pool' and 'equilibrated' formulas for Kt/V. Kt/V is less commonly calculated by Urea Kinetic Modelling -these methods are summarised mathematically in Appendix 1. The diversity of methods can lead to duplication of effort, confusion over the meaning of targets, and impedes comparison between centres, so a single widely used method would be desirable. As the most adjusted method, and the one which has been most commonly validated in outcome literature, eKt/V appears to be optimum, and we have therefore given dose targets in terms of eKt/V. Equivalent targets using other methods may be derived for individual patients depending on their dialysis duration and fluid removal. The literature on clinical outcome at different doses of dialysis is dominated by two randomised studies. The National Cooperative Dialysis Study (NCDS) was the landmark study which led to the concept of a threshold dialysis dose above which treatment was adequate, as well as the establishment of Kt/V as the accepted index of dialysis dose. Reporting in 1981, the study randomised 151 patients in a 2x2 design to high vs low time-averaged urea, and short vs long dialysis duration -the key finding was a lower rate of treatment failure (death or hospital admission) in the low urea (high dialysis dose) group. When reanalysing the group with the newly proposed Kt/V measure, a clear threshold effect appeared, with Kt/V defining the watershed between 'adequate' and inadequate dialysis (Kt/V over vs under 1.0). A large number of observational studies subsequently reported an association between higher dialysis doses (beyond merely achieving the NCDS threshold) and improved survival, and this was tested in the HEMO study. Reporting in 2002 the HEMO study randomised 1846 patients in another 2x2 design to high vs standard dialysis dose (eKt/V 1.45 vs 1.05) and high vs low flux. Over 2.8 years followup with groups well separated in terms of achieved eKt/V (1.53 vs 1.16), higher dose provided no benefit in terms of survival or a number of secondary endpoints. The basic concepts of these studies have not been superseded, hence the recommendation for dialysis dose (eKt/V > 1.2) is based largely on the eKt/V achieved in the standard dose group of the HEMO study. Alternative measures such as URR or spKt/V may be more familiar to some clinicians and equally useful for the majority of patients. Equivalent thresholds using these parameters are approximate since they vary between patients, but the differences are small: Appendix 1 summarises the mathematics behind these concepts. Whether 'adequate' dialysis is the same for all patients or whether dose should be individualised is unclear, but the latter view is supported by several studies suggesting that gender and body size may affect the optimum dialysis dose. Observational studies suggest that dialysis dose is more strongly related to survival in women than men, and when the HEMO study analysis is restricted to women, the high dose group show significantly improved survival. The reason for this interaction between gender and optimum eKt/V is unknown, but may be due to the scaling parameter 'V', which is lower in women and in less muscular patients, and is an independent predictor of survival. Alternative scaling factors such as body surface area, have been suggested, but none is in widespread use, and the collinearity between different body size parameters makes analyses difficult to interpret, but it seems likely that the optimum Kt/V may be higher than 1.2 in women and smaller patients, without a clear definition of 'small'. ## Dialysis time The optimum treatment duration for thrice weekly haemodialysis is slightly less clear, since it is difficult to separate the effect of treatment time from dialysis dose. The evolution of dialysis technology has made dialysis dose targets achievable over short dialysis sessions. However, there are uraemic solutes other than urea, such as phosphate and β2-microglobulin, which are also important predictors of outcome, and which are inefficiently removed by dialysis. Extending dialysis duration increases the removal of these highly sequestered and larger molecules, independent of any change in small solute clearance. In the other part of its 2x2 design, the NCDS study also compared session duration (4.5-5.0 vs 2.5-3.0 hours) and although standard significance 'level' was not achieved (p=0.06), showed reduced treatment failure in the longer session group. Most observational studies also report improved outcomes with longer treatment times. Low mortality rates were reported from Tassin with 8 hour overnight dialysis, attributed to improved blood pressure control and slower ultrafiltration, and lower mortality is associated with longer treatment times in national registry studies (over vs under 3.5 hours in US patients, and over vs under 4.5 hours in Australia. The international DOPPS study examined the effect of treatment time whilst controlling for confounders using standard regression and instrumental variable approaches, concluding that patients with the longest treatment time (at least 4 hours) had the lowest risk for all-cause and cardiovascular mortality. Other clinical markers such as blood pressure, anaemia and phosphate control were also improved. Whilst recognising the limitations of observational studies, a minimum duration for optimum dialysis clearly exists, and is most likely close to 4 hours, at least for patients with minimal residual kidney function. A duration threshold may lead to higher than minimum eKt/V in smaller adult patients, which is appropriate since optimal Kt/V may be higher in this group. ## Summary Optimal outcomes in patients on thrice weekly dialysis are achieved with sessions of at least 4 hours, providing eKt/V at least 1.2. Regular monitoring is strongly recommended, and this occurs monthly in the majority of units. Under achievement may be addressed by attention to vascular access, session duration, blood or dialysate flow, dialyser efficiencyor anticoagulation, and in some patients under achievement may suggest the need for an augmented schedule. Achievement of these targets does not guarantee optimal outcome, with eKt/V being unaffected by missed sessions, for example. These dose targets apply to thrice weekly patients, with minimal residual function, for whom survival duration is a primary treatment goal. There are specific clinical scenarios and different patient values for which it may be appropriate to adjust or disregard numeric targets for dialysis dose. Non-standard schedules (Guidelines 2.1 -2.4) Guideline 2.1 -Augmented schedules We suggest offering an augmented schedule to patients who are unable to achieve adequacy targets or fluid control on a standard thrice weekly schedule. We suggest that relative contraindications to augmented schedules should be considered, such as significant residual function or problematic fistula access. ## [2c] Rationale Dialysis dose on a thrice weekly schedule is limited by patient tolerance and the necessity to utilise 'slots' efficiently, so that sessions over 5 hours are very uncommon. 'Augmented' in this guideline refers to increased frequency (4-6 sessions per week) or thrice weekly dialysis totalling more than 15 hours per week. The latter is usually delivered nocturnally when in-centre, but both are often delivered in the context of home haemodialysis where much of the evidence regarding augmented dialysis schedules has been obtained. Augmented schedules have been assessed in four randomised studies, one interventional study with matched controls, and a handful of observational studies. Evidence of clinical benefit limited to interventional studies is summarised below, with studies divided into three groups for ease of discussion, according to the type of augmented schedule. A fourth group of augmented schedules which might be termed 'modestly frequent' (4 or 5 sessions per week, of up to 4 hours each) is poorly represented in studies. Where assessed, improvements in depression, cognition or anaemia parameters were generally not seen in these studies, although improvements in these aspects have been reported in a number of observational studies. Quality of life is an important outcome since the intervention clearly involves increased treatment burden. Observational studies suggest that quality of life of life is improved in daily dialysis by approximately 6%, whereas nocturnal schedules have not been show to improve quality of life. The randomised studies were not designed primarily to assess mortality within the study period, but two of these published mortality results with follow-up extended by approximately 2.5 years, and mortality effects have also been reported in other types of study. Findings have been surprisingly inconsistent, however, and are summarised in the table below. Authors stress that clinical trials of more intensive dialysis were not designed to evaluate mortality, and that observational analyses often employ statistical techniques which do not adequately address the timevarying nature of the risk factors associated with both the initiation of augmented dialysis and mortality. The larger randomised trials of augmented schedules have also identified potential harms, for example reducing residual function, an important determinant of survival on haemodialysis. In patients who had significant residual function at enrolment, both frequent nocturnal and short daily dialysis led to a more rapid decline in function compared to control groups. Intervention patients had a shorter time to first vascular access intervention, and there were small increases in the burden on carers, as perceived by patients, though the authors highlight that carers themselves were not assessed. Taken together these studies suggest equivalent mortality and modest improvement in some dialysisrelated conditions, offset by increased treatment burden and possible harms to vascular access and residual function. Whilst there is no overall advantage for the average patient these studies do suggest specific groups who would be expected to benefit. For example, adequacy targets could certainly be achieved in those still unable to, despite a reasonably long thrice weekly schedule. Similarly, patients failing to achieve fluid control are likely to benefit from an increase in dialysis frequencythis might include those with resistant hypertension, intra-dialytic hypotension, and those with weekend admissions to hospital. The latter group are the obvious contributors to the excess mortality of the two-day dialysis gap, and may have the most to gain from an increase in dialysis frequency. The augmentation of dialysis in these settings should be aimed at achieving a specific purpose, and it is likely that a fourth session per week would be sufficient in many cases. In conclusion, augmented schedules offer no clear advantage for the majority of patients, but should be considered as a treatment option for those patients whose adequacy or fluid control targets are not met with a standard schedule. A modestly augmented schedule would be sufficient in the majority of these patients. ## Guideline 2.2 -incremental schedules We suggest that lower haemodialysis dose targets may be optimal in patients with significant residual renal function. We recommend that residual renal function should be quantified intermittently in patients on incremental dialysis schedules. [1D] ## Rationale Incremental haemodialysis is based on the common sense concept that the amount of dialysis required for optimal outcome differs between those with significant residual function and those without. The latter group however is larger, and makes up the majority in studies of dose and outcome, which therefore may not be applicable in the former group. Optimal dialysis dose is therefore not fixed but dependent on the level of residual kidney function, and the prescribed schedule may therefore be reduced in frequency or dose in this setting. The practice of incremental haemodialysis is consistent with a concept of progressively increasing therapy over time, which may include augmented schedules at a later stage. Less frequent and reduced dose dialysis practices coevolved along with standard thrice-weekly schedules: reference is made to twice weekly dialysis in observational studies from the 1990s and in the 1997 KDOQI guidelines. For example, in an observational study of 15 000 American patients published in 1999, Hanson reported twice weekly schedules in 6.1% of patients during their first year, and 2.7% of patients thereafter. Outcomes were at least as good, and in fact a mortality advantage was observed with twice weekly schedules, most likely due to differences in baseline factors: no mortality difference was seen after adjustment for the level of residual function at dialysis initiation. The non-inferiority of twice weekly schedules in selected patients has been further supported by more recent studies. In a Thai study of 500 twice-weekly patients Panaput reported equivalent mortality and hospitalisation over the next year, and in a propensity-matched Korean study of 300 patients followed for one year, Park reported equivalent mortality and improved quality of life with schedules less than thrice-weekly. Non-inferiority of clinical outcome with reduced treatment burden therefore provides a powerful argument in favour of incremental schedules, but additional benefits may exist: incremental haemodialysis schedules have also been associated in some observational studies with reduced decline in residual kidney function. Preservation of residual function is of clinical importance since it provides significant solute and fluid removal, and is associated with improved quality of life and survival. The literature on incremental schedules is limited in particular by its observational nature, with inherent problems of selection and lead-time bias. Variation also exists in the definition of incremental dialysis, which is frequently defined as twice-weekly, without reference to residual function. Clinician bias may also be important: clinicians working in the 1990s will remember twiceweekly schedules principally as a resource-sparing exercise, and even in modern series, financially constraints play a part in their use. Patient selection is therefore crucial: factors currently associated with reduced schedule use in a large Chinese study include early vintage, female sex and minimal comorbidity. And the level of residual function appears perhaps unsurprisingly to be the most important factor: in a large American study in which 350 twice-weekly patients were matched with a thrice-weekly group, twice-weekly schedules yielded equivalent one year outcome in many, but were clearly inferior in those with the poorest residual function (clearance less than 3ml/min/1.73m2). Those with residual clearance of 3ml/min or less may still be suitable for a thrice-weekly incremental schedule (i.e. with dose target less than Kt/V 1.2 and/or less than 4 hours). The use of incremental haemodialysis therefore requires regular monitoring of residual function, with function reassessed after major intercurrent illness. Suitable patients should be aware that dialysis duration is likely to increase over time, and should be willing to cooperate with residual function measurements. Incremental dialysis is entirely consistent with the concepts of adequate dialysis dose established in the NCDS and HEMO studies as discussed in Section 1, but incorporates the contribution of residual function, so that dialysis and residual function are seen as both contributing to overall clearance. There are a number of different methods for quantifying combined kidney and dialysis urea clearance (summarised in Appendix 2) which can help with schedule and dose selection. These should be interpreted in clinical context, with due observation of indirect measures of dialysis adequacy such as control of symptoms, blood pressure, fluid gains and electrolytes, so that dialysis dose can be appropriately escalated if treatment appears clinically inadequate. ## Guideline 2.3 -conservative schedules We suggest that lower haemodialysis dose targets may be optimal when quality of life is the primary goal of treatment, rather than longevity. [2D] ## Rationale Whilst concepts of dialysis dose have been developed over the last two decades, the dialysis population has been changing, with the median age of the prevalent dialysis population increasing by nearly 20 years, and diabetes becoming one of the leading causes of established kidney failure. For many patients, dialysis is a long-term maintenance therapy that continues until death or dialysis withdrawal, with increasing comorbidity and frailty developing during this time. This changing demographic has important implications for the clinical application of dialysis dose. Firstly, studies have typically focused on younger patients (median age 49 in the NCDS study including no diabetics, and mean age 58 in the HEMO study) so that applying their conclusions in a more elderly group is an extrapolation. Secondly, studies are generally more concerned with mortality, and many strategies in dialysis are aimed at preventing future complications, whereas current symptoms and quality of life are often more relevant to the frailer patient. And thirdly, the burden of dialysis often increases with increasing frailty, so that there is a greater trade-off when considering the burden versus the benefit of treatment. In the context of this changing demography, it is reasonable to question whether conventional dialysis dosing and targets remain appropriate for this population. Frailty as a clinical syndrome can be defined when a number of factors are present including: unintentional weight loss, self-reported exhaustion, weakness and low physical activity. The presence of frailty is associated with increasing disability and hospitalisation, and in dialysis patients, with an adverse quality of life irrespective of dialysis modality. The optimum dialysis for frail patients has only been studied in small cohorts. Some overlap exists between the features of frailty and those of underdialysis, and it could be argued be that more intensive dialysis might better control some aspects such as fluid overload, intradialytic hypotension or sarcopenia, or conversely that nutritional decline might be accelerated by reduced dialysis. Reductions in dialysis quantity should therefore not be misunderstood as a method of improving these aspects of frailty. However, while increasing hours or frequency of dialysis may theoretically overcome some of these problems, patients often perceive the burden of dialysis on their quality of life more than the symptomatic benefit, and dialysis itself may confer specific harms in this group: a retrospective study identified frequent functional deterioration among dependent patients following the initiation of dialysis. In a challenging clinical area with a paucity of outcome data, it therefore seems entirely appropriate to reduce or disregard numeric targets for dialysis dose, instead individualising dialysis according to specific patient goals. Goal-oriented care is an established approach in patients with multiple co-morbidities which overcomes the problems inherent in disease-specific care processes, with discussions instead concentrating on a patient's individual aims of treatment. Shared discussions about dialysis schedule, driven by patient-centred goals can ensure that patients are neither under or over-treated, and in some cases might be a precursor to dialysis withdrawal. Such discussions may need frequent review following changes in the patient's clinical or personal circumstances. ## Guideline 2.4 -paediatric schedules In children and adolescents we recommend an approach to the assessment of dialysis adequacy which goes beyond biochemical targets, incorporating clinical goals such as growth, bone health, cardiac function and quality of life. [1C] We recommend targeting dialysis dose to achieve a minimum eKt/V of 1.2 for thrice weekly patients, or a standardized Kt/V of 2.2 for those on augmented schedules. We suggest an augmented schedule for children on predominantly liquid nutrition, and those with ventricular systolic dysfunction. [2D] We recommend a blood flow rate of 5-7ml/kg/min for the majority of patients, using consumables appropriate to body size, with extracorporeal volume less than 10% of the patient's blood volume. [1C] ## Rationale The low incidence of dialysis-requiring kidney disease in childhood, means that many treatment decisions are informed by observational data and studies carried out in adults. The small-solute dose target for adults (eKt/V over 1.2) therefore has some relevance to children, though cautious interpretation of a target extrapolated from a different clinical setting would lead many clinicians to aim for a more conservative (i.e. higher) target dose. In addition, unique physiological aspects of childhood, such as growth, may be improved by increased dialysis dose, and there are strong arguments to suggest that optimum Kt/V may be size-dependent in adults, so that a higher minimum Kt/V may be appropriate. The desirable lower limit for eKt/V is therefore thought to be between 1.2 and 1.4. However, as is increasingly recognized now in adults, it has long been argued that the optimal quantity of dialysis for children cannot be characterized by a single numerical measurement. In addition to the desirable clinical outcomes shared with adults, the therapeutic goals for children and adolescents receiving dialysis include achievement of normal growth, bone maturation and social development, along with avoidance of cardiac compromise and disrupted education. The increasing evidence that dialysis dose and schedule is able to improve cardiac function and outcomes in many of these domains argues for a broader concept of "adequacy" which might best be assessed using a constellation of clinical outcomes, as well as biochemical targets. Augmented dialysis, with increased frequency in particular, is therefore increasingly advised by clinicians, and despite the obvious drawback of treatment burden, does not seem to reduce quality of life, even in adolescents. It is possible that augmented schedules are optimal for all children, but some groups seem particularly likely to benefit, including those with cardiac dysfunction and those on a liquid diet, in whom it might otherwise be difficult to achieve safe fluid control. Safe limits appropriate to body size are advocated for many aspects of the extracorporeal circuit, such as a blood flow rate of 5-7ml/min/kg, which is often adequate to achieve dialysis dose with double needles, with arterial aspiration pressures below 200mmHg, to limit endothelial trauma. For single-needle dialysis the highest blood flow rate is obtained using a double pump system (venous flow higher than arterial) monitored by pressure (time pressure regulation), with clamp techniques used to achieve an acceptable compromise between recirculation and blood flow. Consumables appropriate to body size should be selected so that total extracorporeal volume is less than 10% of blood volume, to reduce the volume load with wash-back at the end of the session. System priming with albumin or even blood may sometimes be required for babies and small infants. ## Guideline 2.5 -schedules during pregnancy We recommend counselling women of reproductive age who are receiving or anticipating dialysis, so that they are aware of the interactions between renal replacement therapies and pregnancy which may impact on family planning and modality decisions. For dialysis patients wishing to continue their pregnancy, we recommend changing as early as possible to an individualised, augmented haemodialysis schedule. For those with minimal residual function this should be at least 20 hours per week, delivered over at least 6 sessions. We recommend an individualised dialysate prescription appropriate to the dialysis schedule and biochemistry results, anticipating the frequent need for a high potassium / low bicarbonate dialysate, supplemented with phosphate. We suggest an individualised fluid management protocol, with low ultrafiltration rates and regular clinical assessment, anticipating the typical change in weight during pregnancy. [2C] ## Rationale Successful pregnancies in women on haemodialysis are becoming more common: prior to 1995 data from the USA suggested only 40% infant survival, but outcomes in the current era are substantially better. However, pregnancy complications in haemodialysis patients are still more common than in pre-dialysis and transplant patients, and may result in HLA sensitisation, so delaying until after transplantation may be favourable for some. Conception may be more likely with augmented dialysis schedules, but the possibility of pregnancy or need for contraception should be considered regardless of dialysis schedule. The literature linking haemodialysis prescription to outcome in pregnant dialysis patients is limited to case series and systematic reviews. In a recent metaanalysis of 681 pregnancies in 647 patients between 2000 and 2014, authors found that longer weekly dialysis duration significantly associated with a lower incidence of preterm delivery and babies small for their gestational age. More frequent dialysis was also associated with fewer small babies. Normalisation of biochemistry and fluid status appears to give the best outcome, and virtually every publication advocates intensified dialysis. The best evidence for this approach to date is the comparison of data from the Toronto and US registries of pregnancy in dialysis patients. In women established on dialysis before becoming pregnant, 11 of 13 pregnancies were successful with at least 36 hours per week, compared to 22 of 46 with up to 20 hours (p= 0.02). More intensive dialysis was also associated with reduced preterm delivery and greater birth weight. Residual kidney function facilitates normalisation of fluid and electrolytes, so the accelerated loss of residual function seen with augmented schedules raises concerns about this approach in women with good urine output. In the Toronto/US registry study all of the 17 women who started dialysis partway through the pregnancy had a successful outcome. Since 13 of them were in the shorter treatment group, it appears that longer treatment times would have been unnecessarily burdensome, and possibly detrimental, to patients with significant residual function. In a comprehensive review Hladunewich suggested titrating the dialysis dose to achieve urea 10-15mmol/L after the longest break between sessions. The authors also provide advice on adjusting medication, anaemia management and fetal monitoring which are outside the scope of this guideline. With augmented schedules dialysate should be individualised, with high potassium / low buffer often required. To ensure the needs of foetal skeletal development are met, low serum calcium and phosphate should be avoided, which may involve adjustment of diet, medication and dialysate: supplementation of the dialysate with phosphate is often necessary. Magnesium should possibly be monitored in the third trimester, since low levels may induce uterine contraction. Augmented schedules allow patients with minimal residual kidney function to remain close to their target weight and avoid high ultrafiltration rates. Fluid status needs to be assessed frequently during pregnancy, as there is a high risk of fluid depletion, especially in the second and third trimester, and bioimpedance and urine volume may be useful measurements in this setting. Typical weight gains during a healthy pregnancy range from around 150g/week during the first trimester, to around 450g/week during the third trimester. ## Membrane flux and haemodiafiltration We recommend that patients with minimal residual function should be treated with high-flux dialysers. We suggest that haemodiafiltration may be considered as a treatment for intra-dialytic hypotension refractory to other measures, and for dialysis patients with favourable prognosis who are unable or unlikely to be transplanted. [2B] ## Rationale Convective clearance Haemodialysis removes uraemic toxins by two very different physical processes: diffusion and convection. Diffusion is the movement of solutes independent of solvent when the concentration differs between the two sides of a membrane. The rate is dependent on the concentration difference, the diffusion coefficient of the membrane, as well as the blood and dialysate flows, and this process is extremely efficient for small solutes, such as urea. Convection is the movement of those solutes not excluded by pore size, along with their solvent as it crosses the membrane. The rate depends on molecular size and the ultrafiltration rate, and this process is most important for molecules too large for efficient diffusion, but still smaller than the membrane pores, often termed 'middle molecules'. Convective clearance is therefore a measurable component of dialysis, which is qualitatively and quantitatively distinct from urea clearance and treatment time. Diffusion of a solute is usually quantified by its Kt/V (Appendix 1) whereas convection is best quantified by its sieving coefficient and the ultrafiltration rate (Appendix 3). Ascending quantities of convection are therefore achieved with low-flux dialysis, high flux dialysis, and haemodiafiltration. Historically low-flux dialysis was standard, in part because it requires less accurate ultrafiltration control from the dialysis machine -ultrafiltration in standard low-flux dialysis is simply equal to the fluid removed from the patient, usually around 2 litres. In high-flux dialysis pore size is increased, increasing the sieving coefficient for middle molecules, but also the permeability to water is improved, so that internal filtration (bidirectional movement of water within the dialyser) becomes significant: net ultrafiltration of course remains the same, but total ultrafiltration, all of which contributes to middle molecule clearance, is greater and may be as much as 10 litres. In haemodiafiltration a large volume of replacement fluid is given, to allow net ultrafiltration to be increased to around 20 litres (Appendix 3). There is little difference in clearance of small solutes between these methods. Of the (over 100) uraemic toxins known, many are middle molecules (with molecular weight in the range 0.6-60kDa) for which clearance is largely dependent therefore on convection. Convective quantity does not improve clearance of all poorly-diffusing molecules, with phosphate clearance for example, largely unaffected, but clearance of many, such as β-2microglobulin, is progressively increased by high-flux dialysis and haemodiafiltration. A contribution of convective dialysis quantity to favourable outcome is strongly suspected. Membrane flux Several interventional studies give insight into the impact of membrane flux on dialysis outcomes, for example in the other part of its 2x2 design, the HEMO study group compared high-flux with low-flux dialysis. In the whole group (N=1846) high-flux dialysis did not confer a clear survival advantage (RR 0.92, 95%CI 0.81-1.04) although cardiac mortality was reduced (RR 0.80, 95%CI 0.65-0.99). In the roughly one-third (N=577) of patients with over 3.7 years dialysis vintage prior to randomisation, high-flux dialysis improved survival substantially (RR 0.68, 95%CI 0.53-0.86). The Membrane Permeability Outcome study randomised 738 incident patients to high vs low-flux dialysis, stratified by serum albumin (normal vs subnormal). Over a mean observation of 3 years, high-flux dialysis reduced mortality in the low albumin group (N=493, HR 0.63, 95%CI 0.45-0.90) with a less clear reduction in mortality in the whole group. High-flux was similarly advantageous in the subgroup with diabetes. A meta-analysis of 33 studies comparing high-flux with low-flux dialysis in 3820 patients, found reduced cardiovascular mortality (RR 0.83, 95%CI 0.70-0.99) and a less clear reduction in all-cause mortality (RR 0.95, 96%CI 0.87-1.04). Endotoxin tends to be absorbed within high-flux membranes, rather than passing through, and initial concerns that dialysate endotoxin would be more problematic with high-flux dialysis appear to have been unfounded. Whilst no study has unequivocally demonstrated the superiority of high-flux dialysis for survival, there is clear evidence of improved cardiovascular outcomes, and allcause mortality appears to be improved in several subgroups. At the same time, evidence of harm is lacking, all modern machines have accurate ultrafiltration control, and membrane costs are now equivalent. Further research on this question therefore does not seem to be a high priority. Haemodiafiltration The effect of haemodiafiltration has been informed by four randomised controlled studies, summarised in the table below. In three of these, marginal but non-significant advantages were seen in the haemodiafiltration group, with subgroup analysis suggesting favourable outcome with the highest convection volumes, though the latter to some extent may reflect body size or treatment tolerance. A clear advantage with haemodiafiltration was seen in the ESHOL study, which specified a higher convection volume of 23 litres, but consequently may be confounded by subjects' ability to sustain these volumes, which is dependent on high blood flow, so that censoring may be most frequent in the highest risk patients. Apart from the CONTRAST studythese were all analysed 'as treated', with right-censoring when treatment was discontinued for any reason, leading to potential bias since endpoints are more likely to be hidden in the haemodiafiltration arm. Another criticism concerns the mechanism of the clinical benefit, since middle molecule levels were not demonstrably improved by haemodiafiltration: plasma levels of β-2-microglobulin increased significantly in both arms of the ESHOL study. Reduced mortality with haemodiafiltration was observed with pooled analysis of the four studies (HR 0.86, 95%CI 0.75-0.99) due in particular, to a reduction in cardiovascular events, with authors estimating the prevention of one cardiovascular death for every 75 patient-years of treatment. However, due to biases within study designs, considerable doubt over the superiority of haemodiafiltration remains. Haemodiafiltration was also assessed in a DOPPS study, in which after adjustment, no association between convection volume and survival was observed. Several of these studies also found a lower frequency of intradialytic hypotension with haemodiafiltration compared to the control group, though the authors acknowledge the difficulty in excluding confounding factors such as cooling and positive sodium balance. We suggest a multidisciplinary approach to fluid assessment, with patient involvement and the adoption of patient-friendly terminology such as "target weight", "fluid gain" and "over-hydration". [2D] We suggest supplementing clinical assessment of fluid status with a validated objective measurement, such as bioimpedance, at regular intervals, when clinical assessment is unclear, and following an intercurrent illness. [2C] We recommend a dialysate temperature not greater [formula] than 36'C if standardised. [1C] [/formula] We recommend avoiding excessive ultrafiltration rates by addressing fluid gains, accepting staged achievement of target weight, or using an augmented schedule, as necessary. [1B] We recommend prompt nursing intervention to restore haemodynamic stability in symptomatic / severe intradialytic hypotension, with such interventions leading to clinical review. ## [1c] Rationale Fluid control is an essential clinical goal of maintenance haemodialysis, but correct fluid management requires clinicians to steer between the two competing / overlapping problems of fluid overload and intra-dialytic hypotension. Failure to control fluid overload may lead to obvious short-term effects including hypertension and breathlessness, and nephrology trainees quickly become familiar with the emergency dialysis admission with pulmonary oedema. In the longer term also, chronic fluid overload is one of the main drivers of hypertension and is independently associated with poor outcomes: for example, in a US study of over 10 000 prevalent haemodialysis patients, Flythe reported clinical outcomes over 2 years' follow-up, according to achievement of target weight during the baseline month. Compared to those achieving within 2kg of target weight on at least 70% of sessions, the 15% of patients frequently remaining over-hydrated post dialysis had increased mortality (HR 1.28, 95%CI 1.15-1.43) as did the 7% of patients who were frequently under-hydrated post dialysis (HR 1.22, 95%CI 1.05-1.40). Often competing, though sometimes associated with fluid control, is intra-dialytic hypotension, which also has immediate consequences familiar in the dialysis unit, including dizziness and cramps, as well as more longterm adverse effects. For example, Sands studied the occurrence of intra-dialytic hypotension (defined as a drop in systolic blood pressure of at least 30mmHg, to below 90mmHg) in 1137 patients in 13 dialysis facilities, over an average period of 3 months. With this definition, hypotension complicated 17.2% of sessions, affecting 74.9% of patients at least once, and 16.2% of patients on at least one third of their sessions. Those most prone to intra-dialytic hypotension were older, more comorbid and with lower pre-dialysis blood pressure, with associated sessional factors including high ultrafiltration volume and non-achievement of target weight. Outcomes associated with intra-dialytic hypotension included shortened survival and increased hospital admission. The two main treatment parameters by which clinicians aim to optimise fluid control, are target weight and ultrafiltration rate. Since the earliest days of dialysis, setting ultrafiltration to achieve a set target weight post dialysis, at which the patient is at their correct volume (or "dry") has been the accepted method of maintaining a consistent volume state, but the method is dependent on accurate estimation of the correct target weight. Though most often assessed by clinical examination, the inaccuracy of this method is widely appreciated so that both overestimation and underestimation are common, with the former contributing to hypertension and left ventricular hypertrophy, and the latter accelerating the loss of residual kidney function and perhaps risking myocardial stunning. To improve on clinical assessment, nephrologists at one time advocated "probing" target weight: gradual reduction until patients report symptoms suggesting hypovolaemia, but this may reduce treatment compliance and a more collaborative approach is more common: where possible, patients should be asked to participate in monitoring their fluid status. To this end terminology should be simple and intuitively understood: for example, when discussing target weight, the term "dry weight" can give the impression that the aim is to remove as much fluid as possible, and "ideal weight" can be confusing as it is also used to describe the preferred body mass index. Although less accurate, "hydration" is a more familiar term than "volume" as a description of fluid status. Stable patients should be assessed for target weight changes perhaps quarterly, but staff and patients should be particularly vigilant when changes in flesh weight are likely, such as following hospital admission, or when starting nutritional supplementation. Fluid management often requires input from a multidisciplinary team, so a documented policy may ensure that the approach is consistent. Improvement on clinical assessment using objective methods for selecting target weight has been sought for a long time, though no single measurement has so far gained widespread acceptance. Methods have fallen into one of a number of categories: imaging (such as inferior vena cava diameter), biochemistry (such as brain natriuretic peptide), electrophysiology (such as bioimpedance) and dynamic intradialytic measurement (such as blood volume monitoring). Many publications address one or more of these methods, and several detailed reviews are available. Some of these studies suffer from the limitations of self-referencing design (demonstrating that the use of method X to guide selection of target weight, reduces the frequency of over-hydration as defined by method X) and improvement in clinical outcomes are often harder to demonstrate. For example, Leung studied intradialytic hypotension in 32 haemodialysis patients during 8 weeks of standard care and 8 weeks during which ultrafiltration was informed by blood volume monitoring, but no advantage was seen in terms of hypotension frequency or symptoms. No clear recommendation can be made regarding the optimal method, but when clinical assessment feels uncertain, it seems very reasonable to supplement this with an objective measure, and bioimpedance has some of the most promising data on clinically relevant endpoints. In a randomised study of 156 patients, Nur used bioimpedance data to adjust target weight in the intervention group, whilst control patients had bioimpedance measured but not available to treating physicians. Over the 12 month study, bioimpedancedefined fluid overload was reduced in the intervention group, as was blood pressure and left ventricular mass index (131±36 to 116±29g/m 2 , p<0.001). Regardless of the final volume achieved, the rate of ultrafiltration appears separately to influence intradialytic hypotension and clinical outcome. In a DOPPS study of 22 000 patients in 7 countries, Saran observed that an ultrafiltration rate over 10ml/h/kg was associated with both intra-dialytic hypotension (RR 1.30, p=0.04) and mortality (RR 1.09, p=0.02). And using data from the HEMO study (N = 1846) Flythe divided patients according to ultrafiltration rate into three groups: less than 10, 10-13, and over 13ml/h/kg, demonstrating increased mortality in the highest ultrafiltration rate group (HR 1.59, 95%CI 1.29-1.96). In the same study, when treating ultrafiltration rate as a continuous variable (using a cubic spline method) the authors identified 10ml/h/kg as the threshold beyond which mortality begins to increase, possibly quite sharply. These studies are non-interventional, therefore associations are with observed (rather than prescribed) ultrafiltration rate, and there is also a close interaction with session length (since rate is obviously the volume over the time) but these data provide a convincing argument for avoidance of excessive rates. This should not however be at the expense of non-achievement of target weight and acceptance of over-hydration (though staged achievement over a number of sessions is frequently appropriate) but rather should focus clinicians on session length or addressing fluid gains between dialysis sessions. The ultrafiltration required during dialysis depends on the degree of over-hydration present at the start of the session, so restricting fluid intake reduces ultrafiltration rate, and is part of standard advice for the majority of patients. Consideration must be given to the cause of increased fluid intake such as habitual drinking or thirst associated with either dietary sodium intake or raised blood glucose. Advice on managing fluid intake is therefore best delivered on an individualised basis, as part of a dietary management plan to support adherence and patient experience. This topic is covered in guidelines for the nutritional management of kidney disease. Other relevant aspects of the dialysis prescription include dialysate sodium and temperature. Sodium balance, thirst and fluid control are also influenced by dialysate sodium. Many observational studies report lower fluid gains and lower blood pressure in patients treated with low dialysate Na (typically 136-138mmol/l). Antihypertensive treatment is frequently overlooked in large studies, but reasonable supportive evidence can also be found in interventional studies. For example, Gumrukcuoglu reduced dialysate sodium from 140 to 137mmol/l in 41 patients over 6 months, reporting reduced fluid gains, and no blood pressure change but a reduction in antihypertensive use from 1.9 to 1.2 agents per patient. This potential benefit was not without drawbacks however: in common with other groups, investigators also found that cramps and intra-dialytic hypotension became more frequent. Lowering dialysate sodium therefore does appear to improve fluid control and blood pressure, albeit with some side effects, however another note of caution arises from observations on mortality in different dialysate sodium groups. Studying almost 30 000 patients from DOPPS phases 1-4, with dialysate sodium varying between 138 and 142mmol/l in 90% of patients, Hecking found that higher dialysate sodium was, as expected, associated with modestly increased fluid gain and systolic blood pressure (increasing by 0.17% body weight and 0.66mmHg per 2mmol/l increase in dialysate sodium). However, when addressing indication bias by studying only the 56% of facilities using a standardised dialysate sodium, they found that higher dialysate sodium was unexpectedly associated with reduced mortality (HR 0.88 per 2mmol/l increase in dialysate sodium, 95%CI 0.83-0.94). There is insufficient consistency in the literature for a clear recommendation on dialysate sodium, though if a standardised dialysate sodium is used for all patients, some clinicians would avoid a choice below 140mmol/l. Dialysate temperature has been consistently associated with intra-dialytic hypotension. Even thermoneutral haemodialysis (temperature-matched so that the dialysis circuit neither heats nor cools the patient) leads to an increase in core temperature, though it is not clear if this is due to reduced heat loss (for example due to cutaneous vasoconstriction) or increased thermogenesis (for example due to increased cardiac output). Reduced dialysate temperature has therefore been the subject of a number of interventional studies and two meta-analyses. In the most recent of these, Mustafa reported on 26 studies totalling 484 patients, observing an average 70 (95%CI 49 -89) percent reduction in hypotension, though with an increase in cold-related symptoms. Twenty-four of these studies however were either small (less than 20 patients) or of short duration (less than 3 sessions). The two largest studies provide further insight: in Maggiore's study of 95 patients over 12 sessions, isothermic (in which dialysate temperature is set so that core temperature is unchanged) rather than thermoneutral dialysis reduced hypotension from 50 to 25% of sessions. In Fine's study of 128 patients over 10 sessions, 35'C dialysate rather than 37'C similarly reduced hypotension, but the benefit was seen only in those with subnormal temperature before dialysis. Preventing temperature rise therefore appears to be more important than cooling, which may be achieved on an individual basis using dialysate 0.5 -1.0 degree lower than core temperature or in the whole unit by using dialysate temperature 36'C or lower. The latter is probably adequate for most patients, with individualisation seeming a reasonable option for those with persisting hypotension or cold-related symptoms, and it is reasonably clear that if a standardised dialysate temperature is being used, then the choice should be at or under 36'C. Regardless of the quality of dialysis prescription, intradialytic hypotension will still occur, in some patients more than others, for which prompt nursing intervention is essential. Common measures include leg raised positioning, ceasing ultrafiltration, and fluid administration (saline being as good as albumin and far cheaper. Measures for "simple" intra-dialytic hypotension should be coupled with assessment for underlying intercurrent illness (such as infection or cardiac arrhythmia) or less commonly a specific dialysis complication (such as air embolism or dialyser reaction). Frequent intervention should lead to reassessment of target weight / ultrafiltration setting and a medication review -in some cases predialysis hypertension may be preferable to dialysis intolerance. Specific pharmacological measures are rarely used but the alfa-agonist Midodrine has reasonable supportive evidence: in meta-analysis the average improvement (increase) in systolic/diastolic post-dialysis blood pressure was 12.4/7.7mmHg. ## Guideline 4.2 -paediatric fluid considerations In growing children we recommend clinical assessment of fluid status and target weight, and dietetic assessment, at least monthly. We suggest supplementing clinical assessment with a validated objective measure of fluid status such as bioimpedance, on a monthly basis or more frequently during periods of rapid growth or illness. [2C] We recommend regular assessment of ultrafiltration tolerance, using extended times to avoid excessive ultrafiltration rates. ## [1d] Rationale Assessment of target weight in children and adolescents is particularly challenging as it needs frequent adjustment in line with growth or periods of illness. This is particularly true for infants and adolescents during rapid phases of growth. Overestimation of target weight will result in chronic fluid overload leading to hypertension and left ventricular hypertrophy, whereas chronic under-hydration is likely to detrimentally affect residual kidney function and lead to increased symptomatic hypotension both during and immediately postdialysis. Hypotensive tendency is also multifactorial and cannot alone be relied on to ascertain a patient's target weight. It is therefore essential that target weight is adjusted at least on a monthly basis following clinical assessment, in conjunction with dietetic review. ## Dialysate (guidelines 5.1 -5.4) When the 2 nd edition of the RA Guidelines was published in 1997, the only recommendation relating to the composition of the dialysate was that renal units phase out the use of acetate in favour of bicarbonate buffering, since the improved efficiency of dialysis could overwhelm the capacity to metabolise acetate. The need to keep bicarbonate separate from divalent cations to prevent precipitation meant that dialysate had to be produced using two different concentrates, leading to the modern proportioning system in which sodium bicarbonate is mixed with an electrolyte concentrate ('acid concentrate') at the point of use, allowing independent control of most dialysate constituents. Some dialysate constituents have diversified whereas others have gradually become standardized. Dialysate calcium was often supra-physiological in the 1990's (around 1.75mmol/L) to prevent hypocalcaemia, but this became unnecessary with increasing use of vitamin D analogues and calcium-containing phosphate binders, so that dialysate calcium has become reasonably standardized, usually in the range 1.25-1.50mmol/L. Non-standard dialysate calcium may sometimes be helpful, for example in the context of calciphylaxis, but this is usually driven by bone-mineral considerations and is outside the scope of this guideline. In the 1990's, dialysate was usually glucose-free due to cost and microbiological concerns, and hypoglycaemia was often a problem for diabetic patients. Glucose containing dialysate was initially prescribed for diabetic patients, but extended to all as costs improved, so that a dialysate glucose of 5.5mmol/L is now standard in almost all UK dialysis units. The other constituent of dialysis that has become standardised is magnesium, with low (usually 0.25 or 0.375mmol/L) or high (usually 0.75mmol/L) magnesium being replaced by a dialysate magnesium of 0.5mmol/L, close to the lower end of the normal range. Opposing these trends, there has been significant diversification in dialysate potassium, and similarly, buffer concentrations and practices vary between units and manufacturers, and are discussed below. ## Guideline 5.1 -selection of dialysate potassium We recommend an optimal pre-dialysis serum potassium in the range 4.0-6.0mmol/L, remembering to consider measurement errors (e.g. due to haemolysis) when interpreting levels. [1B] We suggest choosing dialysate potassium between 1.0 and 3.0mmol/L for the majority of patients, using an individualised approach, in general using the highest dialysate potassium that is sufficient to control predialysis hyperkalaemia. [2C] We suggest a combined approach to managing hyperkalaemia, which may include decreasing dialysate potassium and/or other measures, including dietary advice, medication review and increased dialysis frequency. [2D] ## Rationale Historically, it was often difficult to remove the potassium accumulated between dialysis sessions, so dialysate potassium between zero and 2mmol/L was common. The requirement for dialysate with potassium levels that are close to, or within, the normal range reflects the increased efficiency of modern dialysis and the increased age of the modern patient. In most units dialysate potassium is determined by the choice of acid concentrate: zero potassium is no longer used, and suppliers offer concentrates with potassium between 1 and 4mmol/L. Removal of accumulated potassium by intermittent haemodialysis inevitably leads to a fluctuating profile of serum potassium with a risk of cardiac arrhythmias at both high and low concentrations. This probably contributes to the clustering of sudden cardiac death around the peridialytic period, and at the end of the weekend gap. Both low and high pre-dialysis potassium are associated with increased mortality, so that the mortality curve is U-shaped. Low potassium often appears more harmful in unadjusted data: for example, in a study of 483 Taiwanese patients followed from 2004 to 2008, Hwang showed that those with pre-dialysis potassium below 3.5mmol/L had more than twice the risk of mortality than those with higher levels. But this link may be due to confounding by comorbidity malnutrition: in a much larger study of 74219 patients between 2001 and 2004, a U-shaped risk curve was seen, with increased mortality with pre-dialysis potassium outside the range 4.3-5.6mmol/L. After adjustment for case mix and malnutrition parameters however, the increased risk of mortality remained only for the high potassium patients (though the less than 4.0mmol/L category was not subdivided). The optimum pre-dialysis potassium therefore appears to be above 4.0 with an upper limit between 5.6 and 6.0mmol/L, though the broader range seems more appropriate given the considerations below. The relationship between post-dialysis potassium and mortality is unknown, as it is rarely measured, but the risks of post-dialysis hypokalaemia can be inferred from studies of dialysate potassium. For example, Pun compared 502 patients who experienced sudden cardiac arrest in dialysis units between 2002 and 2004, with 1632 age and vintage matched controls, finding that risk was doubled if the patient last dialysed with a low dialysate potassium (less than 2.0mmol/L). The DOPPS review of modifiable practices associated with sudden death included 36235 patients in 12 countries of whom 6606 were dialysed with dialysate potassium at least 3.0mmol/L. An increased risk of sudden death was observed with dialysate potassium below 3.0mmol/L (HR 1.17, 95%CI 1.01-1.37), though it was not clear if this risk extended to those with predialysis serum potassium over 5.0mmol/L. Others have suggested that lower dialysate potassium may prevent sudden death in this subgroup, but the latest DOPPS analysis found no meaningful difference in mortality or arrhythmia events between patients treated with dialysate potassium of 2.0 or 3.0mmol/L. The understandably strong impulse to control predialysis hyperkalaemia should therefore be tempered by consideration of the less visible risk of post-dialysis hypokalaemia. Pragmatically therefore one can conclude the following general principles: Firstly, pre-dialysis hyperkalaemia should be controlled, though an overly tight range may be counterproductive, so the previously recommended target for pre-dialysis potassium still seems optimal (4.0 -6.0mmol/L). Caveats to interpreting this range should be noted: firstly, achievement of pre-dialysis potassium within this range does not necessarily mean that dialysate potassium is optimal, and secondly, consistent adherence to treatment is most likely just as important as specifics of the potassium range or dialysis prescription. Secondly, non-dialysate approaches to hyperkalaemia may sometimes be more favourable. Dietary reduction may be preferable if it can be achieved without an adverse effect on protein-calorie intake, and other dialysis changes may be appropriate, such as increasing blood flow, duration or frequency. Consideration could also be given to potassium binding resins. Thirdly, lower dialysate potassium does increase the removal of potassium during each session, and based on the risk of arrhythmias due to hyperkalaemia, dialysate potassium should be reduced if other measures are not possible or successful. However, dialysate potassium should be no lower than is necessary to achieve this goalindividualization does therefore seem necessary, so that each patient uses the highest dialysate potassium which still controls pre-dialysis hyperkalaemia. This pragmatic approach has probably driven the steady increase in the use of higher potassium dialysates, and reduction in the use of concentrations below 2.0mmol/L, over the 5 DOPPS phases between 1996 and 2015. Finally, and particularly for measurements taken remote from the laboratory, the relatively high frequency of measurement errors (for example due to in vitro haemolysis) should be remembered when interpreting potassium levels. ## Guideline 5.2 -selection of dialysate buffer We recommend an optimal pre-dialysis serum bicarbonate in the range 18.0-26.0mmo/L, remembering to consider measurement errors (e.g. due to exposure to air) when interpreting levels. We suggest the term 'dialysate buffer' rather than 'dialysate bicarbonate' to avoid confusion arising from differences in manufacturers' terminology. We suggest choosing dialysate buffer below or equal to 37.0mEq/L for the majority of patients, using a standardised or individualised approach. [2C] We suggest a combined approach to abnormal predialysis serum bicarbonate, which may include increasing dialysis dose, oral bicarbonate, nutritional support, or individualising dialysate buffer. [2D] ## Rationale We suggest a combined approach to abnormal predialysis serum bicarbonate, which may include increasing dialysis dose, oral bicarbonate, nutritional support, or individualising dialysate buffer. [2D] The literature on dialysate bicarbonate is difficult to interpret due to unclear definitions when reporting the bicarbonate and additional alkali components. Most commonly the electrolyte concentrate contains a nonbicarbonate acid, to reduce the deposition of calcium and magnesium saltsacetic acid is perhaps the most common, but citric acid and sodium diacetate may also be used. When mixed to form the dialysate, acetate reacts with sodium bicarbonate to form sodium acetate, water and carbon dioxide: [formula] HC 2 H 3 O 2 þ NaHCO 3 →NaC 2 H 3 O 2 þ H 2 O þ CO 2 [/formula] The addition of 3mmol of acetic acid to a litre solution containing 35mmol of bicarbonate therefore reduces the bicarbonate concentration to 32mmol/L. In publications, bicarbonate concentration in this dialysate may variably be referred to as having a bicarbonate concentration of 32 or 35mmol/L, with the acetate content rarely reported. In addition, the bicarbonate 'setting' on machines from different manufacturers, refers variably to the bicarbonate concentration either prior to (eg. Braun) or after (eg. Fresenius) mixing with the electrolyte concentrate. The terms 'actual' bicarbonate (because that is what is actually added as sodium bicarbonate) and 'final' bicarbonate (because that is the bicarbonate in the dialysate at the point of use) are sometimes used to separate their meaning. However, the total buffer concentration remains the same before and after this mixing, so this term has a clear unambiguous meaning (equivalent to the sum of bicarbonate and acetate concentrations in the final dialysate). In a discussion of the DOPPS study of dialysate bicarbonate, Tentori observed that when asked either for the bicarbonate or total buffer concentration, most DOPPS units returned the same figure, suggesting that clinicians generally mean 'actual' rather than 'final' bicarbonate, which is the same as total dialysate buffer . The factors affecting pre-dialysis serum bicarbonate levels include protein intake, residual kidney function, interdialytic fluid gain, dialysate buffer concentration, dialysis adequacy, oral sodium bicarbonate and other alkaline medications such as calcium carbonate. Observational studies of pre-dialysis levels usually show a J-shaped mortality curve, with most of the excess risk associated with high levels of bicarbonate, but this appears to be due to the close link between high bicarbonate and malnutrition. For example, in a study of 56385 between 2001 and 2003, Wu observed a progressive increase in mortality as pre-dialysis bicarbonate increased beyond 23mmol/L, but also strong associations between higher bicarbonate and worsening markers of nutrition including albumin, phosphate and protein intake. When adjusted for comorbidity and 12 parameters associated with malnutrition, most of the increased mortality appears with low bicarbonate, at levels below 18-21mmol/L. Some guideline groups have therefore increased the lower limit for optimal predialysis bicarbonate to 20 or 22mmol/L. Post-dialysis bicarbonate is rarely measured, but three considerations argue for caution in attempting to achieve a minimum pre-dialysis bicarbonate. Firstly, the risks associated with abnormal bicarbonate are less clear and of a lower magnitude than those associated with abnormal potassium (mortality hazard ratio of approximately 1.2 for the most extreme category of bicarbonate versus 1.5 for potassium). Secondly, although it is principally low bicarbonate which carries risk, high pre-dialysis bicarbonate also appears to be harmful. Whilst much of the risk observed is attenuated by adjustment, pre-dialysis bicarbonate is still associated with increased mortality at levels above 27mmol/L. Additionally, an increased risk of peridialytic cardiac arrest has been observed with high predialysis bicarbonate: a Fresenius Medical Care memo in 2011 reported an internal case-control study of 941 patients in 667 facilities who suffered cardiac arrest in 2010. Risk was 4.7 times higher in patients with pre-dialysis bicarbonate over 28mmol/L, and 6.3 times higher if they also had pre-dialysis potassium below 4mmol/L [132]. Thirdly, high dialysate buffer is associated with increased mortality. For example, in a large study of dialysate buffer using DOPPS data (collected from 17031 dialysis patients in 11 countries between 2002 and 2011) Tentori observed a lower risk of mortality in patients treated with dialysate buffer less than or equal to 32mmol/L, regardless of predialysis bicarbonate (HR 0.90, 95%CI 0.80-1.01) and higher risk with dialysate buffer at or above 38mmol/L (HR 1.07, 95%CI 0.97-1.19). Pragmatically therefore one can conclude the following general principles: Firstly, pre-dialysis acidaemia should be controlled, though an overly tight range may be counterproductive, so the previously recommended lower target for predialysis bicarbonate still seems optimal, though the upper target could safely be increased (18.0-26.0mmol/ L). As with potassium, achievement of this range does not necessarily ensure optimal dialysis prescription. Secondly, dialysate buffer at or over 38mmol/L should generally be avoided, and the optimal dialysate buffer for the majority of patients is probably in the region of 32-35mmol/L. Thirdly, many other factors affect pre-dialysis bicarbonate, the dominant ones being nutritional state and dialysis dose, so that abnormalities of pre-dialysis bicarbonate should not lead clinicians automatically to think of adjusting dialysate buffer. High bicarbonate in particular should prompt a nutritional thought process initially. It is not clear that adjustment of dialysate buffer is a helpful strategy for optimising pre-dialysis bicarbonate, or that such an adjustment has much impact on pre-dialysis bicarbonate levels. Specific groups however, such as patients with abnormal levels despite optimal diet and dialysis strategy, may have something to gain from dialysate buffer adjustment. Conversely, increased dialysate buffer may be more hazardous in certain circumstances, such as in combination with low potassium dialysate. Whilst it is a very reasonable thing to do, and might prove to be beneficial in future studies, it is not currently clear that individualization of dialysate buffer is superior to standardization. Finally, and particularly for measurements taken remote from the laboratory, the relatively high frequency of measurement errors (for example due to carbon dioxide escape) should be remembered when interpreting bicarbonate levels . ## Guideline 5.3 -supplementation of dialysate with phosphate We suggest considering supplementation of the dialysate with phosphate in patients on augmented dialysis schedules. [2D] ## Rationale The conventional haemodialysis patient struggles to achieve sufficient phosphate removal, and historically dialysate has always been phosphate-free. Guidelines usually focus more on the upper limit than the lower limit for optimal pre-dialysis phosphate and ranges in the region of 1.1-1.7mmol/L are often suggested, with most of the emphasis on treatments to reduce phosphate -indeed, most of the Renal Association's advice on phosphate can be found in the guideline on mineralbone management. However, with demographic and treatment trends of the last decade, low phosphate is becoming more common, and since the symptoms of hypophosphataemia are non-specific, this problem may be easily overlooked. The relationship between pre-dialysis phosphate and mortality is J-shaped, with increased risk occurring at both high and low levels. But phosphate is strongly associated with age and nutritional state, so that the mortality risk associated with low phosphate is substantially (although incompletely) attenuated by adjustment for comorbidity and malnutrition. In the context of low pre-dialysis phosphate therefore, the main clinical focus should be on nutritional assessment and support. When patients are unable to consume sufficient phosphate to match intradialytic loss, supplementation of the dialysate is a logical approach to managing hypophosphataemia. The argument for supplementation is generally accepted in the context of augmented dialysis, when post-dialysis phosphate is often measured, and may be found to be very low in well-nourished patients. It is common practice, for example, to supplement dialysate with phosphate in pregnant patients receiving daily dialysis. Supplementation could also be used to prevent undesired loss of phosphate in patients on conventional regimes with low pre-dialysis phosphate that is refractory to other measures. While this does appear to be clinically helpful in case reports, data to support this approach remain limited. However, as patients with low pre-dialysis phosphate currently receive a form of dialysis which inevitably worsens this abnormality, so the instinct to 'do no harm' may be a sufficiently persuasive argument for some clinicians. Phosphate precipitates in solutions containing calcium or magnesium, so like bicarbonate, must be added to the electrolyte concentrate at the point of use, but there is currently no commercially available phosphate additive approved for use in intermittent haemodialysis. 'In house' supplementation can be achieved by adding phosphate salts to the electrolyte concentrate at the start of the session, but solutions intended for intravenous use typically contain potassium and are too dilute. Pharmaceutical grade phosphate salts in powder form can be used, but require quality assurance on storing, weighing, adding and ensuring complete dissolution. The most common method is therefore 'off label' use of solutions intended as enemas: Cleen (formerly Fleet) Enema for example, is very suitable for enriching dialysate [142], although it contains antimicrobial preservatives (benzalkonium chloride and disodium edetate) which are widely used in medical products such as eye drops, which might have adverse effects in this context. The use of Cleen Enema in dialysate has a good safety record however: Pierratos first reported its use in nocturnal dialysis in the late 1990s, and frequent dialysis programmes in many countries have adopted this method. Practical advice on adding phosphate to dialysate is provided in Appendix 4. ## Guideline 5.4 -paediatric dialysate considerations We recommend individualisation of dialysate electrolyte concentrations, including potassium, buffer and calcium. [1C] We suggest an individualised dialysate temperature, between core temperature and 0.5°C below, with monitoring of intradialytic core temperature for neonates and smaller children. [2D] ## Rationale Adult guidelines for dialysate composition (sections 5.1 -5.3) are generally applicable to children, though there are a number of additional considerations. In children with residual kidney function, tubular dysfunction is not uncommon, leading to electrolyte wasting and hypokalaemia or acidosis. Calcium balance is also more complex in children: the normal range for calcium is age-dependent and growing children require a positive calcium balance, so that hypocalcaemia may be both more common and more harmful, and yet vascular calcification is sometimes seen even in children and adolescents, in whom calcium-phosphate product is an important risk factor. Similarly, dietary protein intake is often proportionately greater than that of adults, and pre-dialysis acidosis therefore more common. The complexity and clinical heterogeneity of these issues therefore argues strongly for a more individualized approach to dialysate composition in children. Thermal exchanges during dialysis may also be more significant particularly in neonates and younger children, due to the proportionately greater blood flow, and sometimes a reduced capacity for compensation due to body size. Hypothermia should therefore be avoided by individualising dialysate temperature, with intradialytic monitoring in those most at risk. Control of thermal exchanges is available on some modern dialysis machines. ## Anticoagulation We recommend that patients without increased bleeding risk should be given unfractionated or low-molecularweight heparin during dialysis to reduce clotting of the extracorporeal system. We recommend that systemic anticoagulation should be omitted or minimised in patients with increased bleeding risk. We recommend that patients with heparin allergies should be prescribed a non-heparin form of anticoagulation. [1A] ## Rationale Platelet activation in the extracorporeal circuit accelerates thrombin generation via the intrinsic coagulation pathway, so that anticoagulation is usually required to prevent thrombosis. Unfractionated heparin is used as the standard anticoagulant worldwide in view of its proven efficacy, ease of use and long safety record unless the patient has recent or active bleeding, thrombocytopenia, heparin allergy or heparin induced thrombocytopenia. With a mean half-life of 1.5 hours, heparin is usually administered as a loading dose of 1000-2000 IU followed by a continuous infusion of 500-1500U/h that is discontinued approximately 30 minutes before the end of the dialysis session. Monitoring can be performed by measuring the activated partial thromboplastin time ratio (aPTTr) or the whole-blood activated clotting time aiming for around 150% of pre-dialysis or centre normal values. But in practice the bolus dose, infusion rate and stopping times are adjusted empirically, according to clot formation in the dialysis circuit, and the time for needle sites to stop bleeding. Heparin dose may need to be increased with higher haematocrit, or reduced / withdrawn in patients at risk of haemorrhage, those with thrombocytopenia or on long term anticoagulation. Alternatively, a low molecular weight heparin may be used, having a longer half-life, given as a single 'arterial limb' bolus at the start of dialysis. Although monitoring can be performed using anti-Xa activity, these are not always available and laboratory testing correlates less directly with clinical effect, so as with unfractionated heparin, dose adjustment is usually empirical, but larger or repeated doses may be needed depending on convective clearance and session length, and reduced doses for those at risk of haemorrhage. Several systematic reviews comparing low-molecular-weight with unfractionated heparin have found no difference in the incidence of bleeding complications, post-dialysis access bleeding, or thrombosis of the extracorporeal circuit. With its convenience for nursing staff, the use of low-molecular-weight heparin is becoming more common in Europe. For patients at increased risk of bleeding, several options are used in clinical practice. Firstly, several techniques require no anticoagulation to be administered during dialysis, including: combining a high blood flow rate and regular pre-dialyzer circuit flushing every 15-30 minutes; using a heparin coated dialyzer; adding heparin to the rinsing solution; or using a dialysate containing citrate. Secondly, a regional anticoagulant can be used such as citrate, prostacyclin (epoprostenol) or nafamostat (not currently available in UK). Regional anticoagulation with citrateand epoprostenololhave both been reported to reduce the risk of haemorrhage compared to heparin, though there are drawbacks: epoprostenol may induce hypotension and is costly, whereas citrate administration requires re-infusion of calcium based on electrolyte monitoring, adding complexity and nursing staff time. Finally, lower doses of unfractionated or low-molecular-weight heparin have been used with caution in patients at risk of bleeding. Heparin induced thrombocytopenia, usually occurring shortly after regular exposure to heparin, and sometimes with thrombosis, may occur in heparin-treated dialysis patients. The risk of heparin induced thrombocytopenia can be estimated using the 4T scoring system, and is usually confirmed by laboratory testing and detailed guidelines on diagnosis and treatment are published by the British Society of Haematology, but in suspected or confirmed cases, all heparins should be withdrawn. The risk of thrombosis increases with the severity of thrombocytopaenia, and anticoagulation is usually started with either the direct thrombin inhibitor argatroban, or a natural (danaparoid) or synthetic (fondaparinux) heparinoid. Argatroban is reversible, given by continuous infusion, and requires careful laboratory monitoring with aPTTr. The heparinoids are renally excreted and have prolonged half-lives in dialysis patients, such that monitoring of the bolus given with a dialysis session can be based on anti-Xa activity prior to the following session. Once the platelet count returns to normal, patients are usually anticoagulated with warfarin, but in the majority of cases antibodies disappear with time, and patients have been successfully re-challenged with unfractionated and lowmolecular-weight heparins once laboratory testing becomes negative. Adverse events during dialysis (Guidelines 7.1 -7.3) ## Guideline 7.1 -routine blood loss We suggest that during washback, dialysis lines and dialyser are observed to ensure residual blood loss is kept to a minimum. ## [2c] Rationale A small amount of blood loss occurs during normal haemodialysis, for example due to blood retained in the dialyser and circuit after washback, and bleeding into the dressing over needling sites, but there is no clear consensus as to what constitutes a 'normal' quantity of blood loss due to dialysis. The literature on minimising blood loss during haemodialysis is sparse, and much of the evidence is of limited quality. The weighed gauze method has been to quantify bleeding after removal of needles, with 'excessive' defined as blood-soaked gauze weighing over 4g. And excessive bleeding has been associated with poor outcomes, for example in a study of 4152 dialysis sessions in 143 patients, Lin found that excessive bleeding following dialysis needle removal occurred regularly, and was associated with lower haemoglobin levels. Kalantar-Zadeh suggested patients can lose up to 3g iron per year, with one gram being lost in the lines and dialyser, and a further gram lost in blood sampling. Though it is unclear how they are derived, these estimates suggest that up to 20ml per session may be normal. In a comparison of buttonhole versus rope-ladder cannulation in 33 patients, Verhallen found no difference in bleeding times after needle removal between the two techniques. Various suggestions have been made, for example McCann suggested needling at an angle of 25 degrees, and Fruits suggested flushing the arterial dialysis needle with saline, and reducing the amount of blood drawn for testing, but none of these measures is well supported by clinical evidence. Currently there is insufficient evidence therefore to support any recommendations regarding blood preservation and management of vascular access. Clotting of the dialysis circuit leads to much greater blood loss than is routine. Adequate but safe anticoagulation is an important component of prevention, and is covered elsewhere in this guideline, but regular monitoring during dialysis and observation of the colour of the lines and dialyser post-dialysis, also play a role. This concept is supported in literature, for example Kalocheritis noted the contribution of this type of blood loss to anaemia, and the relevance of human factors. Reasonable consensus therefore supports the importance of nursing observation, particularly during washback. No evidence was found regarding the effects of excessive blood sampling on blood loss. Daugirdas and Tattersall point out that on-line measurement of adequacy may reduce the need for blood sampling, but describe the benefits mainly in respect of cost and staff time. However, ensuring that blood samples are taken only when required for routine monitoring or for additional diagnostic indications, is perhaps obvious common sense. ## Guideline 7.2 -disconnection haemorrhage We recommend maintaining awareness of the risk of disconnection, the limitations of pressure alarms, and importance of direct observation, through a program of education, including patients and carers. We suggest regular assessment of individual risk, so that high risk patients can have enhanced monitoring, which could include specific devices. ## [2b] Rationale Disconnection leading to haemorrhage may occur at any part of the dialysis circuit, though venous needle dislodgement may be the most frequent and serious, with rapid blood loss occuring at the rate of the blood flow pump, until it is detected. Disconnection incidents are thought to be uncommon, but the true prevalence is uncertain due to inconsistent reporting. Once detected, management begins with haemostasis and fluid resuscitation, as with any major haemorrhage, and the literature concentrates instead on methods to minimise risk and enhance detection, with publications available from the EDTNA/ERCA and the American Nephrology Nurses Association. Variability in human processes is recognised as an important factor, and most units have established protocols to ensure consistency in aspects of care such as taping needles in position to minimise the chance of disconnection. Dialysis machines have several types of safety monitorand if disconnection does occur, the drop in pressure should be detected and cause the machine to alarm. However, it has been repeatedly demonstrated that these alarms cannot be relied on to detect all cases. The use of asymmetric windows (such as -30 to +70mmHg) may be helpful to maximise the detection of disconnection, while minimising alarms from increases in pressure at the venous needle. Because machine alarms cannot be relied on, direct observation remains important, involving vigilance on the part of nursing staff, and unit management, so that lines of sight are not obscured, patients are not dialysing alone and their vascular access sites are not covered. Because of the low prevalence of disconnection, complacency may develop: continuous education is therefore advocated to ensure awareness amongst healthcare staff, patients and their carers. Risk of disconnection is greater in some patients, and enhanced monitoring may be appropriate based on individual risk assessment. Simply placing patients closer to the nursing desk may be sufficient, but reliable monitoring can also be achieved by use of blood loss detection devices, which typically are secured at the site of vascular access and alarm on the detection of blood. Device monitoring may be appropriate for patients at high risk, such as confused or agitated patients, and may have a greater role in home haemodialysis programmes. One interventional study considered the effect of blood loss detection devices on nursing staff, showing an improvement in self-reported feeling of safety when devices were used. ## Guideline 7.3 -immune reactions during dialysis We recommend that dialysis staff should be aware of the features and management of dialysis reactions, and should have access to a range of dialyser types. ## [1c] Rationale From the early 1980s reports appeared describing abrupt clinical reactions occurring soon after the onset of dialysis. These have traditionally been classified into two types. Type A reactions were said to affect less than 1% of patients per year, often re-occurring in the same patient, with onset within the first few minutes of dialysis. Mainly occurring with first use, rather than re-used dialysers the features were quite 'anaphylactic' in nature (itching, flushing, bronchospasm, hypotension, sometimes with burning at the access site) and often severe, with cardiac arrest occasionally described. Associated with eosinophilia, these reactions were caused mainly by residual ethylene dioxide (used to sterilize membranes) with antibodies detectable in many cases. Similar reactions were described to polyacrylonitrile membranes, especially in ACE inhibitor treated patients (by increasing kinin activation) and in hydrogen peroxide treated re-used membranes. Immediate cessation of dialysis was usually necessary, along with anaphylaxis-type treatment. Extra rinsing or a change of membrane sterilisation would often prevent reoccurrence. Type B reactions, said to be more common, occurring later in the dialysis session, were typically less severe, improving with continued dialysis. Characterised mainly by chest and back pain (also sometimes with vomiting, breathlessness and hypotension) they were caused by complement activation and pulmonary cell sequestration, and associated with transient reductions in circulating white cells. These reactions were clearly linked with the 'bio-incompatibility' of cellulose-based membranes. Dialyser re-use, ethylene dioxide sterilisation and unmodified cellulose membranes are all now very uncommon, and as dialysis practices have evolved, the epidemiology of these reactions has changed, reflected in the changing literature. In modern practice dialysis reactions are uncommon but do still occur, including polysulphone allergy, heparin allergy and isolated thrombocytopenia. Reactions with 'type A' (anaphylactic) features continue to occur with polysulphone membranes, though many variants are described, including those with fever as the predominant symptom. Eosinophilia is an important clue, though not invariably present, and other blood tests (tryptase, total IgE) may be useful. The diagnostic hallmark is resolution of the syndrome following a change of membrane type, and (though little guidance is available from literature) anaphylaxis treatments are often given, with steroid pretreatment sometimes used before dialysis sessions. Stopping ACE inhibitors may also reduce the severity. Reactions to intra-dialytic heparin are sometimes described, ranging in severity from asymptomatic to a serotonin-like syndrome of breathlessness and flushing, often with hypertension. These are usually but not always associated with thrombocytopenia (persisting between dialysis sessions) and thrombotic complications may occur. Transient asymptomatic thrombocytopenia has also been described, often recovering between dialysis sessions so that pre-dialysis platelet count may be normal. This reaction has been associated with electron beam membrane sterilization, but the mechanism is unknown. Several complications other than dialyser reactions may present with similar peri-dialytic symptoms. More common ones include bacteraemia and hypovolaemia, whilst disequilibrium, air embolism and the chloramine / hard water syndromes are rarer. Water purification complications may be more common in the home haemodialysis setting. We suggest training patients and/or care partners to achieve a defined set of competencies, using an individualised approach to training method and speed. We suggest units form a contract with patients outlining responsibilities, including an agreement to dialyse as per prescription and trained technique, and including a policy for re-imbursement of directly arising patient costs. We suggest supporting patients with a specific team including nephrologists, technicians, and nurses, with rapid access to dialysis in-centre when required. We suggest an agreed individualised prescription for home haemodialysis, taking into account lifestyle goals, with the same dose and time target considerations as centre-based patients. We recommend enhanced safety measures for patients who dialyse alone or overnight, and an enhanced risk assessment for patients with blood-borne viruses. [1C] ## Rationale There is increasing evidence of the benefits of augmented haemodialysis schedules, in terms of both outcome and health-related quality of life, but providing more frequent dialysis in-centre is a challenge in the UK, and it is widely recognised that augmented schedules are most easily accommodated in the home setting. The literature on home haemodialysis and augmented schedules therefore overlaps substantially, but home haemodialysis additionally is increasingly acknowledged to provide a level of convenience and flexibility not achievable in-centre. Despite these benefits the penetration of home haemodialysis in the UK remains low, comprising only 0.4% of incident and 2% of prevalent dialysis patients. Many organisations such as NICE and KDIGO promote universal availability for clinically suitable patients, acknowledging that collaborative working between centres maybe required. But it is clear from registry data that variability of access still exists, with some centres not offering this modality, and considerable variation in uptake between centres. Home haemodialysis patients must be able to manage their dialysis safely, and monitor their condition. Modality decisions should be supported by a full assessment of clinical and social circumstances, as well as the home environment, including a discussion of the impact of therapy on others within the household. It is essential that patient and carer expectations and fears are appropriately addressed before commencing training. Few data are available to guidance on clinical suitability, but the ability to complete training may be more important than clinical diagnosis: a number of programmes have reported that patients with complex comorbidities can improve with more frequent therapy, more tailored to their needs. Training on a '1 to 1' basis with a specific training staff is widely accepted as optimal, with the learning style and training duration adapted to the individual. Type of vascular access should not be a limiting factor, but appropriate training, surveillance and technique assessment form essential parts of the home haemodialysis programme. The success of a home haemodialysis programme is dependent upon a skilled and specific multi-disciplinary team facilitating education, training and patient support in the community, and optimal individual outcomes are dependent on patient understanding, and appropriate cooperative liaison with this support. This may be facilitated with an explicit contract, so that the manner in which this clinical responsibility is shared is clear. The financial responsibility for treatment rests with the provider, and re-imbursement of directly arising patient costs should be readily available. A home haemodialysis Programme requires adequate medical, nursing and technical support, and should support at least 12 to 20 patients, and train at least 10 patients per year in order to maintain appropriate staff expertise and cost effectiveness, so smaller renal units may find it more appropriate to share resources with other centres. Minimum safe staff to patient ratios are not well defined, but recommendations for peritoneal dialysis (such as minimum of 1 nurse per 20 patients) may be relevant. However, as training for home haemodialysis is more complex, additional staffing should be considered to ensure that training new patients does not detract from the support of established patients. Patient mix should also be considered, so that programmes with a greater number of complex patients are staffed more favourably. Home haemodialysis patients should receive the same level of medical supervision, and the same monitoring and dose considerations as in-centre patients, and as for other patients, the schedule should be individualised depending on patient values and therapeutic goals. Dialysis dose should be quantified as for other augmented schedules, but should be interpreted with the flexibility of the patient's schedule also in mind. To ensure that the home dialysis team can provide the best possible support that is responsive to the individual, recording of sessional details by the patient or carer is desirable. Specific circumstances may require additional risk assessments and/or additional measures: enhanced safety measures, for example to detect disconnection, should be available for patients dialysing alone or overnight, and protection of household contacts of patients with bloodborne viruses should be considered, particularly for those directly involved in therapy. ## Guideline 8.2 -shared haemodialysis care We suggest that all centre-based haemodialysis patients should have opportunity and encouragement to learn aspects of their dialysis treatment, and take an active role in their care. [2D] ## Rationale There is little research that has been directly conducted into shared haemodialysis care, however there is considerable evidence of the benefits of supported selfcare in other long term conditions. Low health literacy amongst dialysis patients is associated with worse survivalwhereas self-motivation and education can result in better care, for example, in phosphate control and fluid balance. As with the broader NHS, dialysis services are experiencing considerable pressure to deliver high quality in the face of fiscal challenge, and an important mechanism to ensure that quality of care is maintained, is to engage service users as true partners in their own treatment: self-management is an ambition in 'Kidney Health: Delivering Excellence'. To achieve this, health care professionals need to enhance their roles, becoming educators and facilitators, supporting patients to take a greater role in their own care, and increasing their opportunities for dialysing at home. Shared haemodialysis care impacts on all domains of health. Central among these are: the enhanced patient safety that comes from education on infection control (see the WHO campaign 'Save lives: clean your hands'; the enhanced equity consequent on offering all patients training in their treatment rather than only those planning haemodialysis at home; and the enhanced experience when patients can put themselves onto dialysis, or manage their own alarms, without waiting for a nurse. The process of haemodialysis can be broken down into approximately 14 tasks (Appendix 5). The exact arrangements may vary between units but the concept is essentially the same: that centre-based patients are given the opportunity to train to perform one or more of these tasks. It is key that patient involvement is voluntary, and that learning is individualised to the style and speed of the individual. Shared haemodialysis care is associated with a range of barriers and enablers that are best explored through quality improvement work, in order to design favourable conditions for successful implementation. ## Guideline 8.3 -intradialytic exercise We recommend that intradialytic exercise should be available in all units, as a treatment for enhancing physical functioning, in patients without contraindications. We suggest that intradialytic exercise be considered as a method of enhancing quality of life. We suggest that exercise regimes be devised by appropriately trained staff. [2C] ## Rationale Whilst cardiovascular disease remains the principal causes of death in dialysis patients, there is a significant interaction with body composition, with muscle wasting in particular exacerbating mortality. Muscle wasting and poor physical fitness also reduce functional abilities including activities of daily living, thus reducing quality of life in haemodialysis patients. However, muscle wasting is modifiable by exercise, and epidemiological studies suggest that regular exercise can even reduce mortality, but unfortunately daily physical activity is typically low in haemodialysis patients, perhaps due to the time burden and symptoms associated with treatment. Based on evidence from eight systematic reviews and meta-analyses, analysing data from 1000 adult participants on dialysis, the clinical effectiveness of exercise on physical function and health related quality of life can be summarised as follows: 1) Despite the high-risk status of dialysis patients, no serious exercise-related adverse events have been reported from over 30 000 patient-hours of exercise observed. Adverse events reported include post-exercise hypotension, fatigue, myalgias, painful feet, and aggravation of foot ulcers, though not with increased incidence in exercise groups. Compliance with exercise programmes ranged from 43 to 100%, and dropout rates from 15 to 50%. 2) Short term (2-6 months) prescribed exercise of any type, frequency and intensity, resulted in significant and clinically moderate/large improvement in cardiorespiratory fitness, with a mean increase in peak VO2 of 5ml/kg/min. 3) Any prescribed exercise delivered during hemodialysis sessions produced significant and clinically moderate improvement in muscle strength, with a mean increase of 9.9kg. 4) Any type of prescribed exercise consistently produced significant and clinically large improvements in some indices of functional capacity, such as 'sit to stand' transfers, whereas other indices, such as walking performance, were improved according to some reviewsbut not others. 5) Self-reported physical function was significantly improved in exercising patients. This often contributes to quality of life scores, and may therefore explain why some studies conclude that exercise improved quality of life. Taken together there is therefore good evidence that the uptake of regular exercise improves physical function and quality of life in haemodialysis patients, without causing significant harm, and that delivery of exercise within haemodialysis sessions can achieve this. Exercise during the dialysis process may also assist with solute clearance. Enhanced urea clearance is predicted by modelling but an impact on Kt/V is found in some studies (nine of eighteen studies reviewed) but not others, whereas improvements in phosphate clearance and serum levels are consistently observed. Some evidence suggests the type of exercise most likely to be beneficial: larger improvements were observed with interventions delivering a progressively increasing exercise volume, at least three times per week, for at least 30 minutes, lasting for at least four months, and including an additional resistance-training component. Comparative evidence for specific exercise programmes is currently unavailable, but some guidance on practical implementation of intradialytic exercise is offered in Appendix 6. ## Guideline 8.4 -dialysis experience for children and adolescents We recommend that haemodialysis for children and adolescents should be delivered in a dedicated paediatric dialysis centre or at home, with the involvement of a paediatric multidisciplinary team. We recommend that adolescents should commence an active transition programme by 14 years, or at the time of presentation in those already over 14. [1D] ## Rationale Haemodialysis sessions are associated with physical symptoms, social restriction, and loss of control, which for children and adolescents may be particularly depersonalising and unpleasant. These effects may be mitigated by an appropriate environment and trained support staff, and in-centre dialysis is therefore best delivered in a dedicated unit, with paediatric nephrologists working alongside the full multidisciplinary team, including nurses, dietitians, psychologists, play therapists, teachers and social workers. In this way children can be supported to reach their full potential despite the burdens of treatment. The first dialysis session is of particular importance in establishing therapeutic trust and parental confidence -psychological preparation for this event can alleviate anxiety, reduce symptoms and improve the tolerability of dialysis. Children and adolescents can be supported to take on aspects of their own care, often along with parents or guardians, and are likely to gain as much benefit as adults from involvement in a shared care program. And home haemodialysis has many advantages for children, allowing an augmented schedule without institutionalisation, and providing a flexibility which can reduce the impact of dialysis on social development. Transition describes the process of preparing adolescents, along with their families, for the move from paediatric to adult care. It should be individualised, taking into consideration the physical and psychological development of the adolescent, and requires a variable amount of time. Adolescents will suffer the least disruption if moved to adult care following engagement with a transition programme, and should be introduced to the concept of transition in early adolescence . For those over 14 when presenting to paediatric services, transition planning should commence immediately alongside other aspects of care. # Appendix 1 Simplified mathematics of urea clearance ## Urea kinetic modelling and kt/v In the design of the NCDS study, 'dose' of dialysis was defined as a target for time-averaged urea (low urea = high dose group). However, urea level in dialysed patients depends as much on protein intake as the amount of dialysis: loss of appetite may lead to low urea, so this cannot be relied on to indicate sufficient dialysis. The concept of Kt/V emerged from this study, where K is dialyser clearance (of urea), t is treatment time and V is volume of distribution (of urea). Despite its appearance, Kt/V is not intended as something to calculate from its constituents K, t and V, since only t is accurately known, but by consideration of the following relationship: the rate of removal of urea is proportional to its concentration. Following this basic rule, the concentration of urea after a dialysis session of duration t, is therefore approximated by: [formula] U post ¼ U pre x e^−Kt=V ð Þ where U post ¼ urea post dialysis U pre ¼ urea pre dialysis [/formula] Kt/V is therefore the negative exponent in a numerical model describing the fall in urea during a single dialysis session. Different forms of Kt/V reflect models with differing levels of complexity, which in addition to the concept above, may also take account of other aspects such as: urea removal by convection, urea generation, and separate "pools" within which urea is distributed. The gold standard Kt/V is derived from 'Urea Kinetic Modelling': iterative computation to give the best fitting coefficients for urea clearance and generation, based on three urea measurements (spanning an interdialytic interval and a dialysis session). This approach is broadly accepted, but although online programs are available (e.g. Solute Solver, www.ureakinetics.org) the nonformula method hinders widespread use, and a number of simplified approaches are more common -three are commonly used and summarised here. ## Log-ratio and urea reduction ratio If the basic model above is used, ignoring other factors, with urea assumed to be distributed evenly in body water, then Kt/V is given by the log ratio: [formula] Kt=V ¼ − log e U post =U pre Â Ã [/formula] This simple form of Kt/V, sometimes called the "Log-Ratio", is mathematically related to the Urea Reduction Ratio (URR), the reduction in urea as a ratio of the predialysis level, often expressed as a percentage: [formula] URR 100 x U pre −U post À Á =U pre Kt=V ¼ log e 100= 100−URR ð Þ ½ [/formula] A threshold for URR is therefore precisely the same as a threshold for Kt/V calculated by the Log-Ratio. URR is the simplest measure of dialysis dose, and is the current audit measure collected by the Renal Registry. URR has the disadvantage that it does not account for clearance due to ultrafiltration, urea generation or urea rebound. It tends to over-estimate dialysis dose in shorter treatments, and under-estimate dose in treatments longer than 4 hours. However, it is long established and there is no argument over its calculation. Single-pool Kt/V (spKt/V) Although the above is technically also a single-pool method, the term 'single pool Kt/V' usually refers to the method proposed by Daugirdas, which calculates Kt/V by a formula taking account of the effect of ultrafiltration: [formula] spKt=V ¼ − log e U post =U pre À Á − t=7500 ð Þ Â Ã þ ½ UF=TW ð ÞÃð4− 3:5Ã U post =U pre À Á À Á where t ¼ dialysis time min ð Þ UF ¼ ultrafiltration litres ð Þ TW ¼ target weight kg ð Þ [/formula] This method takes account of more factors but consistently over-estimates Kt/V. Targets have therefore often been expressed with an adjustment factor if using spKt/V (eg. "eKt/V = 1.2, or spKt/V = 1.4"). Equilibrated Kt/V (eKt/V) The dynamic interaction between urea concentrations in intra-and extra-cellular pools, results in reduced effectiveness of treatment because dialysis removes urea only from the extracellular pool, which is then refilled from the intracellular pool during and after dialysis. This results in a gradual rebound in urea concentration for approximately one hour after dialysis, so that if postdialysis urea is measured immediately, then the treatment effect is over-estimated. Equilibrated Kt/V attempts to correct for this by using a post-rebound urea measurement: [formula] eKt=V ¼ − log e U post−rebound =U pre Â Ã [/formula] Due to the inconvenience of measuring urea postrebound (an hour after dialysis has finished) a formula is used to adjust for this reasonably predictable effect using urea measured immediately. More than one equation has been published but there is very little difference between them. This one is known as the Tattersall version: [formula] eKt=V ¼ spKt=VÃt ð Þ = t þ 35 ð Þ [/formula] Apparent urea rebound is dependent on vascular access, so 35 is replaced by 22 in patients dialysing via a catheter. This method is non-biased and has most often been used in studies of dialysis dose, such as the HEMO study. Targets given in terms of other measures of dialysis dose such as URR may be useful in comparing units, but are not accurate for individual patients. All forms of Kt/V (including eKt/V) implicitly use V to normalise for body size, whereas body surface area is conventionally used to normalise renal function. There are theoretical reasons to believe that normalisation of Kt/V to other body size parameters such as body surface area would be more useful, but these concepts have not gained widespread acceptance. The Log-Ratio is a reasonable approximation of eKt/V since the underestimation (from ignoring ultrafiltration and urea generation) is offset by overestimation (from ignoring urea rebound). In fact, for a 4 hour session, with UF/TW = 0.02, in a fistula patient, the Log-Ratio is almost identical to eKt/V, with URR = 70 being equivalent to eKt/V = 1.2. However, in most other settings, Log-Ratio will underestimate or overestimate dose, so that the target URR required to achieve eKt/V = 1.2 needs to be varied, as in this # Appendix 2 Adjusting dialysis for residual function Since residual renal clearance (Kru) is continuous, and dialysis clearance is intermittent (with Kt/V referring to clearance during a single dialysis session), the quantities of both cannot simply be added. When it is planned to reduce dialysis dose by incorporating the contribution of residual function, it is necessary to somehow add these clearances so that the dialysis component is appropriate. Three methods of combining these clearances have been proposed. Converting Kru to an equivalent eKt/V (Combined eKt/V) In this method, residual kidney function is converted to an equivalent per-session eKt/V, by multiplying by a factor F, which empirically inflates the time over which residual clearance is measured, to account for its greater efficiency compared to that of dialysis, with the value of F depending on dialysis frequency. A "Combined Kt/V" is calculated: Converting Kt/V to an equivalent renal clearance (EKRc) [formula] Combined eKt=V ¼ eKt=V Dialysis þ eKt=V [/formula] An alternative method is to convert per-session Kt/V into an equivalent continuous renal clearance and then add it to Kru. Casino and Lopez computed kinetic estimates of combined dialysis and kidney urea clearance (normalized to volume) which they termed "equivalent renal urea clearance" (EKRc). In the absence of residual function, an eKt/V target of 1.2 equates to EKRc 13ml/ min. For a thrice weekly schedule EKRc is given by the formula: [formula] EKRc ml= min ð Þ¼1 þ 10ÃeKt=V ð Þ [/formula] With this method Kru is added to EKRc and the dialysis component adjusted to achieve a total of 13ml/ min. Converting both eKt/V and Kru to a weekly dialysis dose (stdKt/V) Dialysis schedule and dose can be converted to an equivalent weekly clearance, "Standard Kt/V" (stdKt/V) proposed by Gotch, based on kinetic models which relate urea generation to average weekly pre-dialysis urea. This allows comparison between schedules: a frequent schedule with stdKt/V = 2.1 is equivalent (in terms of small solute clearance) to a thrice-weekly schedule with eKt/V = 1.2. Residual function can be incorporated into stdKt/V (sometimes termed "Total Standard Kt/V") by formulas available. # Appendix 3 ## Quantifying convection Convective clearance of a toxin depends firstly on the sieving coefficient. Seiving coefficient (SC) is a measure of the ease with which a solute passes through the membrane relative to solvent, so this depends largely on the relative size of the solute molecule and the membrane pore cross-section. It can be measured during pure ultrafiltration as the ratio of solute concentration before and after passing through the membrane. SC takes values between 0 (the molecule is unable to pass through the membrane) and 1 (the molecule passes just as easily as water). Secondly, convective clearance depends on the ultrafiltration rate. In pure haemofiltration, clearance is achieved entirely by ultrafiltration. The loss of fluid by ultrafiltration is replaced by infusion into the blood downstream of the filter ("post-dilution"). In this case, clearance (K) for any solute is equal to convective clearance (Kc) and can be calculated from: [formula] K ¼ Kc ¼ QufÃSC where: [/formula] Quf ¼ ultrafiltrate flow rate In haemodiafiltration (HDF), there is a mixture of diffusion and convection. Diffusion reduces the concentrations in the ultrafiltrate, reducing Kc. Clearance in haemodiafiltration can be predicted by the following equation: [formula] Kc ¼ QufÃSCÃ Qp−Kd ð Þ =Qp ð Þ K ¼ Kc þ Kd [/formula] where: Qp ¼ plasma flow rate [formula] Kd ¼ diffusive clearance [/formula] The effect of this is to diminish the convective component. In post-dilution HDF, convection will always increase total clearance, but this increase is negligible for small solutes which diffuse easily (such as urea). For larger molecules (such as beta-2-microglobulin) convection can significantly and usefully increase clearance. Pre-dilution HDF, in which replacement fluid is given upstream of the dialyser, is less commonly practiced, and more complex mathematically. Convection is similarly reduced by diffusion as above, but in addition both convection and diffusion are substantially reduced by the dilutional effect of the replacement fluid. The ultrafiltrate rate and volume are usually adjusted to account for this. In publications the convective component of HDF is quantified as the filtration volume. This means the total sessional filtration volume in post-dilution HDF, or the equivalent adjusted volume in pre-dilution HDF. # Appendix 4 Adding phosphate to dialysate Cleen Ready-To-Use enema comes in a 133ml pack costing 68p (March 2017). The pack is designed to deliver a 118ml dose containing 21.4g of sodium acid phosphate (sodium dihydrogen phosphate dihydrate NaH 2 PO 4 .2H 2 O) and 9.4g sodium phosphate (disodium phosphate dodecahydrate Na 2 HPO 4 .12H 2 O). This gives a concentration of 1.38mmol/ml phosphate. The acid concentrate, together with the added enema, will be diluted according to the proportioning ratio of the dialysis machine. The volume of enema (V E ) that needs to be added to the canister is given by: [formula] V E ml ð Þ ¼ C PO4 ÃV AC ÃDF=1:38 [/formula] where: C PO4 ¼ target dialysate phosphate 0:4mmol=l is commonly used ð Þ V AC ¼ volume of the acid concentrate e:g:6L ð Þ DF ¼ dilution factor for the dialysate eg:35 for machine proportioning at 1 : 34 ð Þ Using these numbers, for example, gives an enema volume of 61ml to be added to the concentrate. Note that this formula depends on the formulation of the enema and is specific to Cleen. This simple formula ignores the small change in concentrate volume, as the effect is below the 5% tolerance allowed for electrolyte concentrations for haemodialysis and related therapies (ISO 23500 Part 4). Albalate used the above formula to prepare dialysates with C PO4 between 0.48 to 1.12mmol/l, reporting good agreement between measured and target C PO4 using Gambro and Fresenius machines and a range of acid concentrates. Sodium content in the phosphate-enriched acid concentrate will be reduced (since the enema sodium is 37g/l, compared to around 83g/l for an acid concentrate that proportions at 1:34, and 107g/l for one that proportions at 1:44). This will lead to a lower dialysate sodium (by 0.7 to 0.9mmol/l) with volumetric proportioning, and a higher concentrate pump rate with conductivity feedback. It is possible that this effect could trigger machine alarms, requiring machine re-programming. thirst, frequent urination, stomach pain, nausea, vomiting, fatigue or confusion), is dehydrated, or is feeling unwell. h. In individuals taking insulin and/or insulin secretagogues, if hypoglycaemia below 5.5 mmol/L (100 mg/dL) is observed, and glucose containing dialysate fails to elevate blood glucose sufficiently, advise patient to eat or drink approximately 15g carbohydrate and re-assess blood glucose concentration after 20 min. Repeat until blood glucose exceeds 5.5 mmol/L. We suggest the following safety monitoring: a. Prior to exercise, ask patient how they feel, record resting blood pressure and heart rate, and if diabetic, record blood glucose concentration. b. During exercise, monitor signs and ask patient to report symptoms of pain, excessive fatigue, altered consciousness, overheating, cyanosis, anxiety, severe breathlessness, chest pain, dizziness/lightheadedness. c. If hypertensive, regularly check blood pressure during exercise. If values exceed 220/105 mm Hg, reduce exercise intensity or cease exercising until blood pressure reduces. d. Use a rating of perceived exertion scale (Borg CR100 or Borg RPE scales) and ensure exercise intensity does not provoke responses greater than 50/strong heavy on the Borg CR100 or 15/hard (heavy) on the Borg RPE scale e. Post exercise, monitor blood pressure and heart rate until resting values are approximately obtained, observe patient for at least 20 min, and be aware of possibility of hypotension during remainder of the dialysis session.	None	https://bmcnephrol.biomedcentral.com/track/pdf/10.1186/s12882-019-1527-3	None
2b57ac795e381888b1d3fb4f894498eff9331eb6	pubmed	None	COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counselling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of postoperative SIAD. They should know hyponatraemia symptoms. Hyponatraemia in COVID-19 is common with a prevalence of 20-30% and is mostly due to SIAD or hypovolaemia. It mirrors disease severity and is an early predictor of mortality. Hypernatraemia may also develop in COVID-19 patients, with a prevalence of 3-5%, especially in ICU, and derives from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.Correspondence should be addressed to M Christ-Crain # Introduction This is an update of the previously published guidelines 1 year ago. While there is not much new literature about diabetes insipidus (DI) and COVID-19, knowledge about the prevalence of dysnatraemia in COVID-19 and about the association of dysnatraemia with the outcome has increased. Patients with pre-existing endocrine conditions may be vulnerable to perturbations in plasma sodium in more severe cases of COVID-19. Especially patients with central DI or pre-existing hyponatraemia may be at risk of more severe, life-threatening dysnatraemia. Regardless of pre-existing endocrine conditions, hyponatraemia is common in patients hospitalized with COVID-19and is associated with disease severity and mortality. This article is intended to advise how endocrinologists can still optimally care for ambulatory patients with central DI and hyponatraemia, where regular physical consultations and biochemical assessments are not possible. Furthermore, we provide guidance on the management of these patients when they are admitted to the hospital with severe COVID-19. ## Diabetes insipidus DI is a rare disease, characterized by hypotonic polyuria and polydipsia. The differential diagnosis of DI involves the distinction between primary forms (central DI) or nephrogenic DI and secondary forms, where polyuria results from primary polydipsia. Treatment of DI consists of fluid administration in case of dehydration, and in cases of central DI, desmopressin as hormone replacement for the absent vasopressin. ## How to manage patients with an established diagnosis of diabetes insipidus in the time of covid-19 ## Management of patients with central di in the outpatient setting - In the majority of cases with central DI, osmoregulated thirst is intact, and oral fluid intake accurately compensates for urinary and insensible water losses. Even prior to treatment with desmopressin, patients are, therefore, typically eunatraemic. To reduce the symptoms of polyuria and polydipsia, desmopressin is given orally or intranasally; the major complication of desmopressin therapy is hyponatraemia. A retrospective review has shown that 27% of central DI patients show mild hyponatraemia (131-134 mmol/L) on routine electrolyte testing, and 15% develop more severe hyponatraemia (≤130 mmol/L) over longterm follow-up. Hyponatraemia develops when the antidiuretic effects of continuous desmopressin therapy prevent free water excretion, even with normal fluid intakes. This can be prevented by delaying doses of desmopressin to allow regular aquaresis, but regular electrolyte checks are recommended during the initiation of therapy. Annual electrolyte checking is recommended for long-term follow-up, though more frequent monitoring is needed where hyponatraemia episodes are more frequent. - The COVID-19 pandemic has limited the accessibility of blood testing, and the priority of routine treatment of central DI should be to avoid hyponatraemia. This emphasizes the importance of delaying desmopressin doses, to allow regular periods of free water clearance, so that excess water intake does not lead to dilutional hyponatraemia. This can be achieved by recommending that the patient delays a dose of desmopressin once or twice per week, until an aquaresis occurs. Some patients regularly delay each dose until they begin to feel polyuric, as they are aware that they otherwise feel bloated by fluid retention. Alternatively, especially in patients known to experience recurrent hyponatraemia, one dose each week can be entirely omitted, though significant polyuria and social disruption may occur. ## Acute infection with suspected or confirmed covid-19 -Although patients with central DI should be no more vulnerable to COVID-19 than the rest of the population, those DI patients who develop respiratory complications of COVID-19 are at significantly increased risk of dysnatraemia. -Epidemiological data show that hypernatraemia is rare in ambulatory patients with DI; in contrast, the rate of hypernatraemia during hospital admission is significant. The aetiology of this hypernatraemia is multifactorial; if cognition is attenuated by critical illness, fluid intake may be reduced, and if the patient is vomiting, oral desmopressin intake may be difficult. Most hospital studies report increased mortality in intensive care units associated with hypernatraemia, and it is a poor prognostic sign in patients who develop DI following head injury. In addition, data from a nationwide Swiss cohort study showed an increased mortality rate in complex hypopituitary patients with central DI admitted to hospital, compared with hypopituitary patients without DI, consistent with vulnerability of DI patients to develop hypernatraemic dehydration in the context of severe illness. The propensity to develop hypernatraemia during hospital admission is particularly marked in patients with adipsic DI, and this subgroup of DI patients has been documented to develop severe hypernatraemia, which may be complicated by thrombotic episodes. Patients with adipsic DI may also have hypothalamic obesity, and there is increasing evidence that obesity per se may be an important risk factor for poor outcome in patients with Covid-19. Thus, these patients may be amongst the most. This report was prompted by a study of patients hospitalized with central DI, which showed that desmopressin treatment had been missed or delayed in 88% of admissions, and that 35% of patients consequently developed dysnatraemia. This was attributed to a lack of understanding of the critical nature of desmopressin amongst clinical staff. In this context, it is very important that patients themselves are empowered with the knowledge of their condition and the essential difference between DI and diabetes mellitus, which caused confusion with serious consequences at the time of admission. The results of these guidelines have generated a sensible basis for the management of DI when patients are admitted to the hospital. - The key practice points in the SfE in 2018 guidelines are particularly valid for DI patients with COVID-19. Most importantly, all patients with central DI admitted to the hospital with COVID-19 should be managed in consultation with endocrinology advice. In addition, a careful prescribing alert system for all patients treated with desmopressin is recommended to reduce prescribing errors and to ensure that essential desmopressin therapy is maintained. - In patients with mild COVID-19 cold symptoms, who are alert and able to drink, it may, in some patients, be advisable to prescribe oral rather than nasal desmopressin due to the limited absorption from congested nasal passages. As COVID-19 is characterized by persistent fever and tachypnoea, insensible water losses are likely to be substantially increased; ordinarily, osmotically stimulated drinking should generate fluid intake sufficient to make up for insensible losses, but if the cognitive function is impaired by fever, hypoxia or sepsis, i.v. fluids may be required. - In patients with severe COVID illness, desmopressin should be given parenterally, usually with a starting dose of 0.5 μg. The i.v. route is generally preferred because it obviates concerns about absorption and has the same total duration of action as the other parenteral routes. Prompt reduction in urine output should occur, and the antidiuretic effect generally lasts for 6-12 h. Urine osmolality and urine volume should be monitored to ascertain whether the dose was effective, and the plasma sodium should be measured at frequent intervals (every 2-4 h) to ensure improvement of hypernatraemia. Since arterial blood gas point of care testing for sodium may be the main laboratory estimation available in some hospitals (particularly 'field hospitals'), sodium measurement can be done using this method instead of sending it to the laboratory. -Hypernatraemia in COVID-19 patients (without central DI) in intensive care units is seen with a prevalence of 2-5% (2, 4, 5, 6, 7, 8); excessive insensible water losses from the constant pyrexia and increased respiration rate may play a major aetiological role in this, as well as this gives rise to the need for significant diuretic use or conservative fluid regimens in some patients in order to aid oxygenation. Hypernatraemic dehydration may, therefore, rapidly develop in patients with DI, particularly in those who need diuretic therapy or in whom desmopressin is withheld or delayed. If diuresis is necessary, the optimum management of these patients should be a collaboration between intensive care and endocrinology. - In patients with hypovolaemic shock due to COVID-19 restoration of blood volume with i.v. 0.9% sodium chloride is preferable, even if there is hypernatraemia. In the absence of hypovolaemic shock, patients with DI and severe dehydration should be treated with hypotonic fluids, either enterally (using water or milk) or, if necessary, intravenously (using 5% dextrose in water). Hypotonic fluids should be administered as an i.v. infusion, with the rate adjusted to exceed the hourly urine output and reverse the calculated total body water deficit. The usual aim is to provide just enough water to safely normalize serum sodium at a rate of < 0.5 mmol/L per h (<10-12 mmol/L per day)https://eje.bioscientifica.com extracellular volume expansion since two-thirds of the administered fluid is distributed intracellularly. Initial data suggested that hypernatraemia, in contrast to other critically ill patients, is not a risk factor for severe mortality in COVID-19. More recent data, however, show that hypernatraemia is associated with adverse outcomes and mortality, similar to other critically ill patients (4, 5, 6, 7). -However, it may be that endocrinologists may have to accept mild hypernatraemia (<155 mmol/L) as the price of preventing pulmonary oedema. In patients with central DI. we will have a major role in ensuring that severe hypernatraemia, which compromises recovery, does not occur, and multidisciplinary input is needed to discuss the individual merits and contingencies of treatment in DI patients with COVID-19. - It is important to stress that, as hypernatraemic dehydration is associated with a hypercoagulable state, the risk of venous thrombosis, and pulmonary embolism, is substantial, particularly in an immobile patient. We, therefore, recommend the routine prescription of prophylactic s.c. low molecular weight heparin during episodes of hypernatraemic dehydration, until eunatraemia is restored. This is particularly important since pulmonary embolism is emerging as one of the factors associated with mortality in COVID-19 patients. Low molecular weight heparin is also recommended in patients with hypercoagulable states in COVID-19. -As the majority of patients with postoperative or post-traumatic central DI also have ACTH deficiency, concomitant stress dose corticosteroids are essential during COVID infection. ## Hyponatraemia Hyponatraemia (plasma sodium < 35 mmol/L) is the most common electrolyte disorder in clinical practice. It is divided into euvolaemic, hypovolaemic, and hypervolaemic hyponatraemia, each of which is treated differently. The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia. ## How to manage patients with hyponatraemia in the time of covid-19 Management of patients with hyponatraemia in the routine endocrine practice -SIAD is seen by endocrinologists after pituitary or other neurosurgeryand as part of consultations throughout the hospital. One effect of the COVID-19 pandemic has been the cancellation of most elective pituitary operations, though neurosurgical interventions for subarachnoid haemorrhage or traumatic brain injury continue to induce SIAD. Patients with SIAD will continue to be treated according to well-established guidelines. As patients who develop SIAD after pituitary surgery characteristically do so after discharge from the hospital, it will continue to be important to draw attention to the possible occurrence of hyponatraemia, to both patients and primary care physicians. Hyponatraemia has been recorded to be the commonest cause of hospital readmission following transsphenoidal surgery; as access to routine phlebotomy may be compromised by the needs for social isolation and the limitations of many health provisions, the emphasis should be on prevention and awareness. Patients should be advised to limit their fluid intake in the 2 weeks following surgery and to drink only to thirst and to measure their body weight daily. We recommend that the primary care physician is contacted if there is weight gain, bloating or unusual headache. Instruction on hyponatraemia-associated symptoms, such as headache, dizziness, nausea or fatigue, is important. -All other patients with chronic SIAD, who are treated with either fluid restriction, urea or vaptans should be instructed to continue their treatment as usual. We recommend advising the patients to daily monitor their body weight and to be aware of hyponatraemia symptoms (see above), where access to phlebotomy for electrolytes is restricted. ## What to look at if patients with hyponatraemia are admitted to the hospital with acute infection with covid-19 -Hyponatraemia occurs in up to 30% of pneumonia cases, and several studies show that admission hyponatraemia predicts increased mortality and morbidity, independent of the underlying disease. Of note, 60% of SARS-COV-1 patients were reported to have mild hyponatraemia. Recent literature suggests that hyponatraemia in COVID-19 patients is as common as in other pneumonia cases. Berni et al. showed a prevalence of hyponatraemia of 22.9%, which is in the range of most other literature showing a prevalence of around 20-30%. An even higher prevalence of 40% has been shown in a large study in 10 000 patients across 13 hospitals in a New York health system (4). Of note, hyponatraemia https://eje.bioscientifica.com seems to be more common in COVID-19 compared to controls hospitalized with similar symptoms, but without COVID-19. There is only limited information about the aetiology of hyponatraemia, but SIAD and hypovolaemia are suggested to be the main causes. One study identified a correlation between serum sodium and interleukin-6 and greater correction of hyponatraemia in patients with COVID-19 who were treated with tocilizumab. This suggests that interleukin-6-mediated vasopressin release may contribute to COVID-19-associated hyponatraemia. COVID-19 can also cause adrenal insufficiency with accompanying hyponatraemia responsive to steroid replacement. In almost all studies, hyponatraemia was associated with an increased prevalence of non-invasive ventilation and ICU transfer and was an independent predictor for adverse outcome and mortality. Each mmol/L of serum sodium reduction was associated with a 14.7% increased risk of death in one study. In another study, each level of worsening hyponatraemia (mild to moderate to severe) conferred a 43% increased odds of in-hospital death, even after adjusting for age, gender, race, BMI, past medical history, laboratory abnormalities, kidney failure, mechanical ventilation and sequential organ failure assessment (SOFA) score. Still, it is unclear whether this association of hyponatraemia and outcome mirrors causality or simply defines hyponatraemia as a marker for severity of the disease. Whatever the case, sodium levels at admission should be considered an early prognostic marker in patients with COVID-19. -As the mortality from hypovolaemic hyponatraemia is higher than that of SIAD, the temptation is, if it occurs in COVID-19 patients, to respond with i.v. fluid resuscitation. However, in severely ill COVID-19 patients, clinical experience dictates that caution should be exercised in the rate of i.v. fluid administration because of the risk of precipitating pulmonary oedema. Similar caution is advised in patients with severe hyponatraemia complicated by symptoms of cerebral irritation. Although guidelines recommend bolus hypertonic saline treatment to rapidly elevate plasma sodium concentration, and published data suggests that this is effective, the sudden volume load might cause pulmonary oedema. In this circumstance, the safer option might be low-dose hypertonic saline infusion, with careful control of the volume of fluid administered; the clinical experience in the COVID-19 situation is insufficient to be definitive about this, and each centre should use the method with which they are most familiar.highlights the risks and preventive measures in patients with DI or hyponatraemia in times of COVID-19 and shows the management of DI and hyponatraemia in the COVID-19 patient in intensive care. In summary, patients with central DI or hyponatraemia should be managed according to existing guidelines as ambulatory patients, with careful explanation to DI patients of how to avoid dilutional hyponatraemia in circumstances where plasma sodium measurements are difficult to access. Patients with DI are vulnerable to adverse effects and potentially poor outcomes if hospitalized with COVID-19. Hyponatraemia seems to be common in patients hospitalized with COVID-19 with a prevalence rate of around 20-30%, mainly due to SIAD or hypovolaemia. Hypernatraemia is less common (prevalence of 2-5%) and is more a problem of COVID-19 in intensive care units, most probably due to insensible water losses from the constant pyrexia and due to increased respiration rate. This tendency may be enhanced in patients with DI, who are at risk of hypernatraemic dehydration. Treatment of dehydration must be tempered with the potential to precipitate pulmonary oedema with i.v. fluid; treatment plans should be carefully agreed upon between endocrinologists and intensivists. Hyponatraemia in severely COVID-19-affected patients should be treated by guideline principles but with similar caution with respect to the volume of i.v. fluids in hypovolaemic hyponatraemia or in acute hyponatraemia with cerebral irritation. # Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this guidance. # Funding This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. ## Disclaimer Due to the emerging nature of the COVID-19 crisis, this document is not based on extensive systematic review or meta-analysis but on rapid expert consensus. The document should be considered as guidance only; it is not intended to determine an absolute standard of medical care. Healthcare staff needs to consider individual circumstances when devising the management plan for a specific patient.	None	None	None
9f0f10be3a970bb6ebd0a102671553d4b31414e6	pubmed	Consensus statement for cancer patients requiring intensive care support	Consensus statement for cancer patients requiring intensive care support This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients. In patients with hematological or oncological malignancies, the disease itself or intensive therapy may result in critical illness in a substantial number of patients. In 1999, the American College of Critical Care Medicine stated that patients with hematological or metastasized oncological malignancies are poor candidates for ICU admission with a mortality rate of up to 90%. Thus, refusal of ICU admission of these patients was the common procedure (Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine, 1999 [bib_ref] Guidelines for intensive care unit admission, discharge, and triage. Task force of..., Tfotacocc [/bib_ref]. However, within the last 25 years, cancer and ICU treatment clearly improved. As shown in recent reports, hospital mortality decreased to less than 40% in these critically ill patients with hematologic malignancies [bib_ref] Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from..., Azoulay [/bib_ref]. Thus, criteria for ICU admission have to be adjusted. Aim of this consensus statement is to provide a review of the recent literature and the development of practical recommendations to hematologists, oncologists, and intensive care specialists. Due to a series of practice-changing investigations on proper ventilation techniques in cancer patients with acute respiratory failure, we put a special emphasis on discussing this topic. # Methods The consensus group was selected to represent the expertise in the field of critical care in cancer patients in Germany and Austria. Experts were sent by the German Society of Hematology and Medical Oncology (DGHO), the Austrian Society of Hematology and Oncology (OeGHO), the German Society of Internal Intensive and Emergency Medicine (DGIIN), and the Austrian Society of Medical and General Intensive Care and Emergency Medicine (ÖGIAIN). All authors are actively supporting the "Intensive Care Medicine in Hematologic and Oncologic Patients (iCHOP)" Initiative (info@ichop.eu). Consensus statements are based on an in-depth PubMed literature retrieval of English as well as German language literature with last access February 01, 2017. For medical heading terms (MeSH) identifying potential relevant literature, please see Appendix. Seven working groups (a: ICU transfer criteria and goals of therapy, b: respiratory failure, c: end of live decisions, d: stem cell transplant patients, e: infections, f: coagulation, and g: miscellaneous) prepared the draft proposals in a first round of consensus development. Working groups decided on references with relevant impact on guideline development, and every group member had to approve the draft guideline subchapter. Finally, the consensus statements were approved by the assembly of the members on March 2nd and 3rd 2017 in Vienna, Austria, a meeting hosted and sponsored by the OeGHO. All statements and manuscript wording underwent voting of the consensus assembly. This guideline follows the structure and definitions of the ESCMID Guideline on Candida diseases [bib_ref] ESCMID Fungal Infection Study Group (2012) ESCMID* guideline for the diagnosis and..., Cornely [/bib_ref]. It is in accordance with the GRADE and AGREE [bib_ref] for the AGREE Next Steps Consortium (2010) AGREE II: advancing guideline development,..., Brouwers [/bib_ref] [bib_ref] Grading quality of evidence and strength of recommendations in clinical practice guidelines..., Brozek [/bib_ref] [fig_ref] Table 1: Strength of the recommendation and quality of evidence [/fig_ref]. All recommendations are given in boldface type. ## Prognosis and icu admission criteria Whom to admit to the ICU/eligibility and goals of therapy This statement, of course, presumes that the acute condition may be reversed by ICU measures, and that age and comorbidities of patients do not contradict such an approach. Typically, full-code management applies to patients with curative therapeutic options, those in remission of their malignancy, as well as to patients in whom cure is not likely but the expected life-span is substantial [bib_ref] Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from..., Azoulay [/bib_ref]. It has been suggested in an earlier consensus that an assumed prognosis of 1 year may be used as cutoff for clinical decision making with regard to full-code status [bib_ref] Intensive care of the cancer patient: recent achievements and remaining challenges, Azoulay [/bib_ref]. The authors of this manuscript believe this number is arbitrary and may be regarded as basis for individual considerations only. Patients with poor performance status not eligible for further anti-cancer therapy, dying patients, as well as those rejecting critical care treatment should not be admitted to the ICU in general (A-III) For patients not fulfilling the above-described criteria for full-code ICU management or ICU refusal, time-limited ICU trials or pre-defined do-not-escalate decisions (e.g., do-not-intubate or do-not-attempt-resuscitation) may be adequate options (B-IIu) In a prospective trial on patients with intermediary prognosis (non-palliative, non-bedridden, non-full-code patients), those with worsening organ failure scores after days 5 of ICU therapy had a high risk of dying. The authors suggested to offer these patients a full-code ICU trial with re-evaluation of the goals of therapy after at least 6 days . We would like to point out that almost all patients who died after day 5 had treatmentlimitation decisions. Therefore, it remains unknown what their course would have been in case of further full-code management. Furthermore, data on cancer patients with poor prognosis suggest that the optimal duration of time-limited ICU trials seems to differ largely between patients with solid tumors and hematologic malignancies [bib_ref] Time-limited trials of intensive care for critically ill patients with cancer: how..., Shrime [/bib_ref]. Thus, proposing a fixed interval from admission to re-evaluation of the goals of ICU therapy in patients undergoing time-limited ICU trials may not be generally appropriate. When to admit to the ICU, indications and screening for organ dysfunction Several observational investigations on cancer patients with septic complications and respiratory failure indicate that early ICU admissions and early interventions, respectively, are associated with improved survival [bib_ref] Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from..., Azoulay [/bib_ref] [bib_ref] Predictive factors of intensive care unit admission in patients with haematological malignancies..., Gruson [/bib_ref] [bib_ref] Intensive care unit management of patients with newly diagnosed acute myeloid leukemia..., Lengline [/bib_ref] [bib_ref] Implementation of modified early-goal directed therapy for sepsis in the emergency center..., Hanzelka [/bib_ref] [bib_ref] Delayed intensive care unit admission is associated with increased mortality in patients..., Mokart [/bib_ref] [bib_ref] Early intervention on the outcomes in critically ill cancer patients admitted to..., Song [/bib_ref]. Thus, early identification of patients at risk for critical deterioration seems crucial. Severity of illness scores can only be used for describing groups of patients and should, therefore, not be used in individual clinical decision making with regard to ICU admissions or prognostication. Cancer patients should be considered for ICU admission in case of manifest or incipient acute organ dysfunction(s) (A-IIu) Cancer ward patients at risk should be screened for the presence of sepsis daily (A-IIt) Cancer ward patients at risk should be screened for the presence of acute organ dysfunction(s) daily (A-IIu) ## Recommendations for local structures and educational matters Mortality of ICU cancer patients has markedly dropped over the last decades, presumably due to improved general ICU management, improved diagnostic and therapeutic strategies for several cancer-specific situations, as well as refined admission criteria [bib_ref] Intensive care of the cancer patient: recent achievements and remaining challenges, Azoulay [/bib_ref] [bib_ref] Managing critically Ill hematology patients: time to think differently, Azoulay [/bib_ref] [bib_ref] Critically ill patients with cancer: chances and limitations of intensive care medicine-a..., Schellongowski [/bib_ref] ]. Yet, prognostication of cancer patients and adequate patient selection remain far from perfect [bib_ref] Outcome of cancer patients considered for intensive care unit admission: a hospital-wide..., Thiery [/bib_ref]. Centers should establish local admission criteria for critically ill cancer patients as well as standardized admission procedures, such as joint assessment by cancer specialists and intensivists, if available (A-III) A recent Brazilian investigation showed an independent correlation between daily joint rounds of cancer specialists and intensivists as well as the number of protocols with lower mortality and more efficient resource use [bib_ref] Effects of organizational characteristics on outcomes and resource use in patients with..., Soares [/bib_ref]. This is supported by Nassar and coworker stating that regular meetings may reduce possible conflicts between intensivists and oncologists [bib_ref] Oncologists' and intensivists' attitudes toward the care of critically Ill patients with..., Nassar [/bib_ref]. Centers should establish daily joint rounds of cancer specialists and intensivists as well as standard-operating procedures for the management of frequent medical conditions of critically ill cancer patients (A-IIu) Although a recent study by Soares and colleagues failed to identify ICU volume as a prognostic marker for ICU survival [bib_ref] Effects of organizational characteristics on outcomes and resource use in patients with..., Soares [/bib_ref] , the majority of available studies demonstrate a significant association of case volume and ICU mortality in cancer patients with septic shock or acute respiratory failure [bib_ref] Case volume and mortality in haematological patients with acute respiratory failure, Lecuyer [/bib_ref] [bib_ref] Intensive care in patients with lung cancer: a multinational study, Soares [/bib_ref] [bib_ref] Impact of case volume on survival of septic shock in patients with..., Zuber [/bib_ref]. This effect might be linked to expertise and specific processes of care. However, some of the available observational studies may not have accounted for potential confounders related to ICU organization, structure, and process of care. Ultimately recognizing and developing Bcritical care of cancer patientsâ s a medical subspecialty may optimally serve the needs of affected patients [bib_ref] CCC meets ICU: redefining the role of critical care of cancer patients, Bergwelt-Baildon [/bib_ref]. Nevertheless, due to the fast-growing demand for critical care for cancer patients, the major practical challenge is how to provide high-quality and affordable care for all patients. Treating all critically ill cancer patients regardless of the underlying condition in specialized centers may not be feasible after all. Therefore, managing some of the rather common cancer-specific ICU problems, such as neutropenic sepsis, should become part of routine expertise for all intensive care specialists. However, in more specific situations, such as chemotherapy administration in critically ill patients with aggressive hematologic malignancies or caring for ICU patients after allogeneic stem cell transplant, transfer to specialized centers should be discussed. ## Centers should establish joint continuous medical education of cancer specialists and intensivists (a-iii) Basic concepts of the care of critically ill cancer patients should be included into the curricula of both cancer specialists and intensivists (A-III) All previous statements are summarized in [fig_ref] Table 2: Admission to ICU, eligibility, and aims of therapy Full-code ICU management in... [/fig_ref]. ## Acute respiratory failure (arf) ## Diagnostic work-up With respect to the critical prognosis of ARF in cancer patients, especially in patients with ARF of unknown origin [bib_ref] The prognosis of acute respiratory failure in critically ill cancer patients, Azoulay [/bib_ref] [bib_ref] Increased mortality in hematological malignancy patients with acute respiratory failure from undetermined..., Contejean [/bib_ref] , diagnostic procedures are of major clinical importance. A systematic diagnostic work-up may lead to a (high-probability) diagnosis in approximately 70-80% of patients with ARF [bib_ref] Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized..., Azoulay [/bib_ref] [bib_ref] Overview of current lung imaging in acute respiratory distress syndrome, Zompatori [/bib_ref]. However, diagnostic procedures should not cause a delay in the start of adequate ARF therapy including prompt antibiotic treatment (modification) in the case of a (suspected) infection (A-III). The diagnostic strategy should encompass a comprehensive analysis of the clinical course of the underlying malignancy, including data on mechanisms of immunosuppression, antineoplastic and antimicrobial treatment, and prophylaxis [bib_ref] Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized..., Azoulay [/bib_ref] [bib_ref] Clinical assessment for identifying causes of acute respiratory failure in cancer patients, Schnell [/bib_ref]. ## Independent of the clinical presentation, chest computed tomography is recommended (a-iit) Bronchoscopy and a BAL-based diagnostic work-up including a broad range of both culture-and non-culture-based diagnostic methods should be added to noninvasive tests depending on pretest probabilities of clinical etiologies (if clinically feasible early after ICU admission and without causing clinical worsening) (A-I) [fig_ref] Table 3: Bacteriological cultures [/fig_ref] provides a summary of diagnostic procedures in cancer patients with ARF. ## Ventilatory strategies Noninvasive ventilation (NIV) remains the first-line standard of care in acute exacerbate chronic pulmonary [bib_ref] Implementation of the German S3-guideline of non-invasive ventilation for acute respiratory failure..., Westhoff [/bib_ref]. However, the role of NIV in hypoxic ARF is far less well documented. While a historic single-center randomized controlled trial (RCT) suggested superiority of NIV over conventional oxygen therapy in immunocompromised (mainly hematologic) patients with regard to intubation and survival rates [bib_ref] Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory..., Hilbert [/bib_ref] , successive (mainly observational) studies have led to conflicting results. The 2015 BClinical Practice Guidelines on noninvasive mechanical ventilation in ARF^on behalf of the German Society of Pneumology and Ventilatory Medicine acknowledge that NIV can be attempted to avoid intubation in immunosuppressed (including hemato-oncologic) patients. In this regard, it is of particular importance to respect common contraindications and termination, i.e., intubation criteria [bib_ref] Implementation of the German S3-guideline of non-invasive ventilation for acute respiratory failure..., Westhoff [/bib_ref]. However, the respective guideline could not account for several meanwhile published investigations: First, a meta-analysis on 2380 mainly hematologic patients revealed that NIV as initial ventilator strategy was associated with lower mortality, whereas this finding is a mere association and cannot be interpreted as proof of principle. Importantly, 61% (range 40 to 78) of patients experienced NIV failure with secondary intubation, which itself was associated with increased mortality [bib_ref] Impact of initial ventilatory strategy in hematological patients with acute respiratory failure:..., Bernal [/bib_ref]. Second, in a large multicenter observational investigation in 1004 cancer patients with ARDS, NIV failure occurred in 71% of patients and was, again, independently associated with mortality, while mortality of ARDS patients undergoing IMV per se had decreased to 52% in recent years [bib_ref] Noninvasive ventilation during acute respiratory distress syndrome in patients with cancer: trends..., Neuschwander [/bib_ref]. Finally, a recent large multicenter landmark RCT compared the use of NIV to conventional oxygen in immunocompromised (mainly hematologic) patients with hypoxic ARF (acute cardiogenic pulmonary edema or hypercapnia, i.e., PaCO 2 > 50 mmHg excluded, pre-specified intubation criteria [bib_ref] Effect of noninvasive ventilation vs oxygen therapy on mortality among immunocompromised patients..., Lemiale [/bib_ref]. The trial did not show any clinical benefits or increased harms associated with NIV. However, the lower than expected mortality rate in the oxygen only group limited the power to detect significant differences, and a higher proportion of patients in the NIV group received high flow nasal oxygen intermittently, which may have limited the demonstrable effects of NIV. Risk factors for NIV failure in cancer patients are depicted in [fig_ref] Table 4: Risk factors for NIV failure in cancer patients with acute respiratory failure [/fig_ref]. High flow nasal oxygen (HFNO) has recently been shown to be associated with reduced intubation (PaO 2 /FiO 2 < 200) and mortality (PaO 2 /FiO 2 < 300) rates in elderly patients with pneumonia and hypoxic ARF when compared to conventional oxygen therapy or NIV [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref]. This effect was also observed in the subset of immunocompromised patients [bib_ref] Effect of non-invasive oxygenation strategies in immunocompromised patients with severe acute respiratory..., Frat [/bib_ref]. However, given conflicting data, the applicability of these findings in cancer patients, and specifically in those presenting with other etiologies than pneumonia, remains to be demonstrated [bib_ref] High-flow nasal cannula oxygenation in immunocompromised patients with acute hypoxemic respiratory failure:..., Lemiale [/bib_ref] [bib_ref] Ventilatory strategies in patients with hematologic malignancies and acute respiratory failure: new..., Schellongowski [/bib_ref]. In case a NIV or HFNO trial is initiated in cancer patients with hypoxic ARF, common contraindications and/or the occurrence of pre-specified intubation criteria should lead to intubation and invasive mechanical ventilation without delay (A-IIu) Given the considerable failure rates of NIV and HFNO in hypoxic ARF and the lack of sufficient data on the safety of such therapies in regular wards, NIV and HFNO should not be attempted in this indication on a regular ward (B-III) ## End-of-life, palliative care Principles in palliative care and end-of-life (EOL) management are not different in cancer patients compared to critically ill patients without a malignancy as underlying disease (A-IIt). However, (i) patient's wish, (ii) progressive (multi-) organ failure despite full-code ICU management and no chance of reversibility, or (iii) rapid progress of cancer disease without further treatment options have to be kept in mind and could change the treatment decision or treatment goals [bib_ref] End-of-life practices in European intensive care units, Sprung [/bib_ref]. These issues have to be discussed between oncologists and the intensive care team in an interdisciplinary manner. In cancer patients admitted to an ICU, current treatment state and estimated prognosis may be unknown to the ICU team. Therefore, consultation of an oncologist is highly recommended to provide valid prognostic information (A-III). Intensive care admissions often represent an additional burden for patients and families in situations without option for cure. Good communication is essential to allow patients and families to meet their preferences regarding EOL. According to the literature, too many EOL decisions are made too late [bib_ref] Admission to intensive care unit at the end-of-life: is it an informed..., Rady [/bib_ref]. Early integration of an interdisciplinary palliative care team for hospitalized patients with life-limiting disease leads to fewer ICU admissions (A-I) [bib_ref] Impact of an inpatient palliative care team: a randomized control trial, Gade [/bib_ref]. Furthermore, integration of pro-active palliative care on ICUs, including palliative care rounds, leads to a shorter length of stay on ICU or in the hospital (A-IIt) [bib_ref] Proactive palliative care in the medical intensive care unit: effects on length..., Norton [/bib_ref] [bib_ref] Prospective study of a proactive palliative care rounding intervention in a medical..., Braus [/bib_ref]. To improve quality of EOL care in critically ill patients regarding important clinical questions, i.e., preparing for withdrawal, assessment and drug management of distress, discontinuation of treatment and monitoring, or dignity conserving care [bib_ref] Dying with dignity in the intensive care unit, Cook [/bib_ref] , the authors refer to published consensus recommendations [bib_ref] Guidelines for the withdrawal of life-sustaining measures, Downar [/bib_ref]. ## Special situations Anticancer therapy during ICU In some cases, for example pulmonary involvement due to high grade non-Hodgkin lymphoma, hyperleukocytosis, etc., despite ICU treatment initiation or completion of anticancer chemotherapy, immunochemotherapy or radiotherapy is necessary to improve patient's clinical situation. Such some decision needs intensive discussions between the responsible hemato-oncologist and intensivist. Again, we recommend joint assessments by cancer specialists and intensivists and that basic concepts of the care of critically ill cancer patients should be included into the curricula of both cancer specialists and intensivists. ## Prevention and treatment of infections in critically ill cancer patients Published guidelines on prevention, diagnosis, and treatment of infections in cancer patients do not specifically address critically ill cancer patients. In addition, few studies and current guidelines on infections in critically ill patients specifically address the particular requirements in the treatment of cancer patients [fig_ref] Table 5: Recommendations on prevention, diagnosis, and treatment of infections in cancer patients [/fig_ref]. Resources on prevention and treatment of infections in cancer patients, which might be largely applicable to critically ill cancer patients, are guidelines on: & Management of neutropenic patients in the intensive care unit [bib_ref] Management of neutropenic patients in the intensive care unit (NEWBORNS EXCLUDED) recommendations..., Schnell [/bib_ref] & Prophylaxis of viral [bib_ref] Antiviral prophylaxis in patients with solid tumours and haematological malignancies-update of the..., Sandherr [/bib_ref] , bacterial [bib_ref] Infectious diseases working P et al (2013) Primary prophylaxis of bacterial infections..., Neumann [/bib_ref] , and fungal [bib_ref] Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014..., Tacke [/bib_ref] infections including Pneumocystis jirovecii pneumonia [bib_ref] Infectious diseases working P et al (2013) Primary prophylaxis of bacterial infections..., Neumann [/bib_ref] & Unexplained fever in neutropenic patients [bib_ref] Antimicrobial therapy of unexplained fever in neutropenic patients-guidelines of the Infectious Diseases..., Link [/bib_ref] (new version in progress) & Diagnosis of invasive fungal infections [bib_ref] Diagnosis of invasive fungal infections in hematology and oncology-guidelines from the Infectious..., Ruhnke [/bib_ref] (new version in progress) & Treatment of invasive fungal infections [bib_ref] Treatment of invasive fungal infections in cancer patients-updated recommendations of the Infectious..., Mousset [/bib_ref] and AIIt [bib_ref] Prophylaxis of infectious complications with colonystimulating factors in adult cancer patients undergoing..., Vehreschild [/bib_ref] Allogeneic stem cell transplant setting ## Criteria for icu admission The prognosis of allogeneic hematopoietic stem cell transplant (HSCT) patients admitted to an ICU has been significantly improved in the last years [bib_ref] Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients, Lengline [/bib_ref]. It is important to note that physicians of the primary hospital have to contact the patient's transplant center immediately in case of critical illness. Allogeneic HSCT patients with early ICU admission or single organ dysfunction benefit from intensive care. However, patients with uncontrolled or refractory graft-versus-host disease (GvHD) should not be intubated for acute respiratory failure (A-III) [bib_ref] Intensive care of the cancer patient: recent achievements and remaining challenges, Azoulay [/bib_ref] [bib_ref] Critically ill allogeneic hematopoietic stem cell transplantation patients in the intensive care..., Saillard [/bib_ref]. Thus, it is important to contact immediately patient's transplant center. For further information regarding isolation procedures, specific monitoring, as well as typical complications, please see supplement. ## Coagulation Venous thromboembolism (VTE), including deep-vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in cancer patients. An increased tumor burden results in a higher risk for VTE with the highest risk in patients receiving systemic chemotherapy or being hospitalized on surgical and medical floors. Although there are no validated data on the risk assessment in cancer patients on the ICU, according to the American Society of Clinical Oncology guidelines, risk scores (Khorana Score, revised Khorana score, Vienna score and Protecht score) are helpful tools to identify patients at highest risk for VTE [bib_ref] Development and validation of a predictive model for chemotherapy-associated thrombosis, Khorana [/bib_ref] [bib_ref] Risk stratification strategies for cancer-associated thrombosis: an update, Khorana [/bib_ref] [bib_ref] A modified Khorana risk assessment score for venous thromboembolism in cancer patients..., Verso [/bib_ref]. For further information on thromboprophylaxis in hospitalized patients with cancer, thromboprophylaxis in surgical patients with cancer, and treatment of thrombosis, please see Supplement [fig_ref] Table 3: Bacteriological cultures [/fig_ref] and accompanying text. ## Complications after new cancer drugs or cellular immunotherapy Pharmacological and cellular treatment of cancer is changing dramatically not only with benefits for patient's outcome and comfort, but also with new toxicity profiles. The vast majority of adverse events can be classified as mild or moderate but there are also some cases of severe and life-threatening complications requiring ICU admission. Diagnosis and management of severe side effects after (monoclonal or bispecific) antibody treatment, tyrosine kinase inhibitors, immune checkpoint inhibitors, and chimeric antigen receptor-modified (CAR-) T cells were summarized recently in a concise review by the iCHOP group [bib_ref] New drugs, new toxicities: severe side effects of modern targeted and immunotherapy..., Kroschinsky [/bib_ref]. ## Vaia ## Transfusions In order to prevent the transfusion-associated graft versus host reaction (GvHR), all cellular blood products have to be irradiated with ≥ 30 Gy for patients with lymphatic diseases, autologous/allogeneic stem cell transplantation, and all patients treated with nucleoside analogues (fludarabine, cladribine) [bib_ref] The irradiation of blood and blood components to prevent graft-versus-host disease: technical..., Moroff [/bib_ref]. Generally, to prevent acute hemolysis, AB0identic transfusions should be carried out. However, after allogeneic HSCT, in exceptional cases, it is possible to transfuse major or minor incompatible blood products according to the AB0 blood group of the patient and the donor as stated in Supplement Table S1 [bib_ref] Stellungnahme der Sektion BTransplantation und Zelltherapie^zur Transplantation hämatopoetischer Stammzellen mit Blutgruppendifferenz, Cassens [/bib_ref]. Pooled platelet concentrates have a higher risk of immunization. Therefore, we recommend the transfusion of apheresis platelet concentrates. ## Cytokine storm disease/sepsis-like syndromes Cancer patients are at risk to suffer from rare sepsis-like syndromes such as hemophagocytic lymphohistiocytosis (HLH), cytokine release syndrome (CRS), drug reaction with eosinophilia and systemic syndromes (DRESS), or capillary leak syndrome (CLS) [bib_ref] Hemophagocytic lymphohistiocytosis : a diagnostic challenge on the ICU, Lachmann [/bib_ref] [bib_ref] Drug-induced lymphadenopathy with eosinophilia and renal failure mimicking lymphoma disease: dramatic onset..., Schnetzke [/bib_ref] [bib_ref] Granulocyte colonystimulating factor-induced capillary leak syndrome confirmed by extravascular lung water measurements, Deeren [/bib_ref] [bib_ref] Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia, Frey [/bib_ref]. Infections, malignancy itself, and drugs are major triggers for these sepsis-mimicking syndromes. Diagnostic vigilance for early recognition is essential to reduce mortality. To validate diagnosis, we recommend to include blood differential (cytopenia, eosinophilia), ferritin, soluble IL2R, fibrinogen, and triglycerides in addition to the routine ICU lab admission panel in cancer patients with sepsis or sepsis-like syndromes in whom there is no apparent focus of sepsis [bib_ref] Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society (2015) Consensus..., Lehmberg [/bib_ref] (see [fig_ref] Table 6: HLH diagnostic criteria [/fig_ref] for HLH diagnostic criteria). Withholding the assumed trigger drug and immediate search for an underlying malignancy or infection are pivotal. HLH patients require immediate immunosuppression with corticosteroids to prevent further progression of organ failure . Early consultation with an HLH expert to stratify treatment according to the most likely trigger is recommended (www.hlh-registry.org). ## Summary During the last years, outcome of patients with malignant hematological or oncological diseases requiring intensive care treatment has clearly improved. From recently published data, we conclude that the severity of the acute illness is more important with regard to short-term survival than the underlying type and stage of malignancy. Patients receiving intensive treatment of their malignancy should be considered for ICU treatment as other severely ill patients without cancer. Centers should establish local admission criteria for critically ill cancer patients as well as standardized admission procedures, such as joint assessment by cancer specialists and intensivists, allowing identification of patients and standardized transfer to the ICU. In some patients, time-limited ICU trials with pre-defined do-not-escalate decisions (e.g., do-not-intubate or do-not-attempt-resuscitation) may be an adequate option until final decision. This implements that critically ill cancer patients should be referred to experienced intensive care units. We strongly recommend establishing a local structure with daily joint rounds of cancer specialists and intensivists as well as standard-operating procedures for the management of frequent medical conditions in critically ill cancer patients. Furthermore, centers should organize continuous medical education of cancer specialists and intensivists. Finally, basic concepts of the care of critically ill cancer patients should be included into the curricula of both cancer specialists and intensivists. In addition, the early integration of an interdisciplinary palliative care team is an urgently necessary measure. In order to improve the management of critically ill cancer patients, knowledge of current practices in German-speaking countries is of utmost interest. To produce more robust data, participation of treating centers in central patient registries, e.g., the iCHOP registry (info@ichop.eu), is highly recommended. ## Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Open Access This article is distributed under the terms of the Creative Comm ons 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.HLH-2004 diagnostic criteria: ≥ 5 must be fulfilled -Fever (≥ 38.3°C) -Splenomegaly -Cytopenias in ≥ 2 lines (hb < 9 g/dL, plt < 100 /nL, neutrophils < 1.0/nL) -Ferritin ≥ 500 μg/L -Hypertriglyceridemia and/or hypofibrinogenemia (fasting triglycerides ≥ 265 mg/dL, fibrinogen < 1.5 g/L) -Hemophagocytosis in bone marrow or spleen or lymph nodes -Low or absent NK activity -Soluble CD25 (soluble IL-2 receptor) ≥ 2400 U/mL [table] Table 1: Strength of the recommendation and quality of evidence [/table] [table] Table 2: Admission to ICU, eligibility, and aims of therapy Full-code ICU management in all critically ill cancer patients with prospect of long-term survival ICU refusal in patients with poor performance status not eligible for further anti-cancer therapy, dying patients, as well as those rejecting critical care Time-limited ICU trial and/or do-not-escalate decisions in patients neither fulfilling full code nor refusal criteria [/table] [table] Table 3: Bacteriological cultures (quantitative or semi-quantitative) including culture media to detect Legionella spp., mycobacteria and fungi • Calcofluor white or equivalent stain (assessment of fungi) • (quantitative, if possible) PCR for Pneumocystis jirovecii • direct immunofluorescence test for Pneumocystis jirovecii • Aspergillus antigen (Galactomannan ELISA) [/table] [table] Table 4: Risk factors for NIV failure in cancer patients with acute respiratory failure [/table] [table] Table 5: Recommendations on prevention, diagnosis, and treatment of infections in cancer patients [/table] [table] Table 6: HLH diagnostic criteria [/table]	None	https://link.springer.com/content/pdf/10.1007/s00277-018-3312-y.pdf	None
e23971bcb16a89e75f297cd201f7aa81dd36f236	pubmed	Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline update	Endoscopy in patients on antiplatelet or anticoagulant therapy: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guideline update ## Summary of recommendations Recommendations for the management of patients on antiplatelet therapy or anticoagulants undergoing elective endoscopic procedures are summarised in figures 1 and 2. Risk stratification for endoscopic procedures are detailed in table 1, for antiplatelet agents in table 2, and for heparin bridging in patients on warfarin table We recommend that all patients are advised of the thrombotic risks of discontinuing antiplatelets or anticoagulants, as well as the haemorrhagic risks of continuing therapy (strong recommendation, low quality evidence). For all endoscopic procedures we recommend continuing aspirin (strong recommendation, low quality evidence), with the exception of ampullectomy (weak recommendation, low quality evidence). If considering aspirin discontinuation, this should be on an individual patient basis depending on the risks of thrombosis versus haemorrhage (weak recommendation, low quality evidence). ## Low-risk endoscopic procedures For low-risk endoscopic procedures we recommend continuing P2Y12 receptor antagonists as single or dual antiplatelet therapy (DAPT) (strong recommendation, low quality evidence). For low-risk endoscopic procedures we suggest that warfarin therapy should be continued (weak recommendation, low quality evidence). It should be ensured that the international normalised ratio (INR) does not exceed the therapeutic range in the week prior to the procedure (strong recommendation, low quality evidence). For low-risk endoscopic procedures we suggest omitting the morning dose of direct oral anticoagulants (DOACs) on the day of the procedure (weak recommendation, low quality evidence). ## High-risk endoscopic procedures For high-risk endoscopic procedures in patients at low thrombotic risk, we recommend discontinuing P2Y12 receptor antagonists 7 days before the procedure (strong recommendation, moderate quality evidence). In patients on DAPT, we recommend continuing aspirin (strong recommendation, low quality evidence). For high-risk endoscopic procedures in patients at low thrombotic risk, we recommend discontinuing warfarin for 5 days before the procedure (strong recommendation, high quality evidence). Check INR prior to the procedure to ensure <1.5 (strong recommendation, low quality evidence). For high-risk endoscopic procedures in patients at high thrombotic risk, we recommend continuing aspirin and liaising with a consultant interventional cardiologist about the risk/benefit of discontinuing P2Y12 receptor antagonists (strong recommendation, high quality evidence). For high-risk endoscopic procedures in patients at high thrombotic risk, we recommend that warfarin should be temporarily discontinued and substituted with low molecular weight heparin (LMWH) (strong recommendation, low quality evidence). ## Guidelines figure 1 Guidelines for the management of patients on P2Y12 receptor antagonist antiplatelet agents undergoing endoscopic procedures: 2021 update. EMR, endoscopic mucosal resection; ERCP, endoscopic retrograde cholangiopancreatography; ESD, endoscopic submucosal dissection;EUS, endoscopic ultrasound; PEG, percutaneous endoscopic gastroenterostomy. For high-risk endoscopic procedures in patients on DOACs, we recommend that the last dose of DOACs be taken 3 days before the procedure (strong recommendation, low quality evidence). For patients on dabigatran with a creatinine clearance (CrCl) (or estimated glomerular filtration rate (eGFR)) of 30-50 mL/min we recommend that the last dose be taken 5 days prior to the procedure (strong recommendation, low quality evidence). In any patient with rapidly deteriorating renal function a haematologist should be consulted (strong recommendation, low quality evidence). ## Post elective endoscopic procedures If antiplatelet or anticoagulant therapy is discontinued, then we recommend this should be resumed up to 2-3 days after the procedure depending on the perceived haemorrhagic and thrombotic risks (strong recommendation, moderate quality evidence). For all patients on antiplatelets or anticoagulants we recommend advising that there is an increased risk of post-procedure haemorrhage compared with patients not on these drugs (strong recommendation, low quality evidence). ## Acute gi haemorrhage We suggest that permanent discontinuation of aspirin for primary prophylaxis should be considered (weak recommendation, low quality evidence). We suggest that aspirin for secondary prevention should not be routinely stopped. If it is stopped, it should be recommenced as soon as haemostasis is achieved, or there is no further evidence of haemorrhage (strong recommendation, moderate quality evidence). We recommend that DAPT is continued if possible in patients with coronary stents in situ and management should be in liaison with a consultant interventional cardiologist (strong recommendation, moderate quality evidence). In the case of major haemorrhage we recommend continuing aspirin if the P2Y12 receptor antagonist is interrupted (strong recommendation, moderate quality evidence). P2Y12 receptor antagonist therapy should be re-instated within 5 days, if still indicated (strong recommendation, moderate quality evidence). We recommend withholding oral anticoagulant and correcting coagulopathy according to the severity of haemorrhage and the patient's thrombotic risk in coordination with a consultant cardiologist/haematologist. The correction of coagulopathy should not delay endoscopy or radiological intervention (strong recommendation, low quality evidence). In patients with haemodynamic instability who take vitamin K antagonists (VKAs), we recommend administering intravenous vitamin K and four-factor prothrombin complex concentrate (PCC) (strong recommendation, low quality evidence), or fresh frozen plasma if PCC is not available (weak recommendation, very low quality evidence). In patients with haemodynamic instability who take DOACs, we suggest considering the use of reversal agents: idarucizumab in dabigatran treated patients, and andexanet in anti-factor-Xa (anti-FXa) treated patients (weak recommendation, low quality evidence), or intravenous four-factor PCC if andexanet is not available (weak recommendation, very low quality evidence). We recommend restarting anticoagulation following acute GI haemorrhage in patients with an indication for long-term anticoagulation (strong recommendation, low quality evidence). In Risk stratification for discontinuation of P2Y12 receptor antagonists clopidogrel, prasugrel or ticagrelor based on the risk of thrombosis patients at low thrombotic risk, we suggest restarting anticoagulation as soon as possible after 7 days of anticoagulant interruption (weak recommendation, low quality evidence). In those at high-thrombotic risk, an earlier resumption of anticoagulation with heparin bridging, preferably within 3 days, is recommended (strong recommendation, low quality evidence). ## Guidelines # Introduction and methods The British Society of Gastroenterology (BSG) and the European Society of Gastrointestinal Endoscopy (ESGE) jointly published guidelines on endoscopy in patients on antiplatelet or anticoagulant therapy, including DOACs in 2016. This is a scheduled 5-year update on the previous guidelines. These guidelines were drafted by a working party comprising members of the BSG and ESGE, two haematologists representing the Thrombosis and Haemostasis Task Force of the British Society of Haematology, an interventional cardiologist representing the British Cardiovascular Intervention Society (BCIS), and two patient representatives from the charities Anticoagulation UK and Thrombosis UK. Guidelines were prepared according to AGREE II principles 3 and comply with the requirements of the National Institute for Health and Care Excellence (NICE). Clinical questions were formulated using the Patients, Interventions, Controls, Outcomes system. Search strategies were delegated to authors with responsibilities for specific sections. Literature searches were conducted using PubMed and OVID Medline, Embase and Cochrane Library. Additional searches were conducted using Google. Literature searches were run up to November 2020, and this time-point should be the starting point in the search for new evidence for future updates to these guidelines. Quality of evidence and strength of recommendations were determined by the authors, and consensus achieved according to the GRADE system. [bib_ref] Grade: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] After agreement on a final version, the manuscript was subjected to internal peer review and revision by the BSG and the ESGE and sent to all individual ESGE members and member societies prior to publication. Conflict of interest statements were submitted by all authors and are listed at the end of this manuscript. This guideline was issued in 2021 and will be considered for review in 2026, or sooner if new evidence becomes available. This guideline has been co-published with permission in both Gut and Endoscopy. ## Patient considerations We recommend that all patients are advised of the thrombotic risks of discontinuing antiplatelets or anticoagulants, as well as the haemorrhagic risks of continuing therapy (strong recommendation, low quality evidence). For all patients on antiplatelets or anticoagulants we recommend advising that there is an increased risk of post-procedure haemorrhage compared with patients not on these drugs (strong recommendation, low quality evidence). As discussed, management of antithrombotic drugs is a balance of the risks of haemorrhage from the procedure versus the risks of thrombosis if antithrombotic medication is discontinued or modified. Haemorrhage secondary to high-risk endoscopic procedures can often be controlled by further endoscopic therapeutic measures, and is rarely fatal. A thrombotic stroke may result in lifelong disability, and a major cardiac event may result in death. Not only do the risks of thrombosis versus haemorrhage need to be assessed on an individual patient basis, but patients should be fully informed, and involved in this decisionmaking process. The risk of a potentially catastrophic thrombotic event such as a stroke may not be acceptable to a patient even if that risk is very low. Once the decision to modify antithrombotic medication is made, then a personal plan for that patient should be made. This should include written as well as verbal information regarding the precise timing of any changes. This should include the time figure 3 Perioperative direct oral anticoagulant (DOAC) management protocol. Reproduced with permission from Douketis et al. [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] Copyright (2019) American Medical Association. All rights reserved. No DOAC was taken on certain days (shaded) and on the day of the elective surgery or procedure (including endoscopy). The light blue arrows refer to an exception to the basic management, a subgroup of patients taking dabigatran with a creatinine clearance (CrCl) less than 50 ng/mL. The orange arrows refer to patients having a high-bleed-risk procedure. Dark blue arrows refer to patients having a low-bleed-risk procedure. The thickened orange arrows refer to flexibility in timing of DOAC resumption after a procedure. of last dose of a drug, and first dose when restarting. If multiple drugs are involved, or substitutions including bridging with heparin, then timing respective to each drug should be clearly communicated. Simple algorithms such as those illustrated in the PAUSE trial for DOACs 5 may be useful (figure 3). Late haemorrhagic complications may occur one to 2 weeks after endoscopic therapy, and antithrombotic therapy will have often been reinstituted prior to this. Patients on antithrombotics should be advised that there is a possible increase in postprocedure haemorrhage, and also advised how to seek urgent medical advice at any time of the day or night. We have produced a patient information sheet based on this guideline to assist with patient engagement (online supplemental file). ## Antiplatelet agents For all endoscopic procedures we recommend continuing aspirin (strong recommendation, low quality evidence), with the exception of ampullectomy (weak recommendation, low quality evidence). If considering aspirin discontinuation, this should be on an individual patient basis depending on the risks of thrombosis versus haemorrhage (weak recommendation, low quality evidence). For low-risk endoscopic procedures we recommend continuing P2Y12 receptor antagonists as single or DAPT (strong recommendation, low quality evidence). For high-risk endoscopic procedures in patients at low thrombotic risk, we recommend discontinuing P2Y12 receptor antagonists 7 days before the procedure (strong recommendation, moderate quality evidence). In patients on DAPT, we recommend continuing aspirin (strong recommendation, low quality evidence). For high-risk endoscopic procedures in patients at high thrombotic risk, we recommend continuing aspirin and liaising with a consultant interventional cardiologist about the risk/benefit of discontinuing P2Y12 receptor antagonists (strong recommendation, high quality evidence). ## Aspirin When given as long-term secondary prevention aspirin reduces vascular events by approximately one-third and vascular deaths by about one-sixth. In patients on long-term low-dose aspirin for secondary prevention, aspirin interruption was associated with a threefold increased risk of cardiovascular or cerebrovascular events, and 70% of these events occurred within 7-10 days after interruption. In a randomised controlled trial (RCT) of 220 patients on low-dose aspirin for secondary prevention undergoing non-cardiac surgery, patients were randomised to continuation or temporary replacement of aspirin by placebo. [bib_ref] To continue or discontinue aspirin in the perioperative period: a randomized, controlled..., Oscarsson [/bib_ref] Major cardiac events occurred within 30 days in 1.8% of the aspirin group compared with 9% in the placebo group (p=0.02). No difference in haemorrhagic complications was seen between the two groups. The risks related to continuation or discontinuation of aspirin for endoscopy are discussed in the sections on endoscopic procedures, and recommendations made accordingly. With regard to patients on a DOAC and a single antiplatelet agent, such as aspirin, the AFIRE trial randomised patients with atrial fibrillation (AF) and stable coronary artery disease to rivaroxaban alone versus rivaroxaban and a single antiplatelet. They demonstrated that rivaroxaban alone was non-inferior for the primary efficacy endpoint (a composite of thromboembolic events or death from any cause) and superior for the primary safety endpoint of major bleeding. However, this trial was not sufficiently powered to address the risk of stent thrombosis. [bib_ref] Antithrombotic therapy for atrial fibrillation with stable coronary disease, Yasuda [/bib_ref] For patients with documented coronary artery disease and an indication for formal anticoagulation, for example, AF, then a life-long single antiplatelet such as aspirin is no longer recommended, beyond the antiplatelet duration required postcoronary stent insertion, in the latest ESC guidelines. [bib_ref] ESC guidelines for the diagnosis and management of chronic coronary syndromes, Knuuti [/bib_ref] However, late stent thrombosis (1-12 months poststent implantation) and very late stent thrombosis (beyond 12 months poststent implantation) occur with a reported incidence of 0.5%-1.0% and 0.2%-0.4%, respectively, and stent thrombosis is associated with a 4%-45% mortality. [bib_ref] Predictors of stent thrombosis and their implications for clinical practice, Gori [/bib_ref] Furthermore, technical aspects of the procedure, for example, left main stents, may have an essential bearing on the subsequent risk of stent thrombosis. The trials addressing whether a long-term antiplatelet agent is needed in patients that have stents and require a DOAC, which suggest a DOAC alone may be safe, are not sufficiently powered to look at the important endpoint of stent thrombosis. Many consultant interventional cardiologists in the UK recommend their patients remain on a single antiplatelet agent if they have stents and need a long term DOAC, although this will very much vary on an individual case-by-case basis. Therefore, in patients with coronary stents who are taking a DOAC the cessation of the single antiplatelet agent should always be discussed in advance with the consultant interventional cardiologist responsible for the patient's care. Following the publication of three RCTs in 2018 the use of aspirin in primary prevention in cardiovascular disease is no longer routinely recommended and should only be considered, on a case-by-case basis, in those with a very high individual risk of cardiovascular events. 13 ## P2y12 receptor antagonists Antiplatelet drugs have a rapid onset of action, and irreversibly inhibit platelet activity. Clopidogrel, prasugrel and ticagrelor are antagonists of the P2Y12 receptor on platelets. Clopidogrel plus aspirin is more potent than aspirin alone. 14 For clopidogrel, platelet function returns to normal 5-7 days after withdrawal of the drug. [bib_ref] Peri-Operative management of antiplatelet therapy in patients with coronary artery disease: joint..., Korte [/bib_ref] Prasugrel and ticagrelor are more rapidly acting and more potent platelet receptor antagonists than clopidogrel. Clopidogrel monotherapy may be used following a thromboembolic cerebrovascular accident, or for peripheral vascular disease. P2Y12 receptor antagonists are frequently used as DAPT with aspirin in acute coronary syndrome (ACS) and after placement Guidelines of coronary stents. High-risk and low-risk indications for P2Y12 receptor antagonists are listed in table 2. Patients on DAPT, with aspirin and a P2Y12 receptor antagonist, particularly in the context of coronary artery stents, are at high risk of thrombosis if drug therapy is discontinued. Without antiplatelet therapy coronary stents are at high risk of occlusion due to thrombosis, and this confers an approximate 40% risk of acute myocardial infarction or death. In one study, discontinuation of DAPT was associated with an HR of 161 for these events. [bib_ref] Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents, Iakovou [/bib_ref] DAPT is generally prescribed for 12 months after drug eluting stents (DES) implantation, though there have been occasional reported instances of thrombosis after this duration. Prasugrel and ticagrelor are now the main drugs of choice used for ACS in the UK. Prasugrel has been shown in a large UK observational series to be associated with a lower mortality. [bib_ref] Association of different antiplatelet therapies with mortality after primary percutaneous coronary intervention, Olier [/bib_ref] This has been confirmed in a large randomised open-label trial. [bib_ref] Ticagrelor or prasugrel in patients with acute coronary syndromes, Schüpke [/bib_ref] The latest NICE guidelines for ACS now recommend prasugrel is used as the first line agent in ACS, unless the patient is on anticoagulant therapy, in which case clopidogrel is recommended. Clopidogrel is generally the first choice of P2Y12 inhibitor in patients undergoing elective percutaneous coronary intervention (PCI) and the current guidelines recommend a 6 month course of DAPT postelective PCI. [bib_ref] ESC guidelines for the diagnosis and management of chronic coronary syndromes, Knuuti [/bib_ref] Where temporary cessation of P2Y12 inhibitors in patients with stents has been agreed, after discussion with the responsible consultant interventional cardiologist, then stopping the P2Y12 inhibitors 7 days preprocedure will minimise the bleeding risk. However, it should be noted that, depending on the P2Y12 agent, this time can be shortened dependent on the P2Y12 agent in use. In patients with a very high risk of stent thrombosis there may also be a role for bridging either with intravenous cangrelor and/or GIIbIIIa agents. However, the role of such bridging agents is beyond the remit of this paper and this decision should be made along with the responsible consultant interventional cardiologist on a case-by-case basis. [bib_ref] ESC focused update on dual antiplatelet therapy in coronary artery disease developed..., Valgimigli [/bib_ref] Bare metal stents (BMS), which only require 1 month of DAPT, are now much less frequently used and the national BCIS audit shows they are used in less than 15% of cases in the UK, and many units no longer even stock them. Their main indication is for use in patients with a high bleeding risk or requiring urgent major surgery. Many UK units now use BioFreedom DES, these are polymer-free drug coated stents, which have a license of 1 month of DAPT and are superior to BMS with respect to major safety endpoints including bleeding and restenosis rates. [bib_ref] Polymer-Free Drug-Coated coronary stents in patients at high bleeding risk, Urban [/bib_ref] Finally, there is increasing evidence that with a number of third generation DESs 1 month of DAPT can safely be used in patients at high bleeding risk without an increase in ischaemic events. [bib_ref] One-Month dual antiplatelet therapy following percutaneous coronary intervention with zotarolimus-eluting stents in..., Kandzari [/bib_ref] [bib_ref] Drug-Eluting stents in elderly patients with coronary artery disease (senior): a randomised..., Varenne [/bib_ref] [bib_ref] Effect of 1-Month dual antiplatelet therapy followed by clopidogrel vs 12-month dual..., Watanabe [/bib_ref] A single antiplatelet agent is continued in all cases after discontinuation of DAPT, this tends to be aspirin. In some cases, for example, patients who had a previous stroke, the patients may have aspirin stopped at the end of the DAPT course and clopidogrel continued long-term. The important issue of a single antiplatelet agent in patients on long-term DOACs is discussed in the previous section. Finally, in patients on a DOAC for AF and stroke prophylaxis who need DAPT after stent implantation, evidence from trials such as the RE-DUAL trial indicate that much shorter courses of triple therapy followed by a course of DOAC and clopidogrel alone are safer than previous practice of triple therapy up to a year. [bib_ref] Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation, Cannon [/bib_ref] The European Society of Cardiology and NICE guidelines, for both ACS and elective stenting, now support shorter durations of triple therapy followed by a DOAC and clopidogrel as the current standard of care. [bib_ref] ESC guidelines for the diagnosis and management of chronic coronary syndromes, Knuuti [/bib_ref] The duration of DAPT post-PCI may also depend on a number of other factors, beyond the scope of this guideline. Therefore, in patients with coronary stents, we recommend that the endoscopist discusses the plan, with respect to potential DAPT cessation, with a consultant interventional cardiologist. Ideally this should be the consultant interventional cardiologist responsible for the patient's care, who did the stent procedure. ## Anticoagulants warfarin and heparin For low-risk endoscopic procedures we suggest that warfarin therapy should be continued (low quality evidence, moderate recommendation). It should be ensured that the INR does not exceed the therapeutic range in the week prior to the procedure (low quality evidence, strong recommendation). ► Tell the patient to continue warfarin and check the INR during the week before the endoscopy. ► If the INR result is within the therapeutic range then continue with the usual daily dose. ► If the INR result is above the therapeutic range, but less than 5, then reduce the daily warfarin dose until the INR returns to within the therapeutic range. ► If the INR is greater than 5 then defer the endoscopy and contact the anticoagulation clinic, or a medical practitioner, for advice. For high-risk endoscopic procedures in patients at low thrombotic risk, we recommend discontinuing warfarin for 5 days before the procedure (strong recommendation, high quality evidence). Check INR prior to the procedure to ensure <1.5 (strong recommendation, low quality evidence). ► Stop warfarin for 5 days before the endoscopy. ► Check the INR prior to the procedure to ensure its value is <1.5. ► On the day of the procedure restart warfarin with the usual daily dose that night. ► Check INR 1 week later to ensure adequate anticoagulation. For high-risk endoscopic procedures in patients at high thrombotic risk, we recommend that warfarin should be temporarily discontinued and substituted with LMWH (moderate quality evidence, strong recommendation). ► Warfarin should be stopped for 5 days before the procedure. ► Two days after stopping warfarin commence daily therapeutic dose of LMWH. ► Administer the last dose of LMWH at least 24 hours prior to the procedure. ► Check the INR prior to the procedure to ensure its value is <1.5. ► Warfarin can be resumed on the day of the procedure with the usual dose that night. ► Restart the daily therapeutic dose of LMWH on the day after the procedure. ► Continue LMWH until a satisfactory INR is achieved. Updated literature searches were conducted on the use of warfarin and heparin in patients undergoing endoscopy. There were no new data to indicate a change to the existing protocols above. Any new data relevant to interventional therapy are discussed in the sections on specific endoscopic procedures. ## Direct oral anticoagulants For low-risk endoscopic procedures we suggest omitting the morning dose of DOACs on the day of the procedure (weak recommendation, low quality evidence). For high-risk endoscopic procedures in patients on DOACs, we recommend that the last dose of DOACs be taken 3 days before the procedure (strong recommendation. low quality evidence). For patients on dabigatran with a CrCl (or eGFR) of 30-50 mL/min we recommend that the last dose be taken 5 days prior to the procedure (strong recommendation, low quality evidence). In any patient with rapidly deteriorating renal function a haematologist should be consulted (strong recommendation, low quality evidence). DOACs have been a major advance in anticoagulant therapy. Dabigatran is an inhibitor of thrombin, and rivaroxaban, apixaban and edoxaban inhibit FXa. They do not need routine monitoring, and INR and activated partial thromboplastin time (aPTT) are unreliable indicators of anticoagulant activity. Unlike warfarin they have a rapid onset of action and full anticoagulant activity is established within 3 hours of the first dose. They have relatively short half-lives, but these may be prolonged in renal failure, particularly for dabigatran. In patients undergoing a high-risk procedure with a low thrombotic risk we recommend that the last dose of rivaroxaban, apixaban or edoxaban is taken 3 days before the procedure. Dabigatran may have to be stopped for longer than this, however, when renal function is significantly reduced. [bib_ref] Perioperative management of dabigatran: a prospective cohort study, Schulman [/bib_ref] For patients on dabigatran with CrCl of 30-50 mL/min we recommend that the last dose of the drug is 5 days before the procedure. Dabigatran therapy is contraindicated in patients with CrCl<30 mL/min. eGFR is a suitable alternative measurement of renal function, and the same numerical values apply for the purposes of these guidelines. If a patient on any DOAC is clinically deteriorating, his/her renal function should be checked before the procedure. These recommendations are supported by the findings of the PAUSE trial. [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] Three thousand and seven patients on apixaban, dabigatran or rivaroxaban due for elective interventional procedures had a standardised interruption of therapy (figure 3): last dose of drug 2 days before low-risk procedures (including diagnostic GI endoscopy) and 3 days before high-risk procedures (including high-risk therapeutic GI endoscopy; eg, polypectomy). This was extended to last dose 5 days before a high-risk procedure for dabigatran patients with CrCL<50 mL/min. Resumption of therapy occurred at 1 day after low bleeding risk procedures and 2-3 days after high bleeding risk procedures. Low rates of major bleeding or arterial thromboembolism were observed. Low rates of venous thromboembolism were also observed although this was not a primary study outcome. We have maintained the recommendation to omit the morning dose of DOAC prior to low-risk endoscopic procedures, although the PAUSE trial demonstrates the safety of omitting the DOAC for 1 day before a low-risk endoscopic procedure if desired. ## Bridging of anticoagulant therapy Unfractionated heparin (UFH) and LMWH (LMWH) have short half lives compared with warfarin and can be employed as an anticoagulation 'bridge' while warfarin is temporarily discontinued for endoscopic procedures considered to have a significant risk of haemorrhage. UFH is administered by continuous intravenous infusion and LMWH by subcutaneous injection once or two times a day. The former requires an inpatient stay in hospital while warfarin is discontinued, and then re-introduced, and also requires frequent monitoring of aPTT; the latter can often be managed in an outpatient setting without monitoring of anticoagulation levels. Some cardiologists have a preference for UFH for bridging warfarin in patients with metal heart valves. A meta-analysis demonstrated higher rates of bleeding in patients with mechanical heart valves bridged with LMWH versus UFH, but numbers were small in the LMWH studies. [bib_ref] Early postoperative bridging anticoagulation after mechanical heart valve replacement: a systematic review..., Passaglia [/bib_ref] A small multicentre registry study found no difference in adverse events between patients bridged with UFH or LMWH in this context,and bridging with LMWH is now commonplace. Guidelines from the American Heart Association and American College of Cardiology do not recommend one strategy over the other. [bib_ref] ACC/AHA guideline for the management of patients with valvular heart disease: a..., Otto [/bib_ref] Prosthetic metal heart valves in the mitral position are at particularly high risk of thrombosis if warfarin is temporarily discontinued for 5-7 days. Heparin bridging for patients with a bileaflet mechanical aortic valve replacement in the absence of AF is considered unnecessary in guidelines from the British Society of Haematology 31 and from the American College of Cardiology/American Heart Association, [bib_ref] AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of..., Nishimura [/bib_ref] but it is recommended in guidelines from the ESC and the European Association for Cardio-Thoracic Surgery. [bib_ref] ESC/EACTS guidelines for the management of valvular heart disease, Baumgartner [/bib_ref] There are no high quality studies to inform us, and consequently levels of evidence are low quality in all three guidelines. We have now placed mechanical aortic valve replacement in the high-risk category requiring bridging, in line with European guidelines, but this should be decided in conjunction with local cardiology or cardiothoracic surgery services given the uncertainty. This should always be discussed with the consultant cardiologist responsible for the patient's care. The risk of thromboembolism with AF increases with additional cardiovascular factors such as hypertension, heart failure and diabetes and this risk has been quantified by the CHADS 2 score (annual risk of stroke increasing from 1.9% with a score of 1 to 18.2% with a score of 6). This has been updated with the CHA 2 DS 2 VASc scoring system in which the annual risk of stroke increases from 1.3% with a score of 1 to 15.2% with score of 9. A randomised, prospective, double-blind placebocontrolled trial was conducted in 1884 patients with AF undergoing a variety of operative procedures including approximately 50% GI endoscopy. [bib_ref] Perioperative bridging anticoagulation in patients with atrial fibrillation, Douketis [/bib_ref] Patients were randomised to LMWH or placebo, and risk factors were well matched. Thirty-eight per cent of the patients had CHADS 2 scores>3, <2% had mitral stenosis and ≤3.4% had CHADS 2 scores of 5 or 6. There was no significant difference in rates of thromboembolism between the LMWH and placebo groups, but there was a significant increase in major haemorrhagic events in the LMWH group versus placebo (3.2% vs 1.3%). Caution should be exercised when interpreting the results in the high-risk thromboembolic groups as the study was not designed or statistically powered to examine these categories. The previous BSG/ESGE guidelines 1 do not recommend bridging for non-valvular AF, ASGE guidelines 35 recommend bridging with LMWH for CHA 2 DS-2 VASc>2 and the APAGE/APSDE guidelines 36 recommend this for CHA 2 DS 2 VASc>5. CHADS 2 scores are unfortunately not directly equivalent to CHA 2 DS 2 VASc scores. Further research on the benefits of heparin bridging is required in high-risk patients with non-valvular AF on warfarin in order to determine the optimum approach, but it would be reasonable to consider bridging patients with CHADS 2 scores >5 as recommended by the British Society of Haematology. [bib_ref] Peri-Operative management of anticoagulation and antiplatelet therapy, Keeling [/bib_ref] This applies to patients with AF and a previous stroke or transient ischaemic attack (TIA), and three of the following factors: congestive cardiac failure, hypertension (>140/90 mm Hg or on antihypertensive medication), age>75 years or diabetes mellitus. Heparin bridging is also recommended for patients with AF who have had a stroke or TIA within 3 months. [bib_ref] Peri-Operative management of anticoagulation and antiplatelet therapy, Keeling [/bib_ref] Bridging with LMWH has also been studied in patients on DOACs. In a German registry, heparin bridging versus no bridging led to a higher rate of major haemorrhage (2.7% vs 0.5%, p=0.01) with no reduction in thromboembolism. [bib_ref] Peri-interventional management of novel oral anticoagulants in daily care: results from the..., Beyer-Westendorf [/bib_ref] In the RE-LY trial bridging of dabigatran with LMWH resulted in higher major haemorrhage rates compared with no bridging Guidelines (6.5% vs 1.8%, p<0.001) with no difference in thrombosis rates between the groups. [bib_ref] Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had..., Douketis [/bib_ref] In a Japanese study of 16 977 patients on warfarin or DOACs undergoing a variety of high-risk endoscopy procedures a propensity matched analysis demonstrated a significant increase in postprocedure GI bleeding and thromboembolism in patients who were bridged with heparin. [bib_ref] Therapeutic endoscopy-related Gi bleeding and thromboembolic events in patients using warfarin or..., Nagata [/bib_ref] It should be noted that all patients were bridged with UFH rather than LMWH. For colonoscopy in patients on warfarin who were bridged with LMWH, several studies have demonstrated an increase in postpolypectomy haemorrhage without a decrease in thromboembolic events. [bib_ref] Heparin-bridging therapy is associated with a high risk of post-polypectomy bleeding regardless..., Ishigami [/bib_ref] [bib_ref] Risk factors for postpolypectomy bleeding in patients receiving anticoagulation or antiplatelet medications, Lin [/bib_ref] [bib_ref] Clinical impact of the perioperative management of oral anticoagulants in bleeding after..., Ono [/bib_ref] Bridging with LMWH should, of course still be advocated for those patients on warfarin at high risk of thromboembolism [fig_ref] Table 3: Risk stratification for discontinuation of warfarin therapy with respect to the requirement... [/fig_ref] , but patients should be advised of the increased risk of post-procedure haemorrhage. The safety of temporary cessation of DOAC therapy, without bridging, is supported by the findings of the PAUSE trial. [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] Patients with a history of venous thromboembolism within 3 months of commencing anticoagulant therapy are at high risk of recurrent thrombosis if anticoagulation is interrupted. Most of these patients are now commenced on a DOAC rather than warfarin, and bridging would not be recommended. Ideally we should not interrupt anticoagulation in this high-risk group due to the risk of thrombosis; an elective low-risk procedure could be performed without interrupting anticoagulation if necessary, but it may be preferable to defer a high-risk procedure beyond 3 months anticoagulation if safe to do so. Patients with thrombophilia syndromes should be discussed with a haematologist. Factor V Leiden and the common prothrombin mutation F2G20210A are low-risk thrombophilias and bridging is not required. Patients with deficiencies of antithrombin, protein C or protein S are at higher risk of thrombosis, but in most of these patients bridging therapy will not be required. ## Endoscopic procedures Minor haemorrhage is not uncommon during therapeutic endoscopic procedures, but we have considered it to be clinically significant when haemoglobin value falls by more than 20 g/L, necessitates blood transfusion, or causes an unplanned hospital admission. Haemorrhage may be apparent at the time of endoscopy, or delayed up to 2 weeks following the procedure. For those in whom antithrombotic therapy is interrupted, the latter situation presents a higher risk, as therapy will usually have been recommenced within that period. There are relatively few studies of the risks of haemorrhage for endoscopic procedures in patients who continue antithrombotic therapy, therefore, much of the data underlying the risk levels for these procedures applies to the baseline risk of haemorrhage without antithrombotic therapy [fig_ref] Table 3: Risk stratification for discontinuation of warfarin therapy with respect to the requirement... [/fig_ref]. ## Diagnostic endoscopy and mucosal biopsy Diagnostic endoscopies, including mucosal biopsy sampling, confer a minimal risk of haemorrhage, and no severe haemorrhage has been reported in studies involving thousands of patients in total. [bib_ref] Towards safer colonoscopy: a report on the complications of 5000 diagnostic or..., Macrae [/bib_ref] [bib_ref] Complications of Fiberoptic Gastrointestinal Endoscopy -Five Years' Experience in a Central Hospital, Reiertsen [/bib_ref] [bib_ref] Complications of flexible fiberoptic colonoscopy and polypectomy, Rogers [/bib_ref] [bib_ref] Gastrointestinal bleeding after cold biopsy, Vu [/bib_ref] [bib_ref] A prospective analysis of 13,580 colonoscopies. reevaluation of credentialing guidelines, Wexner [/bib_ref] No increased risk of haemorrhage from biopsy has been found in studies of patients on aspirin, clopidogrel or warfarin. A prospective case-control study of patients taking antiplatelet or anticoagulant drugs, including DOACs, found no incidence of significant bleeding in either the antithrombotic or control group who had upper GI biopsies taken. [bib_ref] Bleeding risk related to upper gastrointestinal endoscopic biopsy in patients receiving antithrombotic..., Yuki [/bib_ref] Only 19 of the 277 patients who continued antithrombotics were on DOACs. The approximate mean number of biopsies per patient was only two in either group in this study, and in all the above studies only small numbers of biopsies were taken. In a prospective registry study 119 patients were identified who had continuation of DOAC for endoscopy, and 29 patients had biopsies on continued DOAC. [bib_ref] Gastrointestinal endoscopy in patients receiving novel direct oral anticoagulants: results from the..., Heublein [/bib_ref] There were two cases of non-major clinically significant haemorrhage and no cases of major haemorrhage. There is one case report of life-threatening bleeding following multiple biopsies for Barretts oesophagus in a patient on aspirin who was later found to have high grade dysplasia. [bib_ref] Life-threatening bleeding following Barrett's surveillance biopsies, Mannath [/bib_ref] A prospective study of endoscopic practice in Italy 53 regarding adherence to the previous BSG/ESGE antithrombotic guidelines 1 found an increased incidence of haemorrhage in patients undergoing mucosal biopsies in whom DOAC therapy was continued compared with those in whom the morning dose was withheld as recommended in the guidelines (2/38 5.2% vs 2/114 1.7%, respectively). However, numbers of cases were small, the study was not adequately powered to determine this issue, and the difference did not reach statistical significance. The pharmacokinetic profile, and hence pharmacodynamic effect, of DOACs varies such that some individuals will have higher peak levels 2-6 hours after oral administration. [bib_ref] Clinical use of new oral anticoagulant drugs: dabigatran and rivaroxaban, Baglin [/bib_ref] Consequently, at the time of an endoscopic biopsy the anticoagulant effect due to a DOAC is not accurately predictable. Due to this uncertainty regarding the level of anticoagulation on DOACs at the time of endoscopy, and the absence of reliable test of anticoagulation on these drugs, we continue to suggest omitting the dose of DOAC on the morning of the procedure to allow an adequate safety margin. This applies to both once a day and two times a day regimens. ## Resection of gi polyps polypectomy including endoscopic mucosal resection Studies of colonoscopic polypectomy have identified a risk of postpolypectomy bleeding (PPB) of 0.07%-1.7%. It is important to differentiate between immediate and delayed PPB, and also to identify the severity of bleeding; these factors are not always clear in the literature. Delayed PPB is of particular importance in patients in whom antithrombotic therapy has been interrupted, as bleeding will often occur once antithrombotics have been restarted. In a BSG audit of 20 085 colonoscopies in the UK, 52 (0.26%) haemorrhages were reported, but only 3 (0.01%) were major. [bib_ref] The National colonoscopy audit: a nationwide assessment of the quality and safety..., Gavin [/bib_ref] Data from the English National Bowel Cancer Screening Programme found an overall PPB rate of 1.14%, with a rate of severe bleeding requiring transfusion of 0.08%. [bib_ref] Risk factors for adverse events related to polypectomy in the English bowel..., Rutter [/bib_ref] Risk factors for PPB include polyp size 61 use of pure cutting current [bib_ref] Risk factors for immediate postpolypectomy bleeding of the colon: a multicenter study, Kim [/bib_ref] and use of a non-microprocessor-controlled current for endoscopic mucosal resection (EMR). [bib_ref] Risk factors for intraprocedural and clinically significant delayed bleeding after wide-field endoscopic..., Burgess [/bib_ref] Use of endoscopic clips or submucosal injection of diluted epinephrine may also reduce the risk of PPB, Caution is advised, however, when using clips prior to excision for pedunculated polyps as one RCT was closed prematurely due to complications: one perforation (1.5%) and three mucosal burns (4.5%). [bib_ref] Is the use of prophylactic hemoclips in the endoscopic resection of large..., Quintanilla [/bib_ref] An RCT of cold-snare versus hot-snare polypectomy (341 vs 346 polyps, respectively) of polyps 4-9 mm demonstrated no significant haemorrhage in the cold-snare group. [bib_ref] A comparison of the resection rate for cold and hot SNARE polypectomy..., Kawamura [/bib_ref] In all of these studies, patients on antiplatelet therapy or anticoagulation were excluded. A number of studies have examined the risks of resection of small colonic polyps on continued antitcoagulant therapy. A single centre case series of 1177 cold snare polypectomies compared PPB in those on antiplatelets or anticoagulants compared with those not on these drugs. [bib_ref] Safety of cold SNARE polypectomy in patients receiving treatment with antithrombotic agents, Arimoto [/bib_ref] There was an increase in immediate bleeding, mostly in warfarin patients, but no significant difference in delayed bleeding (up to 2 weeks) between the groups. A retrospective study of 223 polypectomies (<1 cm, with or without diathermy) in 123 patients on continued warfarin therapy found a rate of haemorrhage requiring transfusion of 0.8%. This was despite routine prophylactic clipping of polypectomies. [bib_ref] Colonoscopic polypectomy in anticoagulated patients, Friedland [/bib_ref] In an RCT (159 polyps <1 cm in 70 patients) examining hot versus cold snaring of polyps in anticoagulated patients, the rate of immediate haemorrhage in the hot snare versus the cold snare group was 23.0% versus 5.7%, respectively, and that of delayed haemorrhage requiring intervention 14% versus 0%, respectively. [bib_ref] Removal of small colorectal polyps in anticoagulated patients: a prospective randomized comparison..., Horiuchi [/bib_ref] An RCT compared cold polypectomy <1 cm in patients on DOAC or warfarin bridged with UFH compared with cold polypectomy on continued anticoagulant. [bib_ref] Continuous anticoagulation and cold SNARE polypectomy versus heparin bridging and hot SNARE..., Takeuchi [/bib_ref] The incidence of polypectomy-related major bleeding was high at 12.0% in the former group and 4.7% in the latter. The majority of patients in the study would not have not have been considered for bridging by British Society of Haematology guidelines, [bib_ref] Peri-Operative management of anticoagulation and antiplatelet therapy, Keeling [/bib_ref] and LMWH would have been recommended for any that did qualify for bridging. The risk of polypectomy on continued antiplatelet therapy has also been studied. Aspirin monotherapy has been found to be safe in colonoscopic polypectomy. 72-74 A double blind RCT included patients on clopidogrel therapy who required colonoscopy. [bib_ref] Risk of Postpolypectomy bleeding with uninterrupted clopidogrel therapy in an Industry-Independent, double-blind,..., Chan [/bib_ref] They were randomised at 7 days before procedure into either continuing with clopidogrel 75 mg a day or placebo until the morning of colonoscopy. If discontinued, clopidogrel was restarted after colonoscopy when oral intake was allowed. More than 90% of patients had polyps les than 1 cm. There was no significant difference in immediate or delayed PPB, or in cardiothrombotic events, between the two groups. These conclusions, however, need to be treated with some caution. Although the study aim was to examine the effect of clopidogrel, a high proportion of patients were on DAPT. The groups were well matched but numbers were relatively small to examine differences in an infrequent event, and the rate of PPB in the placebo group was higher than expected when compared with other studies of patients undergoing polypectomy not previously on antiplatelet agents. A meta-analysis 76 assessing the risks of immediate and PPB associated with continued clopidogrel use at time of polypectomy included the above trial. A total of five studies were identified which included 655 patients in the 'continuing clopidogrel' group and 6620 controls with interrupted clopidogrel therapy. There was an increased risk of PPB in the continuing clopidogrel group (risk ratio 1.96; 95% CI 1.36 to 2.83; p=0.0003). There was no significant difference in serious cardio thrombotic events occurring within 30 days of the procedure. In the above studies the great majority of polypectomies were <1 cm. Further research is required, particularly with respect to polypectomy on DAPT, but based on the above data, it may be safe to undertake polypectomy for polyps <1 cm in size on clopidogrel monotherapy. To minimise the risk of PPB cold snare polypectomy may be advisable. Alternatively, temporarily substituting aspirin for clopidogrel may be desirable 7 days prior to colonoscopy. In large case series of EMR, the incidence of immediate and delayed bleeding ranged between 3.7%-11.3% and 0.6%-6.2%, respectively. [bib_ref] Risk factors for intraprocedural and clinically significant delayed bleeding after wide-field endoscopic..., Burgess [/bib_ref] For EMR of small lesions (<1 cm), however, PPB rates were similar to those reported following conventional polypectomy. [bib_ref] A national survey of endoscopic mucosal resection for superficial gastrointestinal neoplasia, Heresbach [/bib_ref] A retrospective cohort study did not find aspirin (continued till day of procedure) or P2Y12 receptor antagonists (stopped 5-7 days before EMR) to be significant factors associated with bleeding post-EMR of colon neoplasia. [bib_ref] Factors associated with delayed bleeding after resection of large nonpedunculated colorectal polyps, Elliott [/bib_ref] However, only a small minority (aspirin 20% and clopidogrel 2%) of patients were taking these medications. The rate of delayed post-EMR bleeding in the oesophagus is low (0.6%-0.9%), even in studies that include a high proportion of patients with a temporary cessation of antiplatelet therapy. In two retrospective observational studies of duodenal EMR, delayed bleeding was reported in 14/113 (12.3%) 82 and 7/111 patients (6.3%) [bib_ref] Factors associated with increased bleeding post-endoscopic mucosal resection, Qumseya [/bib_ref] despite the prophylactic use of endoclips in 82% of cases in the latter. There are conflicting studies on the use of prophylactic endoclips for EMR. [bib_ref] Prophylactic clip closure reduced the risk of delayed postpolypectomy hemorrhage: experience in..., Liaquat [/bib_ref] [bib_ref] The prophylactic placement of hemoclips to prevent delayed post-polypectomy bleeding: an unnecessary..., Feagins [/bib_ref] [bib_ref] Prophylactic clip application does not decrease delayed bleeding after colonoscopic polypectomy, Shioji [/bib_ref] A cost-efficacy analysis concluded that prophylactic placement of endoscopic clips after polypectomy was a cost-effective strategy for patients receiving antiplatelet or anticoagulation therapy. [bib_ref] A cost-efficacy decision analysis of prophylactic clip placement after endoscopic removal of..., Parikh [/bib_ref] Prophylactic use of endoclips may therefore be advisable for EMR in patients on antithrombotics due to the increased risk of PPB. ## Endoscopic submucosal dissection There have been several studies of endoscopic submucosal dissection (ESD) on continuous low dose aspirin since the previous version of this guideline. One retrospective multicentre study [bib_ref] A risk-scoring model for the prediction of delayed bleeding after colorectal endoscopic..., Seo [/bib_ref] for colonic ESD, and six retrospective studies of gastric ESD, [bib_ref] Feasibility of gastric endoscopic submucosal dissection with continuous low-dose aspirin for patients..., Harada [/bib_ref] [bib_ref] Effect of continued administration of lowdose aspirin for intraoperative bleeding control in..., Horikawa [/bib_ref] [bib_ref] Should antithrombotic therapy be stopped in patients undergoing gastric endoscopic submucosal dissection?, Igarashi [/bib_ref] [bib_ref] Postoperative bleeding risk after gastric endoscopic submucosal dissection during antithrombotic drug therapy, Kono [/bib_ref] [bib_ref] Continuous use of thienopyridine may be as safe as lowdose aspirin in..., Oh [/bib_ref] [bib_ref] Comparison of the effects of antithrombotic therapy on delayed bleeding after gastric..., So [/bib_ref] comparing continuation with interruption of aspirin, found no significant differences in delayed bleeding the two groups. This was confirmed by two meta-analyses which also reported that continuation of low dose aspirin does not increase the postprocedure bleeding after ESD. This was also observed in the group of patients under DAPT in which aspirin was continued alone. [bib_ref] Feasibility of gastric endoscopic submucosal dissection with continuous low-dose aspirin for patients..., Harada [/bib_ref] Furthermore, inappropriate discontinuation of antiplatelet agents was significantly associated with increased risk of thrombosis. [bib_ref] Should antithrombotic therapy be stopped in patients undergoing gastric endoscopic submucosal dissection?, Igarashi [/bib_ref] A meta-analysis found a thrombosis rate of 2.1% in the aspirin-interrupted versus none in the aspirin-continued group of patients. [bib_ref] Continued versus interrupted aspirin use and bleeding risk after endoscopic submucosal dissection..., Jaruvongvanich [/bib_ref] Continued thienopyridine (clopidogrel or prasugrel) or aspirin use did not increase delayed haemorrhage for gastric ESD in one retrospective study. [bib_ref] Continuous use of thienopyridine may be as safe as lowdose aspirin in..., Oh [/bib_ref] A non-randomised retrospective comparative study found, however, that continuation of any antithrombotic, or heparin bridging, increased the risk of haemorrage with gastric ESD. [bib_ref] Comparison of the effects of antithrombotic therapy on delayed bleeding after gastric..., So [/bib_ref] The risk of haemorrhage following gastric ESD is increased with the number of antiplatelet agents taken or when antiplatelet drugs are combined with anticoagulation. [bib_ref] Influence of anticoagulants on the risk of delayed bleeding after gastric endoscopic..., Tomida [/bib_ref] For colorectal ESD, antiplatelet agents except for aspirin alone were independent risk factors of delayed bleeding (OR 4.04, 95% CI 1.44 to 11.30, p=0.008) in a retrospective multicentre study including 180/1189 patients on antiplatelets. [bib_ref] A risk-scoring model for the prediction of delayed bleeding after colorectal endoscopic..., Seo [/bib_ref] In a large national database including 16 977 patients who underwent high-risk endoscopic procedures under oral anticoagulation, upper and lower GI ESD were found to be significantly associated with postprocedure haemorrhage. [bib_ref] Therapeutic endoscopy-related Gi bleeding and thromboembolic events in patients using warfarin or..., Nagata [/bib_ref] The delayed bleeding rate after ESD at any location has been found to be 16% in patients who have had warfarin or DOACs, including those with heparin bridging (UFH). [bib_ref] Risk factors for delayed bleeding after therapeutic gastrointestinal endoscopy in patients receiving..., Kubo [/bib_ref] A meta-analysis of ESD studies found a significant increase in delayed haemorrhage and an increase in thrombosis with heparin bridging compared with those who discontinued anticoagulation without bridging. [bib_ref] Effects of antithrombotic therapy on bleeding after endoscopic submucosal dissection, Dong [/bib_ref] A meta-analysis focused on heparin bridging therapy (UFH) for gastric ESD patients on warfarin or DOACs found an increased risk of haemorrhage without any benefit in thrombosis. [bib_ref] Continued versus interrupted aspirin use and bleeding risk after endoscopic submucosal dissection..., Jaruvongvanich [/bib_ref] Studies of colonic ESD on anticoagulants have included small numbers and retrospective analysis, and conflicting conclusions have been derived. [bib_ref] A risk-scoring model for the prediction of delayed bleeding after colorectal endoscopic..., Seo [/bib_ref] Few data are available for oesophageal or duodenal ESD on antithrombotics. The risk of bleeding after oesophageal ESD is lower at compared with other locations, but one retrospective study found a significant higher readmission rate after oesophageal ESD for patients with a history of antiplatelet or anticoagulant use (56.4% vs 34.1%; p=0.01). 102 ## Guidelines Several methods have been proposed to reduce the risk of haemorrhage after ESD including pharmacological (PPI), mechanical (clips, endoscopic hand sutures) and local topical (fibrin glue and polyglycolic acid sheets, haemostatic powder) techniques, and these should be particularly considered in patients on antithrombotic therapy. ## Endoscopic retrograde cholangiopancreatography In a meta-analysis (21 prospective studies; 16 855 patients), the overall haemorrhage rate following endoscopic retrograde cholangiopancreatography (ERCP) was 1.3%, with 71% of these being graded as moderate and 29% as severe; the mortality rate was 0.05% overall. [bib_ref] Incidence rates of post-ERCP complications: a systematic survey of prospective studies, Andriulli [/bib_ref] Post-ERCP haemorrhage is most frequently seen after endoscopic biliary sphincterotomy. An ESGE guideline on ERCP-related adverse events has suggested that patients should be considered to be at increased risk for post-sphincterotomy haemorrhage if at least one of the following factors is present: anticoagulant intake, platelet count <50 x10ˆ9/L, cirrhosis, dialysis for end-stage renal disease, intraprocedural bleeding and low endoscopist experience. [bib_ref] ERCP-related adverse events: European Society of gastrointestinal endoscopy (ESGE) guideline, Dumonceau [/bib_ref] There are a number of measures which can reduce the risk of haemorrhage at ERCP including avoidance of sphincterotomy prior to biliary stenting, [bib_ref] Endoscopic management of common bile duct stones: European Society of gastrointestinal endoscopy..., Manes [/bib_ref] and use of a blended current rather than pure-cutting current. [bib_ref] Endocut versus conventional blended Electrosurgical current for endoscopic biliary sphincterotomy: a meta-analysis..., Li [/bib_ref] [bib_ref] European Society of gastrointestinal endoscopy (ESGE) guideline: the use of electrosurgical units, Rey [/bib_ref] [bib_ref] Pure versus mixed electrosurgical current for endoscopic biliary sphincterotomy: a meta-analysis of..., Verma [/bib_ref] These, and other measures to reduce the risk of haemorrhage are discussed in previous ESGE guidelines. Two uncontrolled retrospective studies reported postendoscopic sphincterotomy (ES) bleeding in 8 (19%) of 43 patients under antiplatelet monotherapy or dual therapy, including only one significant episode of haemorrhage. Controlled studies of bleeding following ES performed under antiplatelet therapy have failed to demonstrate an increase in patients taking antiplatelets at the time of ES versus controls, but studies were underpowered to show a difference. [bib_ref] Endoscopic retrograde cholangiopancreatography in patients with previous acute coronary syndrome, Koh [/bib_ref] [bib_ref] Effect of sustained use of platelet aggregation inhibitors on post-endoscopic sphincterotomy bleeding, Lee [/bib_ref] [bib_ref] Do aspirin and non-steroidal anti-inflammatory drugs increase the risk of post-sphincterotomy hemorrhage--a..., Onal [/bib_ref] A single retrospective study (762 patients) has compared post-ES bleeding rates in patients who discontinued antiplatelets for >7 days (n=29), <7 days (n=83) or did not discontinue antiplatelets (n=49). [bib_ref] Effect of sustained use of platelet aggregation inhibitors on post-endoscopic sphincterotomy bleeding, Lee [/bib_ref] The incidence of bleeding (defined as clinical evidence of bleeding or a drop in haemoglobin>20g/L) was respectively 10.3% (delayed, 6.9%), 6.0% (delayed, 2.4%) and 16.3% (delayed, 14.3%). The only significant association was between sustained antiplatelet use and the delayed type of post-ES bleeding. Of note, a majority of antiplatelet users were taking aspirin only. A retrospective study in which 50/191 patients undergoing ES were on aspirin, showed no statistically significant increase in haemorrhage in the aspirin group. [bib_ref] Major hemorrhage from endoscopic sphincterotomy: risk factor analysis, Nelson [/bib_ref] Haemorrhage following endoscopic sphincteroplasty has been reported in 0%-8.6% of patients. [bib_ref] Large balloon dilation post endoscopic sphincterotomy in removal of difficult common bile..., Rouquette [/bib_ref] One small case series suggested that continued aspirin therapy may be safe, [bib_ref] Large-balloon dilation of the sphincter of Oddi after sphincterotomy or infundibulotomy to..., Poincloux [/bib_ref] but there are no data on other antithrombotics. There are no data for biliary mechanical lithotripsy, cholangioscopy or electrohydraulic lithotripsy therapy in patients taking antiplatelets or anticoagulants. ## Ampullectomy A meta-analysis (29 studies, 1751 patients) reported that haemorrhage occurs in 10.6% of ampullectomies with approximately 25% and 5% requiring blood transfusion and non-conservative management, respectively. [bib_ref] Endoscopic papillectomy for neoplastic ampullary lesions: a systematic review with pooled analysis, Spadaccini [/bib_ref] Various measures to prevent haemorrhage have been studied, but more research is required to make definitive conclusions. A non-randomised pilot study (n=80) suggested that routinely closing the mucosal defect with clips following ampullectomy is effective to prevent delayed bleeding (5% vs 22.5%, p=0.026). [bib_ref] Effect of preventive closure of the frenulum after endoscopic papillectomy: a prospective..., Kagawa [/bib_ref] An RCT has suggested that, compared with the autocut mode, the endocut mode may prevent immediate but not delayed bleeding in cases with tumours>14 mm; it causes more frequent crush artefacts. [bib_ref] Impact of electrical pulse cut mode during endoscopic papillectomy: pilot randomized clinical..., Iwasaki [/bib_ref] Prophylactic argon plasma coagulation has been reported as effective in a retrospective study (n=82) and ineffective in an RCT (n=54) to prevent post-ampullectomy bleeding. Submucosal injection prior to ampullectomy did not prevent bleeding in an RCT (n=50) and a retrospective matched cohort analysis (n=50) ; furthermore it was associated with higher tumour recurrence rate and a shorter recurrence-free survival in the retrospective study. [bib_ref] Effect of submucosal injection in endoscopic papillectomy of ampullary tumor: Propensity-score matching..., Chung [/bib_ref] There are no data on ampullectomy on anticoagulants or P2Y12 receptor antagonists as these are usually withdrawn. Given the high haemorrhage rate, withdrawal of aspirin should be considered on an individual basis depending on the risks of thrombosis. ## Endoscopic ultrasound-guided with fine-needle aspiration, and other interventions The incidence of haemorrhage following endoscopic ultrasound (EUS)-guided sampling has been analysed in several systematic reviews; the figure per thousand was 1.28 for EUS-guided with fine-needle aspiration (FNA) (51 studies, 10 941 patients), [bib_ref] Assessment of morbidity and mortality associated with EUS-guided fna: a systematic review, Wang [/bib_ref] [bib_ref] Assessment of morbidity and mortality associated with endoscopic ultrasound-guided fine-needle aspiration for..., Zhu [/bib_ref] Four studies reported on haemorrhage following EUS-guided sampling in patients prescribed antithrombotic agents. [bib_ref] Bleeding risk of endoscopic ultrasound-guided fine-needle aspiration in patients undergoing antithrombotic therapy, Inoue [/bib_ref] [bib_ref] A prospective multicenter study evaluating bleeding risk after endoscopic ultrasound-guided fine needle..., Kawakubo [/bib_ref] [bib_ref] A prospective control study of the safety and cellular yield of EUS-guided..., Vu [/bib_ref] [bib_ref] Outcomes of EUS-FNA in patients receiving antithrombotic therapy, Polmanee [/bib_ref] The only significant differences were between patients on prophylactic LMWH and controls. [bib_ref] A prospective control study of the safety and cellular yield of EUS-guided..., Vu [/bib_ref] In the largest study, however, no severe haemorrhage was found in patients who continued or discontinued antithrombotic therapy, and only one thromboembolic event occurred. [bib_ref] Outcomes of EUS-FNA in patients receiving antithrombotic therapy, Polmanee [/bib_ref] EUS-guided biliary drainage, an alternative to ERCP-guided biliary stenting, has been suggested to be safely feasible in patients with sustained use of antiplatelets and/or anticoagulants. In a retrospective study that included 41 patients on antiplatelets and/or anticoagulants (23 patients under DAPT, anticoagulant or a combination of antiplatelet and anticoagulant) and 154 controls, bleeding rates were not significantly different in the antiplatelet/anticoagulants and control groups (7.3% and 2.6%, respectively). [bib_ref] Antiplatelet and/or anticoagulant treatment does not increase hemorrhagic adverse events during EUS-guided..., Ogura [/bib_ref] The safety of EUS-guided biliary drainage should however be confirmed in prospective studies, adequately powered to evidence a significant difference, before a recommendation can be made. Invasive therapeutic procedures such as EUS and cystgastrostomy or necrosectomy have a significant risk of major haemorrhage and should be considered as high risk for P2Y12 receptor antagonists or anticoagulants. The risk on aspirin is unknown. ## Endoscopic dilatation Review of studies which included greater than 100 patients with benign upper GI strictures, either anastomotic, achalasia, post-ESD, eosinophilic, gastric outlet obstruction or mixed aetiology, reveals a risk of haemorrhage well below 1%. [bib_ref] Outcomes of pneumatic dilatation and Heller's myotomy for achalasia in England between, Harvey [/bib_ref] [bib_ref] Endoscopic balloon dilation and submucosal injection of triamcinolone acetonide in the treatment..., Qi [/bib_ref] [bib_ref] Risk factors and clinical outcomes of endoscopic dilation in benign esophageal strictures:..., Vermeulen [/bib_ref] [bib_ref] Outcomes and predictors for Re-stenosis of esophageal stricture in epidermolysis bullosa: a..., Pope [/bib_ref] [bib_ref] Esophageal dilation with either bougie or balloon technique as a treatment for..., Dougherty [/bib_ref] [bib_ref] Outcomes of esophageal dilation in eosinophilic esophagitis: safety, efficacy, and persistence of..., Runge [/bib_ref] [bib_ref] Etiological spectrum and response to endoscopic balloon dilation in patients with benign..., Kochhar [/bib_ref] [bib_ref] Endoscopic dilation of bariatric RNY anastomotic strictures: a systematic review and meta-analysis, Baumann [/bib_ref] [bib_ref] Complications of endoscopic dilation for esophageal stenosis after endoscopic submucosal dissection of..., Kishida [/bib_ref] [bib_ref] Endoscopic dilation of benign esophageal anastomotic strictures over 16 mm has a..., Van Halsema [/bib_ref] A systematic review and meta-analysis of studies of endoscopic dilatation of gastroduodenal Crohn's disease strictures revealed a 2.1% per procedure risk of haemorrhage. [bib_ref] A pooled analysis of efficacy, safety, and long-term outcome of endoscopic balloon..., Bettenworth [/bib_ref] In a prospective study of dilatation in 55 patients with oesophageal carcinoma no clinically relevant haemorrhage was observed. [bib_ref] Balloon dilation for endosonographic staging in esophageal cancer: a phase 1 clinical..., Molina [/bib_ref] Dilatation for lower GI strictures, either iatrogenic or related to inflammatory bowel disease, revealed no significant haemorrhage in prospective studies or larger retrospective case series (over 100 patients). [bib_ref] Endoscopic treatment of pouch inlet and afferent limb strictures: stricturotomy vs. balloon..., Lan [/bib_ref] [bib_ref] Efficacy and safety of endoscopic balloon dilation in inflammatory bowel disease: results..., Andújar [/bib_ref] [bib_ref] Endoscopic Stricturotomy versus balloon dilation in the treatment of anastomotic strictures in..., Lan [/bib_ref] [bib_ref] Outcomes of endoscopic balloon dilation vs surgical resection for primary ileocolic strictures..., Lan [/bib_ref] [bib_ref] Long-Term results of endoscopic balloon dilation for treatment of colorectal anastomotic stenosis, Biraima [/bib_ref] No data were found regarding dilatation in malignant colonic strictures. A study of the complications arising from 504 balloon dilations in 237 patients with achalasia revealed 4 (1.7%) asymptomatic haematomas, but no clinically significant haemorrhage. [bib_ref] Risk factors for immediate complications after progressive pneumatic dilation for achalasia, Metman [/bib_ref] There were, however, 7 (3%) perforations. In an RCT of pneumatic dilatation versus laparoscopic myotomy for achalasia there were no reported haemorrhages but 8/108 (9.5%) patients experienced perforation during the treatment course. [bib_ref] Pneumatic dilation versus laparoscopic Heller's myotomy for idiopathic achalasia, Boeckxstaens [/bib_ref] Dilatation of GI strictures in the upper or lower GI tract appears to be a low-risk procedure, with the exception of Crohn's disease-related ileal strictures, and balloon dilatation for achalasia. There are no data, however, on dilatation of strictures on antiplatelets or anticoagulants. This, together with the inaccessibility of the site of haemorrhage for endoscopic haemostasis, has led us to continue to consider endoscopic dilatation as a highrisk procedure on P2Y12 receptor antagonists or anticoagulants. ## Endoscopic stenting There are no studies on endoscopic stenting at any site in the GI tract in patients taking antiplatelets or anticoagulants. Available data regarding haemorrhage risk, from RCTs, prospective and mostly retrospective studies, are heterogeneous regarding details of the time interval from stent placement until clinically relevant haemorrhage occurred, In deciding whether stent insertion is a high or low-risk procedure we considered haemorrhage within 7 days of insertion. Previous reviews of risks associated with endoscopic stent insertion have been confounded by the variety of stents used and the evolution of stent design with time. With respect to oesophageal self-expanding metal stents (SEMS), eight recent studies of demonstrated a risk of 0% significant haemorrhage within 7 days of insertion. [bib_ref] Fully vs. partially covered selfexpandable metal stent for palliation of malignant esophageal..., Didden [/bib_ref] [bib_ref] Clinical outcomes of esophageal stents in patients with malignant esophageal obstruction according..., Kim [/bib_ref] [bib_ref] Stents in patients with esophageal cancer before chemoradiotherapy: high risk of complications..., Mão-De-Ferro [/bib_ref] [bib_ref] Assessment of safety and efficacy of an Indigenous self-expandable fully covered esophageal..., Padhan [/bib_ref] [bib_ref] Efficacy and safety of fully covered self-expanding metal stents for malignant esophageal..., So [/bib_ref] [bib_ref] Through-the-scope placement of a fully covered metal stent for palliation of malignant..., Vermeulen [/bib_ref] [bib_ref] Biliary metal stents for proximal esophageal or hypopharyngeal strictures, Bechtler [/bib_ref] [bib_ref] The role of biodegradable stents in the management of benign and malignant..., Mccain [/bib_ref] However, studies including delayed haemorrhage showed a risk of 9% in an RCT comparing small-diameter stents with large-diameter stents and an 8% risk in a large retrospective series of 997 patients. Causes of haemorrhage included aorta-oesophageal fistula formation, and continued oozing from tumours. With respect to duodenal SEMS, large (>100 patients) and recent retrospective and prospective studies showed a haemorrhage risk within 7 days of less than 1%. [bib_ref] Winged partially covered Self-Expandable metal stent to prevent distal migration in malignant..., Choi [/bib_ref] [bib_ref] Palliation of malignant gastroduodenal obstruction with self-expandable metal stent using side-and forward-viewing..., Kumar [/bib_ref] [bib_ref] Covered metallic stents with an anti-migration design vs. uncovered stents for the..., Lee [/bib_ref] The one exception was a retrospective study including 152 patients, whereby the safety and benefits of SEMS combined with chemotherapy were investigated: in total 4 patients (2.6%) suffered from haemorrhage that requiring blood transfusion. Though none of these patients had concomitant chemotherapy, two-thirds had coexisting biliary obstruction for which an intervention was simultaneously performed. [bib_ref] Safety and benefits of self-expandable metallic stents with chemotherapy for malignant gastric..., Miyabe [/bib_ref] With respect to colonic SEMS, a large prospective series of 513 patients and 6 retrospective studies found the risk of clinically relevant haemorrhage within 7 days to be 0%. [bib_ref] Colorectal stenting for palliation and as a bridge to surgery: a 5-year..., Bayraktar [/bib_ref] [bib_ref] Colonic acute malignant obstructions: effectiveness of self-expanding metallic stent as bridge to..., Consolo [/bib_ref] [bib_ref] Endoscopic Self-Expandable metallic stent insertion without fluoroscopic guidance is feasible and safe..., Feng [/bib_ref] [bib_ref] Endoscopic stent placement in the management of malignant colonic obstruction: experiences from..., Gürbulak [/bib_ref] [bib_ref] 03:54 PM Abstract No. 312 comparison of through-the-scope stent insertion with standard..., Cheng [/bib_ref] [bib_ref] Safety evaluation of preoperative stent insertion and clinical analysis on comparison of..., Han [/bib_ref] [bib_ref] Endoscopic stenting as bridge-to-surgery (BTS) in left-sided obstructing colorectal cancer: experience with..., Parodi [/bib_ref] [bib_ref] Self-Expanding Metallic Stents (SEMS) in Left-Sided Colonic Cancer--a Cancer Center Experience, Saeed [/bib_ref] [bib_ref] Predictors of clinical outcome of colonic stents in patients with malignant large-bowel..., Faraz [/bib_ref] [bib_ref] Newly developed self-expandable Niti-S MD colonic metal stent for malignant colonic obstruction, Miyasako [/bib_ref] A systematic review identifying 40 studies on SEMS for the management of emergency malignant large bowel obstruction identified 9 studies reporting on clinical relevant bleeding which occurred in 0.5% (8 out of 1474 patients). [bib_ref] Self-Expanding metallic stents for the management of emergency malignant large bowel obstruction:..., Atukorale [/bib_ref] We have considered endoscopic stenting at all sites in the GI tract to be low risk for haemorrhage within 7 days. Patients on antithrombotics may be at increased risk of delayed haemorrhage, however. ## Percutaneous endoscopic gastrostomy Minor haemorrhage around the wound site at percutaneous endoscopic gastrostomy (PEG) placement is usually short-lived. Severe haemorrhage is rare, and may be secondary to PEG tract bleeding, injuries to the gastric artery, splenic or mesenteric vein (massive retroperitoneal bleeding), or rectus sheath haematoma. [bib_ref] Percutaneous endoscopic gastrostomy: indications, technique, complications and management, Rahnemai-Azar [/bib_ref] [bib_ref] Percutaneous endoscopic gastrostomy: complications and suggestions to avoid them, Schurink [/bib_ref] [bib_ref] Rectus sheath hematoma complicating percutaneous endoscopic gastrostomy, Ubogu [/bib_ref] Rarely, laparotomy may be required as a result of puncturing of the gastric artery at the time of insertion. [bib_ref] Percutaneous endoscopic gastrostomy: complications and suggestions to avoid them, Schurink [/bib_ref] The overall risk of haemorrhage for PEG placement was 1.5% in a case series of 950 patients. [bib_ref] Complications and early mortality in percutaneous endoscopic gastrostomy placement in lombardy: a..., Anderloni [/bib_ref] There are few data on continued administration of antithrombotics at the time of PEG insertion. A meta-analysis showed continuing antiplatelet therapy such as clopidogrel may be safe. [bib_ref] Risk of bleeding in patients undergoing percutaneous endoscopic gastrotrostomy (PEG) tube insertion..., Lucendo [/bib_ref] A German retrospective study of PEG insertion with patients on UFH, phenprocoumon, LMWH, aspirin, clopidogrel and combinations showed no evidence of increased haemorrhage. [bib_ref] Risk factors and complications following percutaneous endoscopic gastrostomy: a case series of..., Richter-Schrag [/bib_ref] A further study concluded that giving aspirin or clopidogrel either 72 hours before or 48 hours after the procedure did not increase bleeding risk. [bib_ref] Bleeding after percutaneous endoscopic gastrostomy is linked to serotonin reuptake inhibitors, not..., Richter [/bib_ref] The above studies are, however, of inadequate quality to definitively demonstrate an effect due to the drugs studied. A large retrospective study of patients undergoing endoscopic procedures on anticoagulants included 2322 PEG performed on warfarin and 1484 on DOACs, with a risk of post-endoscopy bleeding of 2.0% and 1.2%, respectively. 39 ## Device-assisted enteroscopy Single-balloon, double-balloon and spiral enteroscopy devices are available. The risk of haemorrhage from enteroscopy has been reported at 0.2%-0.3%. Spiral enteroscopy was not associated with a risk of clinically significant haemorrhage in a small case series. [bib_ref] The spiral enteroscopy training initiative: results of a prospective study evaluating the..., Buscaglia [/bib_ref] Double balloon enteroscopy is associated with a perforation rate of 0.1%-0.4% and this rises to 1.5% if polypectomy is performed. [bib_ref] Complications in and performance of doubleballoon enteroscopy (DBE): results from a large..., Möschler [/bib_ref] In a retrospective single centre study of 420 patients undergoing double-balloon enteroscopy, it was noted that 13% were on anticoagulation. [bib_ref] Predictors for outcomes and readmission rates following double balloon enteroscopy: a tertiary..., Shelnut [/bib_ref] Although the risk of bleeding may be low for diagnostic procedures, therapeutic procedure such as polypectomy would confer a high risk of haemorrhage on antithrombotics. Endoscopic therapy was performed in 47.1% of 257 double-balloon procedures in a UK case series. 188 ## Oesophageal variceal banding Generally, variceal band ligation (VBL) is undertaken when there is recent or active bleeding. However, elective variceal banding may be necessary at surveillance. In a case-control study of bleeding following VBL 3.4% of patients had haemorrhage secondary to banding induced ulcerations. [bib_ref] Predictive factors of bleeding related to post-banding ulcer following endoscopic variceal ligation..., Vanbiervliet [/bib_ref] In a study of 605 patients undergoing VBL, 21 (3.5%) patients had spontaneous bleeding due to band slippages confirmed at endoscopy and 11 died. [bib_ref] Predictive factors of bleeding related to post-banding ulcer following endoscopic variceal ligation..., Vanbiervliet [/bib_ref] Multivariate analysis found no increased risk of bleeding in those on aspirin, although this applied to only 8/605 patients A study of planned VBL in cirrhotic patients, including 265 patients on LMWH, showed no increase in post-procedural haemorrhage or reduction in survival compared with those not on LMWH. [bib_ref] Low molecular weight heparin does not increase bleeding and mortality post-endoscopic variceal..., Bianchini [/bib_ref] An uncontrolled case series of five patients undergoing elective VBL on continued warfarin observed no postbanding haemorrhage. [bib_ref] Endoscopic band ligation of esophageal varices in patients on anticoagulation, Bajaj [/bib_ref] Placing no more than six bands per session may help reduce the risk of post-banding ulcer haemorrhage. [bib_ref] Ulcer bleeding after band ligation of esophageal varices: risk factors and prognosis, Dueñas [/bib_ref] In a large retrospective series, the risk of haemorrhage in patients undergoing variceal banding on DOAC or warfarin was high for both groups at 19.2% and 25.9%, respectively p=0. There are no studies of VBL in patients on P2Y12 receptor antagonists. ## Ablative therapies Radiofrequency ablation (RFA) in the oesophagus is a wellestablished treatment for dysplasia within Barretts oesophagus. ## Guidelines A meta-analysis of studies of oesophageal RFA has found a rate of haemorrhage of 1%. [bib_ref] Adverse events after radiofrequency ablation in patients with Barrett's esophagus: a systematic..., Qumseya [/bib_ref] RFA has been used to treat gastric antral vascular ectasia, but we have only small case studies to inform us, as demonstrated in a systematic review. [bib_ref] Radiofrequency ablation for treatment of refractory gastric antral vascular ectasia: a systematic..., Maida [/bib_ref] In one case series of 21 patients there was a 10% ulceration rate necessitating discontinuation of RFA therapy. We have therefore classified oesophageal and gastric RFA as high risk for haemorrhage with respect to P2Y12 receptor antagonists and anticoagulants. There are no data on aspirin, but we advise continuation in other procedures with similar rates of haemorrhage. Argon plasma coagulation is used as an ablative therapy for a wide variety of indications throughout the GI tract, including ablation of vascular abnormalities including angiodysplasia and radiation proctitis, ablation of tumours and margins of resected polyps, ablation of dysplastic Barretts oesophagus, and occasionally as a haemostatic measure. With different indications there is variation in size of the ablated mucosal field, energy delivered, and consequences including rarely perforation. There are no data on continued use of antithrombotics with respect to the risk of haemorrhage from APC, and we are therefore unable to provide specific guidance in this regard. ## Restarting antithrombotic therapy for elective procedures There are few data to inform us on the optimal time to restart antithrombotic therapy, if discontinued, after elective endoscopic therapy. Decisions in all cases will be based on the perceived risk of haemorrhage following the procedure versus the risk of thrombosis to an individual patient. It should be remembered that DOACs exert an anticoagulant effect within hours, compared with days for warfarin. Data from the PAUSE study indicates that restarting a DOAC 2-3 days after a high-risk procedure has a low risk of thromboembolic events. [bib_ref] Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant, Douketis [/bib_ref] Data on restarting therapy after acute GI haemorrhage are discussed in that section. A prospective cohort study in Italy 53 evaluated the risks of haemorrhage and thrombosis in relation to compliance with the previous version of this BSG/ESGE guideline. For cases who underwent polypectomy there was a trend to more intraprocedural bleeding if DOAC was not stopped as per the guideline for high-risk procedures. Stopping longer than the guidelines did not reduce the intraprocedural bleeding risk. Also, restarting the DOAC immediately after polypectomy, rather than a delay of 24-48 hours (as suggested by the guidelines) in high-risk patients led to an almost doubling of the delayed bleeding risk without a reduction in thrombosis, although these measures did not reach statistical significance. For procedures with a very high risk of haemorrhage such as ESD, it may be desirable to delay restarting antithrombotics beyond the intervals recommended in these guidelines. In a meta-analysis, post-ESD bleeding risk was not significantly increased if antithrombotic therapy was resumed at least 1 week after ESD whereas resumption of antithrombotic therapy immediately or within 1 week after ESD was significantly associated with post-ESD bleeding. [bib_ref] Effects of antithrombotic therapy on bleeding after endoscopic submucosal dissection, Dong [/bib_ref] The incidence of thrombosis was not analysed, however, and this needs to be considered on an individual patient basis. ## Risk stratification for elective endoscopic procedures Endoscopic procedures carry a higher risk of haemorrhage, and certain clinical situations will result in a high risk of thromboembolic complications should antiplatelets or anticoagulants be withdrawn. Procedures have been classified as high-risk or low-risk for haemorrhage primarily based on the risks of haemorrhage in patients not taking antiplatelets or anticoagulants, as well as some limited data available regarding endoscopy in patients in whom these drugs were continued [fig_ref] Table 3: Risk stratification for discontinuation of warfarin therapy with respect to the requirement... [/fig_ref] stratify risk for discontinuation of P2Y12 receptor antagonists or warfarin respectively according to clinical scenario, and the risks of thromboembolic sequelae on discontinuation of therapy. Diagnostic endoscopic procedures, with or without biopsy, are classified as low-risk for haemorrhage, though there is concern regarding biopsy on DOACs. The likelihood of having to undertake therapy with a risk of haemorrhage should also be considered, for example, colonoscopy when polyps have been found in 22.5%-34.2% of patients in large studies. Endoscopists may therefore choose to manage colonoscopies as highrisk procedures with respect to P2Y12 receptor antagonists and anticoagulants. Similar considerations apply to ERCP if there is uncertainty as to whether sphincterotomy will be required. ## Acute gi haemorrhage on antiplatelets and anticoagulants antiplatelets We suggest that permanent discontinuation of aspirin for primary prophylaxis should be considered (weak recommendation, low quality evidence). We suggest that aspirin for secondary prevention should not be routinely stopped. If it is stopped, it should be recommenced as soon as haemostasis is achieved, or there is no further evidence of bleeding (strong recommendation, moderate quality evidence). We recommend that DAPT is continued if possible in patients with coronary stents in situ and management should be in liaison with a consultant interventional cardiologist (strong recommendation, moderate quality evidence). In the case of major haemorrhage we recommend continuing aspirin if the P2Y12 receptor antagonist is interrupted (strong recommendation, moderate quality evidence). P2Y12 receptor antagonist therapy should be re-instated within 5 days, if still indicated (strong recommendation, moderate quality evidence). Antiplatelets confer an increased risk of spontaneous haemorrhage, but also present an increased risk to the patient when this occurs. In the case of life-threatening haemorrhage, this is of urgent concern, but withdrawal of antiplatelet therapy confers a risk of thrombosis. A meta-analysis of studies of patients on aspirin for secondary prophylaxis found that discontinuation of aspirin was associated with a threefold increased risk of major adverse cardiac events, increasing to an OR of 89 for major cardiac events in patients with coronary stents. [bib_ref] A systematic review and metaanalysis on the hazards of discontinuing or not..., Biondi-Zoccai [/bib_ref] If GI haemorrhage occurs in a patient with a recently placed coronary stent on DAPT, then life-threatening thrombosis could occur if therapy is interrupted. The imperative, after adequate resuscitation, is to achieve haemostasis within the GI tract and urgent facilities should be available to provide this. Liaison with a consultant interventional cardiologist should occur in the emergency setting. If it is deemed necessary to temporarily discontinue antiplatelet therapy, this should be limited to the P2Y12 receptor antagonist, and aspirin continued. [bib_ref] Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents, Eisenberg [/bib_ref] The timing of restarting antithrombotic therapy after acute GI haemorrhage will be determined by the risk of re-bleeding and the risk of acute thrombosis without antithrombotic therapy. [bib_ref] Reintroduction of anti-thrombotic therapy after a gastrointestinal haemorrhage: if and when?, Scott [/bib_ref] P2Y12 receptor antagonists in patients with coronary stents should be restarted within a maximum of 5 days due to the high risk of stent thrombosis after this time. This timeframe represents an optimal balance between haemorrhage and thrombosis, [bib_ref] Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents, Eisenberg [/bib_ref] though it has not been tested prospectively. For patients on aspirin monotherapy for secondary prophylaxis, there is a benefit to continued therapy. A prospective placebo-controlled RCT of 156 patients following endoscopically controlled upper GI haemorrhage, demonstrated a reduction in all-cause mortality in the group receiving low-dose aspirin (1.3% vs 12.9%). [bib_ref] Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial, Sung [/bib_ref] There was an excess of bleeds in the aspirin group (10.3% vs 5.4%) but none were fatal. Five patients in the placebo arm died of thromboembolic events. If aspirin is stopped then it should be reintroduced as soon as haemostasis has been achieved. A retrospective study of 118 patients on antiplatelets or anticoagulants presenting with acute GI haemorrhage compared outcomes in those who had antithrombotic therapy permanently discontinued compared with those in whom it was restarted. [bib_ref] Stopping antithrombotic therapy after acute upper gastrointestinal bleeding is associated with reduced..., Siau [/bib_ref] In those in whom antithrombotic therapy was discontinued the HR for thrombotic events was 5.77 (95% CI 1.26 to 26.35) and for mortality 3.32 (1.07-10.31) compared with those in whom it was restarted. It is therefore important to have a plan for consideration of restarting antithrombotic therapy in all such patients presenting with GI haemorrhage. ## Anticoagulants We recommend withholding oral anticoagulant and correcting coagulopathy according to the severity of haemorrhage and the patient's thrombotic risk in coordination with a consultant cardiologist/haematologist. The correction of coagulopathy should not delay endoscopy or radiological intervention (strong recommendation, low quality evidence). In patients with haemodynamic instability who take VKAs, we recommend administering intravenous vitamin K and fourfactor PCC (strong recommendation, low quality evidence), or fresh frozen plasma if PCC is not available (weak recommendation, very low quality evidence) In patients with haemodynamic instability who take DOACs, we suggest considering the use of reversal agents: idarucizumab in dabigatran patients, and andexanet in anti-FXa treated patients (weak recommendation, low quality evidence), or intravenous four-factor PCC if andexanet is not available (weak recommendation, very low quality evidence). We recommend restarting anticoagulation following acute GI haemorrhage in patients with an indication for long-term anticoagulation (strong recommendation, low quality evidence). In patients at low thrombotic risk, we suggest restarting anticoagulation as soon as possible after 7 days of anticoagulant interruption (weak recommendation, low quality evidence). In those at high-thrombotic risk, an earlier resumption of anticoagulation with heparin bridging, preferably within 3 days, is recommended (strong recommendation, low quality evidence). Anticoagulant use is reported in up to 15% and 25% of patients presenting with acute upper and lower GI bleeding, respectively. 199-201 GI bleeding-related mortality in these patients is high (up to 8%-12%), but mainly related to patients' comorbidities. Anticoagulants are independent predictors of neither mortality nor in-hospital rebleeding, [bib_ref] External validation of the Oakland score to assess safe hospital discharge among..., Oakland [/bib_ref] [bib_ref] Acute Gi bleeding in the setting of supratherapeutic international normalized ratio in..., Rubin [/bib_ref] [bib_ref] Systematic review: the presenting international normalised ratio (Inr) as a predictor of..., Shingina [/bib_ref] [bib_ref] Early predictors of severity in acute lower intestinal tract bleeding, Strate [/bib_ref] provided they are managed appropriately. Temporary discontinuation of anticoagulation is the 'standard of care' in patients with clinically significant GI bleeding. The anticoagulant effect of VKAs such as warfarin can persist for 3-5 days. The need for a rapid correction of VKArelated coagulopathy with reversal agents mainly depends on the severity of haemorrhage, but their use requires caution in patients at high thrombotic risk (eg, mechanical heart valve) since their use has been associated with thromboembolism. [bib_ref] Impact of Inr monitoring, reversal agent use, heparin bridging, and anticoagulant interruption..., Nagata [/bib_ref] Vitamin K takes several hours to correct anticoagulation, so the use of 4-factor PCC may be necessary to rapidly reverse anticoagulation in patients with active bleeding and haemodynamic instability. PCC is preferred over FFP, for a lower volume load, faster onset of action, and no need to check the patient's blood group. Concomitant low-dose vitamin K is recommended in this situation to prevent an 'INR rebound'. Unlike VKAs, DOACs are characterised by a relatively short half-lives, so that their anticoagulant activity usually rapidly wanes-off over 12-24 hours. Consequently, most cases of major GI haemorrhage can be managed by withholding the drug and waiting for the anticoagulant effects to resolve. In haemodynamically unstable patients, acute reversal of anticoagulation may be required. Vitamin K, FFP, and protamine administration are ineffective. Idarucizumab, a humanised antibody fragment that neutralises the effect of dabigatran, is now currently available as first-line reversal agent in dabigatran patients presenting with life-threatening/uncontrolled bleeding. Idarucizumab reverses dabigatran-related coagulopathy rapidly (within a few minutes) and persistently (for about 24 hours) in more than 98% of the patients, with a low thrombotic complication rate (6% at 90 days). Andexanet alfa, an inactive form of FXa that neutralises circulating FXa inhibitors, has recently been approved as an antidote to apixaban and rivaroxaban in patients with life threatening haemorrhage, but its clinical use is hindered by its limited availability, the prohibitive cost and safety concern about possible procoagulant effect. [bib_ref] Full study report of Andexanet alfa for bleeding associated with factor Xa..., Connolly [/bib_ref] Four-factor PCC at fixed dose (2000 IU) may represent an alternative to andexanet alpha, with lower thromboembolic risk, but uncertain efficacy. [bib_ref] Management of rivaroxaban-or apixabanassociated major bleeding with prothrombin complex concentrates: a cohort..., Majeed [/bib_ref] [bib_ref] Management of direct factor Xa inhibitor-related major bleeding with prothrombin complex concentrate:..., Piran [/bib_ref] [bib_ref] Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients..., Smith [/bib_ref] Correction of coagulopathy, when required, should not delay urgent endoscopic or radiological interventions when indicated, as these procedures can be safely and effectively performed at therapeutic levels of anticoagulation in the context of acute haemorrhage. After bleeding cessation, observational studies 219-222 and two meta-analyses consistently indicate there is a net clinical benefit of restarting anticoagulation, due to a reduced risk of thromboembolism and death, despite an increased risk of rebleeding. However, evidence on the optimal timing for restarting anticoagulation is limited. A single retrospective study indicates an excess risk of GI bleeding and of thromboembolism for an interval of warfarin interruption shorter than 7 days and longer than 30 days, respectively. [bib_ref] Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation, Qureshi [/bib_ref] Since there is a trend toward a reduced incidence of thromboembolic events the earlier warfarin is introduced, it is reasonable to restart warfarin as soon as possible by day seven following its interruption. Data on the optimal timing of DOAC resumption are lacking. In analogy with warfarin, restarting DOACs as soon as possible by day seven after their interruption seems reasonable in most cases. The DOAC rapid onset of action, resulting in a full anticoagulation within 2-4 hours, warrants some caution with an earlier resumption. In patients at very high thrombotic risk (eg, prosthetic metal heart valve in mitral position), cardiology societies recommend an earlier resumption of anticoagulation with UFH in those at highest risk, rapid titration of prophylactic doses of LMWH to therapeutic doses within 48-72 hours. The choice of strategy should be discussed with the patient's cardiologist. If the risk of restarting anticoagulation is estimated to outweigh the benefits, a consultation with the referral specialist (haematologist, neurologist and/or cardiologist) is advisable, and alternatives to anticoagulation, such as a left atrial appendage occlusion in AF, or inferior vena cava filter for acute deep venous thrombosis, may be considered. Pole Digestif, Hôpital Universitaire L'Archet 2, Nice, France [bib_ref] Predictors of stent thrombosis and their implications for clinical practice, Gori [/bib_ref] Interventional Cardiology, University Hospital Southampton NHS Foundation Trust, Southampton, UK [bib_ref] Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation, Lopes [/bib_ref] Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands Twitter Jo Jerrome @ThrombosisUK Acknowledgements We gratefully acknowledge the contribution of Dr Sanne Hoogenboom from the Academic Medical Centre, Amsterdam, who undertook the literature searches for risks associated with endoscopic dilatation and endoscopic stenting. We are indebted to Professor Tony Gershlick, an interventional cardiologist who made a major contribution to the antiplatelet advice in the 2008 and 2016 versions of this guideline, and which underpin the recommendations in this update. Professor Gershlick sadly died due to COVID-19 before being able to contribute to this updated document. Contributors AMV convened the guideline development group, assigned tasks, led on recommendations and revisions and edited the final manuscript. All other authors provided written contributions, developed recommendations and provided comments on the complete manuscript prior to submission. funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. disclaimer These joint BSG and ESGE guidelines represent a consensus of best practice based on the available evidence at the time of preparation. They may not apply in all situations and should be interpreted in the light of specific clinical situations and resource availability. Further controlled clinical studies may be needed to clarify aspects of these statements, and revision may be necessary as new data appear. Clinical consideration may justify a course of action at variance to these recommendations, but we suggest that reasons for this are documented in the medical record. BSG and ESGE guidelines are intended to be an educational device to provide information that may assist endoscopists in providing care to patients. They are not rules and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring or discouraging any particular treatment. Competing interests FR has received speaker fees from Bristol-Meyers Squibb, Pfizer and Boehringer Ingelheim. Dr Alikhan has received fees from Alexion, Bayer, Boehringer Ingelheim, Bristol-Meyers Squibb, Daiichi, Pfizer and Portola. WL has received speaker fees from Sanofi Aventis and Leo Pharma, speaker fees and advisory board fees from Bayer, Daichii Sankyo, Pfizer and Boehringer Ingelheim, and support to attend a scientific meeting from Boehringer Ingelheim. JEV-H has received departmental research grant support from Cook Medical and Abbott, lecture fees from Medtronics and Cook Medical, and consultancy fees from Boston Scientific and Olympus. ## Patient consent for publication not required. Provenance and peer review Not commissioned; externally peer reviewed. supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. [table] Table 3: Risk stratification for discontinuation of warfarin therapy with respect to the requirement for heparin bridging Thrombophilia syndromes do not usually require heparin bridging, but individual cases should be discussed with a haematologist. *Heparin bridging for a metal aortic valve is recommended by European Society of Cardiology and the European Association for Cardio-Thoracic Surgery guidelines 2017,33 but this varies between international guidelines31 32 and local guidance should be established in conjunction with cardiology or cardiothoracic services. †Blood pressure>140/90 mm Hg or on antihypertensive medication. ‡The majority of patients are now on direct oral anticoagulants for venous thromboembolism and bridging is not appropriate. Consider deferring a high-risk procedure beyond 3 months therapy in this high-risk group for thromboembolism. INR, international normalised ratio. [/table]	None	https://gut.bmj.com/content/gutjnl/70/9/1611.full.pdf	This is a collaboration between the British Society of Gastroenterology (BSG) and the European Society of Gastrointestinal Endoscopy (ESGE), and is a scheduled update of their 2016 guideline on endoscopy in patients on antiplatelet or anticoagulant therapy. The guideline development committee included representatives from the British Society of Haematology, the British Cardiovascular Intervention Society, and two patient representatives from the charities Anticoagulation UK and Thrombosis UK, as well as gastroenterologists. The process conformed to AGREE II principles and the quality of evidence and strength of recommendations were derived using GRADE methodology. Prior to submission for publication, consultation was made with all member societies of ESGE, including BSG. Evidence-based revisions have been made to the risk categories for endoscopic procedures, and to the categories for risks of thrombosis. In particular a more detailed risk analysis for atrial fibrillation has been employed, and the recommendations for direct oral anticoagulants have been strengthened in light of trial data published since the previous version. A section has been added on the management of patients presenting with acute GI haemorrhage. Important patient considerations are highlighted. Recommendations are based on the risk balance between thrombosis and haemorrhage in given situations.
ecb684f08ef5af040a09aba76c957c6d94b262c0	pubmed	7th Brazilian Guideline of Arterial Hypertension: Chapter 3 - Clinical and Complementary Assessment	7th Brazilian Guideline of Arterial Hypertension: Chapter 3 - Clinical and Complementary Assessment ## Basic laboratory investigation, assessment of subclinical and clinical target-organ damage Complementary assessment is aimed at detecting subclinical or clinical TOD to better stratify CV risk. To stratify global CV risk, the classical RF (Chart 3), as well as Abdominal or thoracic murmurs (renovascular, coarctation of the aorta, disease of the aorta or its branches) Decreased femoral pulses (coarctation of the aorta, disease of the aorta or its branches) ## Difference of bp between arms (coarctation of the aorta and subclavian stenosis) *For further information, see Chapter 12. ## Chart 3 -additional cardiovascular risk factors Age (men > 55 years, women > 65 years) ## Smoking habit Dyslipidemias: triglycerides > 150 mg/dL; LDL-C > 100 mg/dL; HDL-C < 40 mg/dL DM Family history of premature CVD: men < 55 years, women < 65 years the new ones identified, should be considered, although they have not been incorporated to the clinical scores of risk stratification. [bib_ref] Task Force Members. 2013 ESH/ESC guidelines for the management of arterial hypertension:..., Mancia [/bib_ref] [bib_ref] General cardiovascular risk profile for use in primary care: the Framingham Heart..., Sr [/bib_ref] Of the new RF, the following stand out: fasting glycemia between 100 mg/dL and 125 mg/dL, abnormal glycated hemoglobin (HbA1c), abdominal obesity (metabolic syndrome -MS), PP (SBP-DBP) > 65 mm Hg in the elderly, 5 history of preeclampsia, and family history of AH (for borderline hypertensive patients). The laboratory assessment shown in Chart 4 should be part of the initial routine of all hypertensive patients. [bib_ref] Task Force Members. 2013 ESH/ESC guidelines for the management of arterial hypertension:..., Mancia [/bib_ref] The Cockroft-Gault formula is used to calculate creatinine clearance: 6 CrCl (mL/min) = [140 -age] x weight (kg) /serum creatinine (mg/dL) x 72 for men; for women, multiply the result by 0.85. To estimate glomerular filtration rate (GFR) use the CKD-EPI equation. ## Chart 5 -tests recommended for certain populations test/assessment recommended population and indication Chest X ray Follow-up of patients with clinical suspicion of cardiac (GR: IIa; LE: C) and/or pulmonary impairment. Assessment of hypertensive individuals with aorta impairment when echocardiogram is not available. [bib_ref] The Chest Radiograph. A useful investigationin the evaluation of hypertensive patients, Rayner [/bib_ref] Echocardiogram More sensitive than ECG to diagnose LVH. Important in the assessment of the geometrical forms of left atrial hypertrophy and size, analysis of systolic and diastolic function. Consider LVH when left ventricular mass corrected for body surface is equal to or greater than 116 g/m 2 for men and 96 g/m 2 for women.Evidence of LVH on ECG or patients with clinical suspicion of HF (GR: I; LE: C). [fig] Chart 1 -: Objectives of clinical and laboratory assessment [/fig]	None	None	Clinical assessment Clinical history Complete clinical history with questions about time since AH diagnosis, course and previous treatment should be obtained. Information on the family history is essential to increase the chance of an accurate diagnosis of primary AH.1 (GR: I; LE: B). The patient should be asked about specific RF for CVD, comorbidities, socioeconomic aspects and lifestyle,2 in addition to previous and current use of medications or other substances that can interfere with BP measurement and/or AH treatment. Similarly, evidence of a secondary cause of AH should be investigated.
69effc6baf28c6121a7e0978471893677791caba	pubmed	British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic	British Society of Gastroenterology guidance for management of inflammatory bowel disease during the COVID-19 pandemic # Abstract The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government's advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials. # Introduction Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a condition in which the gastrointestinal immune system responds inappropriately. IBD is therefore often treated with immunosuppressing medications to control inflammation and prevent 'flares', a worsening of symptoms, which may be unpredictable. While it is known that 0.8% of people in the UK currently have IBD (approximately 524 000 patients), only 44% have been to a clinic in the past 3 years 1 2 . There will be many patients who are worried about the effect of the coronavirus pandemic (SARS-CoV-2 or COVID-19 disease) on their IBD and vice versa, many of whom will be unknown to secondary care. During the COVID-19 outbreak, we will do everything we can to keep our IBD patients safe. The greatest risks relate not only to the infection itself, but also the emergency reorganisation of hospital and general practice services to deal with the pandemic. This will result in significant changes to routine IBD services. A combined approach covering both primary and secondary care is therefore required to keep vulnerable patients with IBD out of hospital as much as possible. Insights from Hubei, China and from Italy suggest hospital attendance for non-COVID-19 illness may provide a reservoir for further spread of infection. However, alterations to the way we deliver IBD care in the UK must be balanced against the risks of under treated, active IBD. Importantly, patients with active IBD are likely to have a higher risk of infection both in the community and during inpatient care, even in the absence of immunosuppressive treatment. [bib_ref] Serious infection and mortality in patients with Crohn's disease: more than 5..., Lichtenstein [/bib_ref] Therefore, it is of paramount importance to control intestinal inflammation in IBD to prevent adverse outcomes. ## Covid-19 disease and ibd The impact of immunosuppression on the severity of COVID-19 disease remains unclear. Data reported from 1099 Chinese patients with COVID-19 did not observe immunodeficiency as a risk factor for severe disease (defined according to the American Thoracic Society guidelines for community acquired pneumonia). [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan W-Jie [/bib_ref] The currently understood predictors associated with COVID-19 mortality at the time of hospital admission are older age (OR 1.1; 95% CI 1.03 to 1.17 per year increase), higher No specific recommendations are being made regarding IBD and pregnancy, and pregnant women with IBD are encouraged to follow the guidance available from the UK government for pregnant women in the general population. This guidance was last updated by the BSG COVID-19 IBD Working Group on 2 April 2020, and was based on expert opinion and the available evidence at the time. *The UK government advises those at increased risk, but not reaching the highest risk, of severe illness from coronavirus (COVID-19) to be particularly stringent when applying social distancing recommendations. †That is, at least one of (comorbidity listed above or age ≥70 years) plus at least one of (therapy from middle column or moderate to severely active disease). ‡Patients should be categorised as highest risk (requiring shielding) within 6 weeks of starting biologics if they are on concomitant immunomodulator treatment or systemic steroids, whether started simultaneously or prior to the biologic. After 6 weeks they may enter the 'moderate' risk category provided they do not meet other highest risk criteria, for example, moderate-severe disease not controlled by treatment. Biologic plus immunomodulator in stable patients may increase the risk over monotherapy but there is no specific evidence for this situation. §As judged by the clinical team responsible for patient care. ¶Patients who have stopped biologics or immunomodulators should remain within their pre-treatment cessation risk category for 3 months; for drugs with a much shorter half-life (eg, tofacitinib), we advise clinician discretion. 5-ASA, 5-aminosalicylic acid; IBD, inflammatory bowel disease; TNF, tumour necrosis factor. sequential organ failure assessment score (OR 5.65; 95% CI 2.61 to 12.23) and d-dimer >1 µg/mL (OR 18.42; 95% CI 2.64 to 128.55). [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] However, smoking, comorbidity, particularly hypertension, vascular disease, diabetes and male sex have been associated with poor outcome. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan W-Jie [/bib_ref] [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic..., Yang [/bib_ref] [bib_ref] COVID-19 and smoking: a systematic review of the evidence, Vardavas [/bib_ref] [bib_ref] COVID-19: the gendered impacts of the outbreak, Wenham [/bib_ref] Prolonged illness and complications from respiratory infection are perhaps more common when non-steroidal anti-inflammatory drugs (NSAIDs) are used, but no data in COVID-19 currently exist. Given NSAIDs have also been implicated in IBD flare, paracetamol is advocated as firstline analgesia/antipyretic. [bib_ref] British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel..., Lamb [/bib_ref] At the time of writing, the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)-IBD registry has reported 239 (54% male) cases of COVID-19 in IBD patients (137 CD, 94 UC, 5 IBD unclassified), of whom 64 were hospitalised and 11 patients died.Seven patients underwent ventilation. Among the 11 patients who died, a range of medications were seen; five patients were receiving mesalazine alone or no therapy, although all were aged 69 years or older; four were receiving steroids alone or in combination; and the youngest patient who died was 33 years and was receiving combination therapy with adalimumab, azathioprine and prednisolone.The British Society of Gastroenterology (BSG), in line with the International Organisation for the Study of IBD and the European Crohn's and Colitis Organisation, recommend that patients with IBD do not routinely stop their medication to prevent infection or adverse outcome with COVID-19. 'Social distancing' (https://www. gov. uk/ government/ publications/ covid-19-guidance-on-social-distancing-andfor-vulnerable-people/ guidance-on-social-distancing-foreveryone-in-the-uk-and-protecting-older-people-and-vulnerable-adults) and 'shielding' (https://www. gov. uk/ government/ publications/ guidance-on-shielding-and-protecting-extremelyvulnerable-persons-from-covid-19/ guidance-on-shielding-andprotecting-extremely-vulnerable-persons-from-covid- [bib_ref] A prospective analysis of the incidence of and risk factors for opportunistic..., Naganuma [/bib_ref] are measures to reduce spread within the population and to protect high risk groups. These are also an understandable source of anxiety for patients with IBD. [bib_ref] Implications of COVID-19 for patients with pre-existing digestive diseases, Mao [/bib_ref] On behalf of the BSG, a UK-wide IBD COVID-19 Working Group has been established and has defined patient risk as highest, moderate and lowest for COVID-19 related poor outcome (see [fig_ref] Table 1: British Society of Gastroenterology inflammatory bowel disease COVID-19 risk grid [/fig_ref] and below for justification of groupings). Patients classified as at highest risk, correspond to group 5 in the UK government's instruction to undergo 'shielding', the most stringent form of isolation. The moderate group are recommended to be even stricter at following the government's instructions regarding social distancing. Note that all patients should still attend for infusions of biologics, irrespective of risk stratification. The UK Department of Health has requested patient contact details from local secondary care IBD services for those that meet the highest risk. A pragmatic approach to identify individuals within the highest risk group has been adopted: 1. Where feasible, national datasets are being interrogated to identify 'highest risk' patients. ## Direct communication with patients via the bsg, and Crohn's and Colitis UK workflows. 3. Patients may self-identify into risk group (https://www. ibdregistry. org. uk/ covid-19) and/or contact their local IBD team (ideally by email). 4. Secondary care IBD teams will then provide patient details to the National Health Service (NHS). The self-identification tool (point 3 above) was developed using the information in table 1 in partnership with the IBD Registry as a pragmatic solution to obtain up to date information from UK patients with IBD and maximise the ability to identify patients in the highest risk group. Early identification and intervention (shielding education) to 318 Chinese IBD patients in Hubei at risk of COVID-19 was well received by patients and may have protected them from infection, with none of them reporting infection, as of 28 February 2020.At the time of writing, there is a lot of activity at UK government level around the wearing of masks by the general population in public spaces and hospitals. The BSG recommends members of the public to follow the most up to date advice from the government with respect to this. Most IBD patients will fall into the moderate or lowest risk groups. Defining a 'highest risk' group is not exact, with little or no evidence specific to COVID-19. The grouping has therefore been determined following extensive discussion among UK IBD specialists with input from international colleagues. Based on the current evidence, we understand increasing age, heart disease, diabetes and hypertension are the among the greatest risk factors for poor outcome in COVID-19. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan W-Jie [/bib_ref] [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic..., Yang [/bib_ref] [bib_ref] COVID-19 and smoking: a systematic review of the evidence, Vardavas [/bib_ref] [bib_ref] COVID-19: the gendered impacts of the outbreak, Wenham [/bib_ref] As such, priority has been given to these factors alongside medications, other than individuals on high dose steroids (table 1 and below). Where risk is primarily determined by IBD (patient and treatment factors), we recognise this is a dynamic process-that is, patients may move between risk categories over the duration of the pandemic. This is a very busy time for clinical teams with redeployment in order to manage the COVID-19 pandemic. We have therefore aimed for simple clear messages wherever possible. For this reason, we have deliberately not provided a drug by drug description of clearance, and recommend it is 3 months after cessation of a drug therapy before a patient changes risk category. In part, this is to discourage the practice of stopping drugs purely to switch risk category. The exception is steroids, which is covered explicitly in the grid. As a working group, we have had some discussion about tofacitinib which has a much shorter halflife; in this case, we advise clinician discretion regarding the time point at which cessation impacts on risk categorisation. We wish to strongly emphasise: ► Patients should continue their current medications. ► Access to injectable treatment (infliximab, vedolizumab, ustekinumab, adalimumab, certolizumab and golimumab) should be maintained, irrespective of risk category and distancing/isolation recommendations. ► Infusion suite services (with appropriate social distancing methods) should be maintained as a priority area to prevent treatment flare, admission and increased risk of immunogenicity. ► Home care provision of subcutaneous medicines should be maintained as a priority for IBD patients. General advice for all IBD patients is provided in box 1. ## Changes to current primary and secondary care practices Hospital services are being reorganised to better deal with severe COVID-19 infections. Elective work is being suspended to maximise staffing and space for acute admissions. We also need to be very careful that rapid institution of telemedicine services does not adversely impact on primary care (eg, phlebotomy and drug prescribing). Consideration should be given to reorganising services to support well staff working from home when possible, to minimise their own viral exposure. Staff sickness is likely to become a major factor during this pandemic and so efforts should be made to minimise this from the earliest stages. Pre-symptomatic transmission has been reported, although estimated rates vary between studies. Face to face meetings between staff, particularly in confined spaces, should be minimised and, where necessary, should avoid people being in close proximity if possible. Services such as Microsoft Teams (https:// teams. microsoft. com), WebEx (https://www. webex. com) and Zoom (https:// zoom. us) can be used to facilitate virtual meetings (see also https://www. ecdc. europa. eu/ sites/ default/ files/ documents/ RRA-sixth-update-Outbreak-of-novel-coronavirusdisease-2019-COVID-19. pdf). ## Ibd nurse phone and email helpline To manage and support patients with IBD when outpatient clinics are being converted to telephone review, the minimum service provision needs to include a telephone/email helpline to support patients having disease flares and to answer queries regarding immunosuppressant/biologics management. Ideally, provision should be made for one member of the nursing team to work from home to ensure this is maintained, with appropriate senior review to support the clinical decision making process. This would reduce the burden on both primary and secondary care, in particular the accident and emergency department. This should be supported with capacity for patients to have urgent review if needed in a 'safe clinic'. Patients are being asked to keep taking their usual IBD therapy. If patients stop taking their medications without discussing it with their clinical team first, there is a risk of disease flare. Active disease is associated with an increased risk of infection, exposure to steroids (increased risk from infection), hospitalisation and major surgery. ## Outpatient clinics Conduct clinical appointments by telephone or a formal telemedicine system where possible. Routine bloods may be deferred until the situation has improved, depending on local capacity. Access to faecal calprotectin (FC) testing, a potential alternative to endoscopy, may become limited due to the presence of virus in the stool. If accessible, consider introduction of point of care calprotectin testing. FC point of care kits could be most effectively issued to high risk patients at a new patient/flare clinic or on discharge from hospital (sampling every 2-3 months depending on capacity). Given the limited access to endoscopic disease assessment, the combination of FC and clinical disease scores (eg, partial Mayo/Simple Clinical Colitis Activity Index, Paediatric Ulcerative Colitis Activity Index, Harvey-Bradshaw index or weighted Paediatric Crohn's Disease Activity Index) may help to guide treatment decisions more objectively. ## New ibd patients In line with the Joint Advisory Group/BSG endoscopy guidance released on 26 March 2020, all non-emergency endoscopy should stop immediately. Careful case by case discussion will need to be given to decide the timing of diagnostic endoscopy for the most urgent suspected new IBD cases. If centres are delayed in assessing new IBD patients, a telephone triage system should be adopted to assess clinical urgency. ## Urgent outpatient review Patients who may require hospitalisation will need to continue to be assessed in a timely manner. Consider the most appropriate location to do this that is away from COVID-19 assessment areas. Daily 'flare clinics' (virtual where possible) with limited numbers of patients who are at high risk of imminent hospitalisation should be considered. Where possible, limit visits to hospital and limit the patient journey around the hospital geographically. ## General considerations regarding ibd medications ► Balance the risk of immune modifying drugs with the risk associated with active disease. ► Patients are advised not to stop or reduce their medication without discussing with the IBD team, due to the risk of flare leading to a need for steroids or other additional immunosuppression or hospitalisation. ► Immunosuppressive effects of medications may persist for many weeks or months after treatment cessation. ► Identify an experienced/senior person to oversee blood tests, initiation of biologics and prescribing of biologics, and support patients accordingly. Reduce any therapy associated monitoring blood tests to a minimum safe frequency. ► Administrative support should be identified to ensure prescriptions for subcutaneous biologics are forwarded to home care in a timely manner. ► Patients should be given helpline details to arrange contact for advice regarding delayed deliveries. ► Maintaining a functional infusion service throughout the pandemic should be a priority. ## Therapy specific considerations Given the paucity of data regarding the effects of IBD medications on the course of COVID-19, contributing confirmed cases to the international registry (SECURE-IBD, https:// covidibd. org) is encouraged. ► Corticosteroids -Should be avoided if possible but will still be necessary for some who should then observe 'shielding' while prednisolone dose is ≥20 mg daily. -High dose steroids are an established risk factor for respiratory tract infection and opportunistic infection in IBD and septicaemia. [bib_ref] A prospective analysis of the incidence of and risk factors for opportunistic..., Naganuma [/bib_ref] ## Service considerations Remote monitoring of disease activity can be achieved through virtual clinics using blood tests taken at sites remote to the hospital (eg, satellite facilities or via a general practitioner), with standard laboratory or point of care FC monitoring where available. The infusion service is a priority area. Consider moving off site to a 'clean' area if possible or facility with alternative access, avoiding the need to pass through the main hospital. Visitors should no longer be permitted. Patients should not attend for infusion if they are symptomatic for COVID-19 and where possible should be screened on arrival for symptoms and fever. Two metre spacing should be employed between patients, and there should be a dedicated separate waiting area if possible. A strict hand washing policy on arrival should be enforced. Infusion chairs should be appropriately cleaned between patients. Parenteral electrolyte and iron replacement services should be reserved for urgent cases only. If capacity is reduced due to staff shortages, daily/weekly triage of infusions should take place. ## Endoscopy The BSG has provided separate guidance on endoscopy and COVID-19 (https://www. bsg. org. uk/ covid-19-advice/). IBD surveillance procedures should be deferred. IBD disease assessment scopes will need to be carefully assessed for priority. Alternative methods of disease assessment, including the use of biomarkers, radiology and capsule endoscopy should be considered. ## Imaging The capacity for outpatient imaging may be reduced. However, this should be discussed within individual hospitals. Access to different imaging modalities may vary during the pandemic and this may influence the choice of investigation for patients with IBD. surgery Routine elective operations have been deferred in most centres. Where possible, urgent management of perianal sepsis should be undertaken as a day case procedure. Complex IBD surgery should be deferred where possible and its timing should be reviewed regularly at multidisciplinary meetings. Emergency procedures (e.g. subtotal colectomy in acute severe UC, intestinal resection to control penetrating disease in CD) will continue as part of routine care. As with active disease, the choice of postoperative therapy to prevent recurrence will need to be considered in the context of the COVID-19 pandemic. If surgery is required for subacute obstructive symptoms, it may be possible to avoid or delay surgery by using partial or exclusive enteral nutrition regimens. 21 ## Clinical trials The National Institute for Health Research (NIHR) and Chief Scientist Office (CSO) have produced guidance on the management of clinical trials which will be updated regularly (NIHR https://www. nihr. ac. uk/ news/ dhsc-issues-guidance-on-theimpact-on-covid-19-on-research-funded-or-supported-by-nihr/ 24469; CSO http://www. nhsresearchscotland. co. uk/ news/ covid-19---guidance-for-sponsors-sites-and-researchers). Many trials will have already been paused by their sponsors. Where this has not happened, participant screening, recruitment and continuation (for participants already recruited) should be reviewed at the local level for appropriateness in the current clinical situation. The benefits of avoiding surgery and/or corticosteroids by receiving trial medication that may not be otherwise available must be balanced against the risk of face to face visits and the unknown effects of the investigational medicinal product on the course of COVID-19. Where possible, trial visits should occur virtually, and investigations that require hospital attendance should be postponed unless clinically important. Protocol amendments should be made to the relevant regulatory bodies, and advice should be sought from research and development directors promptly to protect participants, as formal approval may be significantly delayed. Blinded trials pose a particular concern; principal investigators should be prepared to unblind participants where the information will influence the participant's treatment or when assessment and management of coronavirus is being considered. In addition, patients who may be on a placebo medication that does not require self-isolation or social distancing should have this highlighted to them in case they wish to withdraw from a study. Sponsors should consider minimising the burden of administrative tasks while healthcare teams are stretched; many members of the research team are already being redeployed into direct clinical care. ## Advice for nhs staff with ibd Frontline staff with IBD should follow the same precautions as other IBD patients. However, given the high risk of exposure of frontline staff to SARS-CoV-2, it would be advisable that hospital teams consider utilising team members with IBD in roles where exposure is limited (i.e. telephone clinics as opposed to endoscopy lists and ward work), especially if that individual is at 'moderate' risk or has other comorbidity, in which case they should be supported in working from home if possible. If it is essential for them to work in a hospital environment, they should ensure they avoid close contact with other staff members and can maintain social distancing. # Conclusion The COVID-19 pandemic has posed unprecedented challenges to healthcare providers across the globe. The IBD community must continue to demonstrate adaptability in this rapidly moving field. Collaborative working is vital to ensure we gather as much knowledge as possible collectively, sharing ideas to provide the best outcomes for our patients as new evidence emerges. [table] Table 1: British Society of Gastroenterology inflammatory bowel disease COVID-19 risk grid: Stratification of risk of serious COVID-19 disease into highest, moderate and lowest risk categories for patients with inflammatory bowel disease [/table]	None	https://gut.bmj.com/content/gutjnl/69/6/984.full.pdf	The COVID-19 pandemic is putting unprecedented pressures on healthcare systems globally. Early insights have been made possible by rapid sharing of data from China and Italy. In the UK, we have rapidly mobilised inflammatory bowel disease (IBD) centres in order that preparations can be made to protect our patients and the clinical services they rely on. This is a novel coronavirus; much is unknown as to how it will affect people with IBD. We also lack information about the impact of different immunosuppressive medications. To address this uncertainty, the British Society of Gastroenterology (BSG) COVID-19 IBD Working Group has used the best available data and expert opinion to generate a risk grid that groups patients into highest, moderate and lowest risk categories. This grid allows patients to be instructed to follow the UK government’s advice for shielding, stringent and standard advice regarding social distancing, respectively. Further considerations are given to service provision, medical and surgical therapy, endoscopy, imaging and clinical trials.
2006b11d1caafacc97a151676061b37fd5febdcd	pubmed	Guidelines on the use of extracorporeal photopheresis	Guidelines on the use of extracorporeal photopheresis # Introduction Extracorporeal photopheresis (ECP, also known as extracorporeal photochemotherapy, extracorporeal photoimmunotherapy or just photopheresis) is a leukapheresis-based therapy that is available at more than 200 centres worldwide. [bib_ref] Extracorporeal photopheresis: past, present, and future, Knobler [/bib_ref] During ECP, the patient's whole blood is processed outside the body: blood is collected via an ante-cubital vein, or via a permanent catheter if access is cumbersome, and the white blood cells are separated from the red blood cells and plasma by centrifugation in a device that is specifically constructed for the procedure. The white cells are exposed to ultraviolet A (UVA) light in a separate plastic chamber, and then returned to the patient. [bib_ref] Extracorporeal photopheresis technical aspects, Schooneman [/bib_ref] Initially, when this methodology was first developed, patients treated with ECP were given oral 8-methoxypsoralen to produce an effective plasma concentration, and their blood was then leukapheresed. [bib_ref] Extracorporeal photopheresis: past, present, and future, Knobler [/bib_ref] This meant that they were still exposed to the gastrointestinal (GI) and ocular side-effects of psoralen, which include nausea and vomiting; moreover, differences in GI absorption due to individual variability 3 resulted in inconsistent blood concentrations of 8-MOP. [bib_ref] Extracorporeal photopheresis: past, present, and future, Knobler [/bib_ref] To avoid the problems associated with oral 8-MOP, the procedure was subsequently modified to use a liquid formulation of 8-MOP (UVADEX â ; Therakos Inc. West Chester, Pennsylvania, USA), which is added directly to the buffy-coat/plasma blood fraction circulating through the plastic chamber before UVA radiation and re-infusion. This eliminated the side-effects of 8-MOP, as well as the need for pre-medication with this drug and monitoring of its blood levels. [bib_ref] Parenteral administration of 8-methoxypsoralen in photopheresis, Knobler [/bib_ref] The first investigational study of ECP in cutaneous T-cell lymphoma (CTCL) was completed in 1983, [bib_ref] Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy preliminary results, Edelson [/bib_ref] and the first system for ECP, which was a closed system (UVAR â ; Therakos), was granted approval by the United States Food and Drug Administration in 1988, followed by multiple approvals in Europe and around the world. Although ECP was initially developed for use in CTCL, it has shown promising efficacy in a number of other severe and difficult-to-treat conditions, most widely in graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, but also in systemic sclerosis, prevention and treatment of rejection in solid organ transplantation, Crohn's disease and various other diseases. [bib_ref] Extracorporeal photopheresis: past, present, and future, Knobler [/bib_ref] [bib_ref] Photopheresis (extracorporeal photochemotherapy), Trautinger [/bib_ref] Several closed and open ECP systems are now available for clinical use, and some of the currently used approaches are compared in [fig_ref] Table 1: ECP approaches in current use in adults and children [/fig_ref].In a closed ECP system (i.e. a 'one-step' method), the cell separation, drug photoactivation and re-infusion stages are fully integrated and automated and all the components are validated for use together, tested and approved for use with methoxsalen [fig_ref] Table 2: European CE mark and FDA approval status of the 'one-step', closed photopheresis... [/fig_ref]. There is no risk of improper reinfusion when they are used according to their labelling and the risk of infection and contamination associated with the medical device itself is low. Open ECP systems use separate devices for cell separation and drug photoactivation ('two-step' methods), which have not been validated for use together: the combination of a device approved for separation and one approved for photoactivation is not equivalent to a device approved for ECP. Although the components may be CE marked or have FDA approval, they are not specifically approved for photopheresis [fig_ref] Table 2: European CE mark and FDA approval status of the 'one-step', closed photopheresis... [/fig_ref]. As several steps are involved in delivering therapy, there is a potential risk of infection and contamination, as well as a risk of cross-contamination and patient re-infusion error. In general, open systems can only be used by certified centres for handling blood components separately, whereas the closed systems do not have this limitation. Regardless of the system used, treatment with ECP is usually well-tolerated and no severe World Health Organization grade III-IV side-effects have been reported. A few patients may experience transient hypotension during treatment, and mild anaemia and/or thrombocytopenia have also been reported. Some patients are not suitable for treatment with ECP, including those with: a known sensitivity to psoralen compounds such as 8-MOP; comorbidities that may result in photosensitivity; aphakia (UVADEX â Sterile Solution is contraindicated in patients with aphakia because of the significantly increased risk of retinal damage due to the absence of lenses), pregnancy; history of heparin-induced thrombocytopenia, unsatisfactory cardio-circulatory function and low haematocrit values. In addition, special care needs to be taken in patients with a low bodyweight, in children and in those with problematic venous access. In these contexts, specific small port systems with an appropriate blood flow per minute should be used. Ideally, ECP treatment should be initiated as early as possible after the indication is confirmed, which, in most cases, is as second-line therapy after first-line therapy has failed. At the present time, ECP treatments are generally performed as in-patient therapy in most centres in Europe. Monitoring before and during treatment should be based on the standards of care for each indication. Even though heparin is registered for use with ECP, the use of either heparin or acid citrate dextrose as anticoagulants during ECP can be decided on the basis of the operating prac-tices in individual centres and adjusted according to individual patients' medical conditions (e.g. danger of increased bleeding, etc.). While the use of UVA protective glassware is recommended (based on experience with PUVA and oral 8-MOP), it does not appear to be necessary due to the very low levels of psoralen that are used in ECP. ## Mode of action Although ECP has been in clinical use for more than 25 years and is widely used for a variety of clinical entities, the mode of action remains elusive. The original focus included clinical studies and the identification of new indicationsas the initial regimen was (by chance) successful, there was lack of incentive to study the mechanism of action to optimize therapy. Indeed, doses and treatment intervals in current use are more or less the same as those used in the 1980s. Early studies indicated that ECP induced apoptosis in lymphocytes, which in some way contributed to the therapeutic effect. [bib_ref] Extracorporeal photopheresis induces apoptosis in the lymphocytes of cutaneous T-cell lymphoma and..., Bladon [/bib_ref] [bib_ref] Investigation of annexin V binding to lymphocytes after extracorporeal photoimmunotherapy as an..., Gerber [/bib_ref] More recent studies, most using animal models despite their clinical limitations, have shown the mechanism of action of ECP to be primarily attributable to an immunomodulatory effectthe principal basic mechanisms comprising modulation of dendritic cells, alteration of the cytokine profile, and induction of particular T-cell subpopulations. [bib_ref] Extending the horizon for cell-based immunotherapy by understanding the mechanisms of action..., Voss [/bib_ref] [bib_ref] Update on the mechanism of action and on clinical efficacy of extracorporeal..., Goussetis [/bib_ref] ECP, like psoralen plus UVA (PUVA), induces psoralen-mediated DNA crosslinks, which cause apoptosis of lymphoid cells, particularly natural killer (NK) and T cells. [bib_ref] Effect of UVA and 8-methoxypsoralen, 4, 6, 4'-trimethylangelicin or chlorpromazine on apoptosis..., Wolnicka-Glubisz [/bib_ref] The therapeutic effect of ECP in S ezary syndrome (SS), however, cannot be explained by depletion of malignant cells, as only a minority of the entire lymphocyte pool is included in a photopheresis cycle. Monocytes treated in the same way appear to be more resistant than lymphocytes to apoptosis, undergoing a differentiation process within 2 days and expressing surface markers that are characteristic of immature dendritic cells (CD83, X-11, Alpha-V, Beta-V, CD1a). [bib_ref] Transimmunization, a novel approach for tumor immunotherapy, Berger [/bib_ref] [bib_ref] Photochemotherapy induces the apoptosis of monocytes without impairing their function, Hannani [/bib_ref] [bib_ref] Maturation state of dendritic cells during the extracorporeal photopheresis and its relevance..., Spisek [/bib_ref] This differentiation appears to be independent of psoralen-induced photoactivation, and is mostly driven by contact of the cells with plastic and other synthetic materials during passage through the photopheresis system. The apoptotic lymphocytes are phagocytosed and eliminated upon re-infusion this phagocytosis of apoptotic lymphocytes by immature dendritic cells, which subsequently undergo maturation and present antigenic peptides, has been designated transimmunization. [bib_ref] Transimmunization for cutaneous T cell lymphoma: a Phase I study, Girardi [/bib_ref] Indeed, it has been suggested that transimmunization induces an immune response against lymphoma cells, which might explain the beneficial effect of ECP in SS. The ECP-initiated cellular mechanisms of differentiation are associated with the release of a variety of cytokines. These None See above for MNC and AutoPBSC procedure CFC Suitable for low body weight patients. Only cell separation is automated, while the UVA irradiator is operated manually. Other dedicated continuous or intermittent cell separators may also be used such as Amicus (Fenwal, MNC kit), AS104 (Fresnius Kabi) which has extracorporeal volumes of 163 and 175 mL respectively. †Three-step methods involve standard mononuclear cell collection using dedicated continuous cell separators, followed by red blood cell priming of UVAR-XTS instrument and photoactivation treatment of the 8-methoxypsoralen treated mononuclear cells within the UVAR-XTS instrument after programming the instrument that the last ECP cycle has occurred. CFC, continuous flow centrifugation; ECV, extracorporeal cell volume; Hct, haematocrit; IFC, intermittent flow centrifugation; MNC, mononuclear cell; RBC, red blood cell. include tumour necrosis factor (TNF)-a and interleukin (IL)-6, which induce the activation of CD36-positive macrophages. [bib_ref] Extracorporeal photochemotherapy induces a significant increase in CD36 + circulating monocytes in..., Fimiani [/bib_ref] Indeed, it should be pointed out that long-term immunological alterations can be induced by continuous ECP. Depending on its severity, CTCL is associated with an imbalance in the Th1/Th2 immune response, which includes increased release of IL-4 and IL-5, reduced activity of NK cells, and reduced cytotoxicity of CD8-positive T cells. In a study of patients with early-stage CTCL (stage IB) undergoing ECP for 1 year, Di Renzo and colleagues observed not only an increase in CD36-positive monocytes in the peripheral blood but also a change in the cytokine reaction profile of peripheral blood lymphocytes upon stimulation with phytohaemagglutinin. [bib_ref] Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell..., Renzo [/bib_ref] This implies that ECP reverses the pathologic shift towards a Th2 immune response in CTCL patients and restores the Th1/Th2 balance. In addition, antiinflammatory cytokines appear to be induced by ECP, whereas pro-inflammatory cytokines are reduced. [bib_ref] Extracorporeal photopheresis: a focus on apoptosis and cytokines, Bladon [/bib_ref] Over time, ECP has been shown to be beneficial not only in patients with CTCL but also in those with GVHD, transplant rejection and various autoimmune diseases. The above-mentioned findings, however, cannot explain the effects of ECP in these patients and, as these conditions respond to immunosuppressive therapies, it was surmised that ECP might also exert inhibitory effects on the immune system. Furthermore, in patients with GVHD, ECP was shown to induce IL-10 via modulation of arginine metabolism. [bib_ref] Extracorporeal photochemotherapy induces arginase 1 in patients with graft versus host disease, Merlin [/bib_ref] In contrast to immunosuppressive therapy, ECP is not associated with any major side-effects, including opportunistic infections. It has been postulated that the therapeutic effect of ECP operates presumably via the induction of regulatory T (Treg)-cells, without causing general immunosuppression. Using a murine contact hypersensitivity model, Maeda and colleagues demonstrated the induction of Treg-cells by an 'ECP-like' procedure (intravenous injection of leucocytes exposed to 8-MOP and UVA in vitro). [bib_ref] Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T..., Maeda [/bib_ref] Treg-cells induced in this way appeared similar to UVB-induced Treg-cells, which express CD4, CD25, CTLA-4 and the transcription factor Foxp3, and which suppress the activity of other lymphocytes. [bib_ref] Phenotypic and functional characterization of ultraviolet radiation-induced regulatory T cells, Maeda [/bib_ref] Furthermore, the release of IL-10 appears to be involved in this process. [bib_ref] Experimental extracorporeal photopheresis inhibits the sensitization and effector phases of contact hypersensitivity..., Maeda [/bib_ref] A recent study of 46 patients with chronic GVHD (cGVHD) measured serum B-cell activating factor (BAFF) and found that BAFF levels at 1 month after ECP predicted 3-and 6month skin response, with levels <4 ng/mL being associated with a significant skin improvement. [bib_ref] Circulating B-cell activating factor level predicts clinical response of chronic graft-versus-host disease..., Whittle [/bib_ref] The manifestation of acute GVHD (aGVHD) in patients with allogeneic grafts can be associated with a low number of Tregcells, [bib_ref] Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells, Gatza [/bib_ref] [bib_ref] High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low..., Rezvani [/bib_ref] [bib_ref] Regulatory T-cells in the graft and the risk of acute graft-versus-host disease..., Wolf [/bib_ref] [bib_ref] Correlation of the CD4 + CD25high T-regulatory cells in recipients and their..., Zhai [/bib_ref] and induction of T cells with regulatory properties following ECP has been confirmed in a murine GVHD model. [bib_ref] Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells, Gatza [/bib_ref] Hence, several research groups have studied the effect of ECP on the number of Treg-cells. In the majority of both CTCL and GVHD patients, an increase in Treg-cells was observed, as well as an enhanced suppressive activity. [bib_ref] Reciprocal modulation of circulating CD4 + CD25 + bright T cells induced..., Quaglino [/bib_ref] [bib_ref] Cutaneous T cell lymphoma and graft-versus-host disease: a comparison of in vivo..., Rao [/bib_ref] [bib_ref] Regulatory T cells and extracorporeal photochemotherapy: correlation with clinical response and decreased..., Biaso [/bib_ref] [bib_ref] Extracorporeal photophoresis augments function of CD4 + CD25 + FoxP3 + regulatory..., Schmitt [/bib_ref] [bib_ref] Extracorporeal photopheresis in refractory chronic graft-versus-host disease: the influence on peripheral blood..., Tsirigotis [/bib_ref] [bib_ref] Extracorporeal photochemotherapy is accompanied by increasing levels of circulating CD4 + CD25..., Biagi [/bib_ref] This could explain, at least partially, the beneficial effect of ECP in both GVHD and autoimmune diseases, although how this relates to the positive effect of ECP in patients with CTCL remains unknown. In patients with SS, however, reduced numbers of Treg-cells have been observed, [bib_ref] FOXP3 + CD25-tumor cells with regulatory function in Sezary syndrome, Heid [/bib_ref] [bib_ref] Paucity of FOXP3 + cells in skin and peripheral blood distinguishes Sezary..., Klemke [/bib_ref] and their suppressive function appears to be impaired. [bib_ref] Lack of suppressive CD4 + CD25 + FOXP3 + T cells in..., Tiemessen [/bib_ref] This has led to speculation on whether Treg-cells have the capacity to suppress CD4-positive tumour cells in patients with SS, and this remains to be determined. A recent study showed that ECP slightly increased or stabilized the number of peripheral CD4 + CD25 + FoxP3 + Treg-cell counts in lung transplant recipients who showed functional stabilization. [bib_ref] Role for CD4(+)CD25(+) T cells in inhibition of graft rejection by extracorporeal..., George [/bib_ref] Overall, the re-infusion of the treated leucocytes mediated a specific suppression of both the humoral and cellular rejection response, and thereby induced tolerance of the allograft, thus prolonging the survival of transplanted tissues and organs. The mechanism by which ECP counteracts cardiac rejection was studied using a murine model of ECP. 38 Splenocytes exposed to 8-MOP and UVA were injected into syngeneic mice both before and after heterotopic cardiac allograft transplant. None of the mice received immunosuppressive agents. The treatment group showed extended cardiac allograft survival and increased levels of FoxP3-expressing CD4 + CD25 + T cells when compared with controls. The authors concluded that the murine model of ECP extends graft survival in fully histo-incompatible strain combinations with no immunosuppression. [bib_ref] Role for CD4(+)CD25(+) T cells in inhibition of graft rejection by extracorporeal..., George [/bib_ref] In Crohn's disease, activation of the counterbalancing regulatory response induced by Treg-cells directed against the hyperactive adaptive arm of the immune system could compromise general functionality against pathogenic danger signals. Re-infusion of ECP-generated apoptotic leucocytes back into the patient are hypothesized to generate a tolerogenic response via Tregcells; indeed, re-circulation of DNA-adduct-positive cells to the intestinal mucosa has been described following ECP. [bib_ref] Experimental extracorporeal photopheresis inhibits the sensitization and effector phases of contact hypersensitivity..., Maeda [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in patients with steroid-dependent Crohn's disease: a prospective pilot study, Reinisch [/bib_ref] Murine models of inflammatory bowel disease have provided information on the potential therapeutic role of Treg-cells in overcoming the disease in humans. [bib_ref] Homeostasis and inflammation in the intestine, Garrett [/bib_ref] In the only randomized, double-blind, placebo-controlled trial of ECP in children with type 1 diabetes (T1D), the effects of ECP on the immune system were also studied. [bib_ref] Photopheresis at onset of type 1 diabetes: a randomised, double blind, placebo..., Ludvigsson [/bib_ref] There were no major effects of ECP on lymphocyte populations. However, in the placebo group, the proportions of activated CD4 + and CD8 + cells increased over time, whereas such changes were not seen in the ECP-treated group. These findings probably reflect an activation of lymphocytes as part of the natural course of T1D and that ECP may have some suppressant effects, preventing lymphocyte activation. [bib_ref] Effect of photopheresis on lymphocyte population in children with newly diagnosed type..., Ernerudh [/bib_ref] ECP produced cytokine changes reflecting a Th2-like response. [bib_ref] The immunological effect of photopheresis in children with newly diagnosed type 1..., Faresjo [/bib_ref] Placebo-treated patients showed reduced T-cell-associated activity, which seemed to be counteracted by ECP, whereas ECP-treated patients showed preserved T-cell activity. These data indicate that ECP acts to maintain Treg-cellassociated activity in recent-onset T1D. [bib_ref] Regulatory T cell-associated activity in photopheresis-induced immune tolerance in recent onset type..., Jonson [/bib_ref] Although partial aspects of the mode of action of ECP, such as the induction of Treg-cells, are quite clear, we are still far away from a complete understanding of how ECP works. The recent establishment of animal models will give the opportunity to modify the ECP procedure with regard to the number of cycles, doses of 8-MOP and UVA, and the number of cells infused, with the ultimate aim of optimizing the regimens that are currently used. In addition, greater understanding of the mechanism of action will finally enable this therapy to be directed towards those patients who could most benefit from it. # Methodology Guidelines on the use of ECP were identified through a literature search, an internet search of relevant medical databases and a search of relevant professional bodies, as well as expert opinion on the appropriate use of ECP based on 'best medical practices'. The literature evaluated in the existing guidelines, brought up to date with more recently published data, serves as the basis for the present set of guidelines. ECP is not widely available and is generally used for severe refractory disease courses, or in situations in which other therapies have been tried and have failed. Therefore, the use of this treatment is not generally based on data from controlled and randomized clinical trials, which are usually required for evidence-based medicine, but on multiple small-cohort or casecontrol studies. Double-blinded trials are difficult, and sham photopheresis may be unethical in patients with severe disease. The guidelines presented here were drawn up to present the indications for which ECP is currently considered as effective, as well as other indications where studies with ECP have shown promising results. For the major indications, namely CTCL and GVHD, the recommendations were developed by a group of experts who are leaders in the development of specific guidelines in these disease areas. For minor indications, expert committees were brought together to examine the available evidence and to make recommendations based on this. The aim was to answer the following questions for each clinical condition: 1 Which diseases are indicated for treatment with ECP? 2 Are there currently any guidelines/consensus statements on ECP in this indication? 3 Which patients should be considered for ECP treatment? 4 What is the optimal treatment schedule and how long should ECP treatment be continued? 5 How is therapeutic efficacy assessed? The recommendations were developed and discussed for consensus decision at a number of consensus meetings where the authors and experts were present for reaching consensus agreements (Gothenburg, Sweden, [bib_ref] Extracorporeal photopheresis induces apoptosis in the lymphocytes of cutaneous T-cell lymphoma and..., Bladon [/bib_ref] Cutaneous T-cell lymphoma CTCL describes a heterogeneous group of rare lymphoproliferative disorders, which are characterized by the accumulation of malignant T-cell clones that home to the skin. [bib_ref] Maintenance therapy in cutaneous T-cell lymphoma: who, when, what?, Dummer [/bib_ref] The most common variants are mycosis fungoides (MF), which accounts for about 60% of CTCL cases, and SS, which accounts for 5% of cases. MF is characterized by the presence of a clonal T-cell population in the cutaneous environment and, in the early stages of the disease, presents as scaly patches or plaques, which may resemble eczema or psoriasis in appearance and are often associated with pruritus. As the disease progresses, patients may experience the growth of nodular lesions and large tumours, also with severe pruritus, which may ulcerate and result in chronic septicaemia, thrombosis and pain. SS is the 'leukaemic' form of CTCL, in which the dominant T-cell population also circulates in the peripheral blood and may affect internal organs such as the lungs and spleen. MF/SS is classified into clinical stages from IA (the earliest stage) to IVB according to the degree of skin, lymph node, peripheral blood and visceral organ involvement. [bib_ref] Revisions to the staging and classification of mycosis fungoides and Sezary syndrome:..., Olsen [/bib_ref] Curative therapies are not available and treatment is usually directed towards palliation and the induction of long-term remissions. The aim was to reduce or clear skin lesions, including tumours and reduce pruritus, thereby providing symptom relief and improving patient quality of life. [bib_ref] Maintenance therapy in cutaneous T-cell lymphoma: who, when, what?, Dummer [/bib_ref] In the early stages of MF, treatment usually involves skin-directed therapies, such as topical corticosteroids, topical chemotherapy (nitrogen mustard or bis-chloronitrosourea) or phototherapy (narrow-band UVB or PUVA). Systemic therapies, including chemotherapy and biological response modifiers [such as interferon (IFN)-a and bexarotene] are used if the disease progresses, or for those who present with more advanced-stage disease, often in combination with skin-directed therapies. [bib_ref] EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome, Trautinger [/bib_ref] PUVA, in which patients take an oral formulation of 8-MOP to induce photoactivation followed by exposure of their skin to UVA radiation, is a widely used and effective skin-directed therapy for early-stage, skin-localized CTCL, [bib_ref] EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome, Trautinger [/bib_ref] which can produce relatively long-lived remissions. It is, however, associated with short-term side-effects of oral psoralen intake and possible longterm complications such as photosensitivity and the potential for development of skin cancer. [bib_ref] ECP versus PUVA for the treatment of cutaneous T-cell lymphoma, Geskin [/bib_ref] ECP has enabled the safety profile of PUVA to be improved, avoiding the potential complications associated with long-term skin exposure to UVA. It also means that the benefits of therapy can be extended beyond the treatment of patients with predominantly early disease to patient populations with more advanced disease and the presence of a circulating malignant clone in their peripheral blood. [bib_ref] ECP versus PUVA for the treatment of cutaneous T-cell lymphoma, Geskin [/bib_ref] Many studies have demonstrated that ECP is of significant value in the treatment of CTCL. However, because of the rarity of the disease and specialized delivery of therapy, there are no prospective, placebo-controlled, randomized clinical trials that evaluate the impact of treatment on survival, and any comparisons made are usually with 'historical controls'. The initial study of ECP in patients with CTCL resistant to other treatments was reported by Edelson and colleagues in 1987 and showed it to be a promising therapy. 5 Among 37 patients, 27 (73%) responded to treatment, with an average 64% decrease in cutaneous involvement; nine of these patients had a complete response (CR). Data from this study have recently been re-analysed using modern criteria, resulting in a skin overall response rate of 74%, with 33% of patients achieving ≥50% partial skin response and 41% achieving ≥90% improvement. [bib_ref] Long-term follow-up and survival of cutaneous T-cell lymphoma patients treated with extracorporeal..., Knobler [/bib_ref] An update on the overall survival (OS) of these patients was also provided, which was 9.2 years from diagnosis and 6.6 years from initiation of ECP. Since 1987, numerous studies have been conducted. A metaanalysis of 19 studies in more than 400 patients at all stages of CTCL reported a combined overall response (OR) rate of 56% with ECP used as monotherapy and 56% when used in combination with other agents, of which 15% and 18%, respectively, were CRs. [bib_ref] The treatment of cutaneous T-cell lymphoma with photopheresis, Zic [/bib_ref] For erythrodermic disease, the OR rate was 58% and the CR rate was 15%. Importantly, ECP was effective in SS, showing an OR rate of 43%, with 10% CRs. [fig_ref] Table 3: Summary of studies using extracorporeal photopheresis as monotherapy or in combination with... [/fig_ref] (adapted from the UK consensus statement on the use of ECP for the treatment of CTCL and GVHD 50 ) provides a summary of the published response rates with ECP in the treatment of CTCL from 1987 to 2011. Based on the 30 separate studies in 689 patients published from 1987 to mid 2007 that were analysed in the UK consensus statement, the mean OR rate in the studies that reported these data was 63% (range 33-100%), and response rates were generally higher among patients with erythrodermic CTCL. [bib_ref] consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous..., Scarisbrick [/bib_ref] The CR rate, where recorded, ranged from 0% to 62% (mean 20%). More recent studies published from late 2007 to 2011 51-57 report OR rates ranging from 42% to 80%, with CR rates ranging from 0% to 30%. It is clear that ECP is beneficial in the treatment of CTCL, but it is also apparent that there are considerable differences in response rates between centres. Such differences may relate to a number of factors, including differences in patient selection, stage of disease, prior treatments received, ECP protocol used, duration of ECP and the definition of response that is used. [bib_ref] consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous..., Scarisbrick [/bib_ref] Similar considerations apply to studies reporting survival in patients with CTCL treated with ECP. Variable median survival data have been reported for SS, ranging from 30 months 58 to 60 months, [bib_ref] Photopheresis therapy of cutaneous T-cell lymphoma: the Yale-New Haven Hospital experience, Heald [/bib_ref] which probably reflects the use of different diagnostic criteria. Much longer median survival for CTCL treated with ECP has been reported, but not all patients in the studies had erythrodermic disease or they had received other therapies in combination. [bib_ref] Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination..., Gottlieb [/bib_ref] [bib_ref] Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracorporeal photochemotherapy, Zic [/bib_ref] The studies listed in [fig_ref] Table 3: Summary of studies using extracorporeal photopheresis as monotherapy or in combination with... [/fig_ref] include ECP used as monotherapy and in combination with other therapies. Such combination therapies have been investigated as a way to further improve response rates, particularly in patients with a high tumour burden. The largest series of CTCL patients treated by ECP was recently published by Rook and colleagues in the USA, who reported their experience over a 25-year period in 98 erythrodermic CTCL patients treated with at least 3 months of ECP and one or more systemic immunostimulatory agents. [bib_ref] High clinical response rate of Sezary syndrome to immunomodulatory therapies: prognostic markers..., Raphael [/bib_ref] A clinically significant improvement was obtained in 75% of patients with this multimodality therapy, with 30% having a CR. Previously, Suchin and colleagues reported on 47 patients who had received at least 6 cycles of ECP: 68% had stage III or IV CTCL and 89% had circulating malignant T cells. [bib_ref] Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience..., Suchin [/bib_ref] Thirty-one patients received treatment with ECP and one or more other systemic agents, including IFN-a, IFN-c, granulocyte-macrophage colonystimulating factor (GM-CSF; sargramostim) or systemic retinoids, for 3 months or more. Overall, 79% of patients responded to therapy, with 26% having a CR. Among patients receiving combination therapy, 84% achieved a response, with 20% having a CR, whereas the OR rate with ECP monotherapy was 74%, of which 38% were CRs. The median survival was 74 months with combination therapy vs. 66 months for ECP monotherapy, although the difference was not statistically significant. A prospective observational study in 48 patients with erythrodermic CTCL (36 with SS) reported a response rate of 58% with ECP alone, compared with 64% with combination therapy in patients with more adverse prognostic factors. [bib_ref] Extracorporeal photopheresis for the treatment of erythrodermic cutaneous T-cell lymphoma: a single..., Quaglino [/bib_ref] Similarly, Duvic and colleagues reported a slightly higher response rate among 32 patients treated with ECP in combination with IFN-a, bexarotene or GM-CSF compared with 54 who had received ECP monotherapy (OR > 50% in 56% vs. 43% respectively). [bib_ref] Extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma, Duvic [/bib_ref] A number of other studies with ECP plus IFN-a have been published that report an increased response rate compared with ECP monotherapy. [bib_ref] Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination..., Gottlieb [/bib_ref] [bib_ref] Treatment of stage II cutaneous T-cell lymphoma with interferon alfa-2a and extracorporeal..., Wollina [/bib_ref] [bib_ref] Extracorporeal photochemotherapy alone or with adjuvant therapy in the treatment of cutaneous..., Bisaccia [/bib_ref] However, none of these studies was controlled or randomized, making it difficult to assess how much of the clinical benefit was due to IFN-a and how much to ECP, and what synergistic effects can be obtained. ECP has also been used in combination with total skin electron beam (TSEB) therapy. A retrospective study of 44 patients with erythrodermic MF/SS treated with TSEB with or without ECP reported an overall CR of 73% with a 3-year disease-free survival of 63%. [bib_ref] Experience with total skin electron beam therapy in combination with extracorporeal photopheresis..., Wilson [/bib_ref] Among those receiving combined TSEB and ECP, the 3-year disease-free survival was 81% compared with 49% with TSEB alone. On the basis of these data, further studies with the TSEB and ECP combination are warranted. Most of the studies with ECP in CTCL have primarily included patients with advanced stages of the disease. Guidelines recommend ECP as first-line systematic therapy for erythrodermic MF and SS. [bib_ref] EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome, Trautinger [/bib_ref] [bib_ref] consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous..., Scarisbrick [/bib_ref] [bib_ref] Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for..., Whittaker [/bib_ref] Its use in early stages of CTCL is controversial but warrants further investigation. A literature review of data from 16 studies with ECP or ECP plus adjuvant therapy from 1987 to 2007, which included a total of 124 patients with early-stage (stage IA, IB, IIA) CTCL, found that the response rates ranged from 33% to 88% if ECP was used as monotherapy and from 50% to 60% with ECP plus adjuvant therapy. [bib_ref] Review of extracorporeal photopheresis in early-stage (IA, IB, and IIA) cutaneous T-cell..., Miller [/bib_ref] Furthermore, many early-stage patients treated with ECP achieved long-lasting regression of disease. In a recent study, 19 patients with early-stage MF were treated with ECP on two consecutive days every month for 6 months. [bib_ref] Multicenter photopheresis intervention trial in early-stage mycosis fungoides, Talpur [/bib_ref] Patients with a partial response (PR) continued with ECP alone for 6 months, whereas non-responders could receive additional therapy with oral bexarotene and/or IFN-a. The OR rate for ECP alone was 42% (8/19, including 1 CR; 7 PR), with an overall duration of response of 6.5 (range 1-48) months. Seven patients with stable disease at 3 months received additional bexarotene and/or IFN-a and four (57%) responded. For all 19 patients, the OR rate was 63% (2 CR, 10 PR). Most guidelines do not indicate use of ECP in early stage disease, but the National Comprehensive Cancer Network (NCCN) Guidelines recommend ECP in those patients with stage IA, IB and IIA refractory disease.In summary, for patients with advanced CTCL (such as those with erythroderma or the presence of peripheral blood involvement), which are typically resistant to treatment and weighted by a poor prognosis, ECP, either as monotherapy or combined with other immunotherapies, offers good treatment efficacy and the possibility of prolonged survival. Given the very low side effect profile of ECP compared with other therapies and its demonstrated efficacy in later-stage CTCL, this treatment modality is possibly also beneficial in earlier stages of the disease, as recently suggested, [bib_ref] Multicenter photopheresis intervention trial in early-stage mycosis fungoides, Talpur [/bib_ref] although further studies that focus on this patient population are needed. There is, however, inter-patient variability in the response to ECP in CTCL, so attempts have been made to characterize those patients who are most likely to be responders. The prognostic factors that have been identified include the following 50,70,71 : - short duration of disease, preferably <2 years; - absence of bulky lymphadenopathy or major internal organ involvement; - white blood cell count <20 000 mm À3 ; - presence of a discrete number of S ezary cells (10-20% of mononuclear cells); - natural killer cell activity close to normal; - cytotoxic T lymphocytes close to normal (CD8 + > 15%); - absence of prior intensive chemotherapy; and - plaque stage disease not covering more than 10-15% of total skin surface. Although these criteria are useful in identifying the likely best responders to ECP, they are not absolute, and some patients who fall outside these criteria will also respond. [bib_ref] Extracorporeal photochemoimmunotherapy in cutaneous T-cell lymphoma, Knobler [/bib_ref] A critical factor for success is that the patient must be able to mount an immune response against the malignant cells that have passed through the photoactivating device. [bib_ref] Rapid generation of maturationally synchronized human dendritic cells: contribution to the clinical..., Berger [/bib_ref] [bib_ref] Extracorporeal photopheresis in Sezary syndrome: hematologic parameters as predictors of response, Evans [/bib_ref] Existing clinical guidelines Several professional organizations have produced guidelines on the management of CTCL and the use of ECP. In the European Organization for Research and Treatment of Cancer (EORTC) consensus recommendations for the treatment of MF/SS (published in 2006), [bib_ref] EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome, Trautinger [/bib_ref] ECP was recommended for the first-line treatment of MF stage III and for first-line treatment of SS, with a strength of recommendation of C (on a scale from A to D). In MF, the level of evidence was rated as 4 (evidence from case series, poor-quality cohort or case-control studies) and in SS as 2b (evidence from individual cohort study or poor-quality, randomized, controlled trial). Although not a recommendation, it was mentioned that the usual ECP treatment schedule was two successive days every 4 weeks, continued for up to 6 months, followed by maintenance therapy tailored according to disease course and severity. The UK Photopheresis Expert Group consensus statement on the use of ECP 50 is a comprehensive document published in 2008, which, after reviewing the literature, recommended that ECP should be considered for the treatment of patients with CTCL who fulfil both of the major criteria of erythroderma and stage III or IVA CTCL (histology consistent with CTCL), as well as one of the minor criteria: circulating clonal disease (circulating T-cell clone by polymerase chain reaction or Southern blot analysis); evidence of circulating S ezary cells (>10% of circulating lymphocytes); CD4/CD8 ratio >10. The recommended treatment cycle was one cycle (i.e. two consecutive days) every 2-4 weeks (to be given more frequently in symptomatic patients and in those with a high peripheral blood tumour burden). Treatment should be tapered at maximal response or greater to one cycle every 6-12 weeks before stopping. Guidance was provided on monitoring treatment, and assessments at 3-monthly intervals were recommended, to allow non-responders to be offered combination or alternative therapy and to ensure that ECP treatment was not prolonged in detriment to their health, and to avoid ECP being given alone for more than 6 months in patients with responses of less than 50%. The British Photodermatology Group and UK Skin Lymphoma Group published a report in 2006 on evidence-based practice of ECP based on data from 1987 to 2001, [bib_ref] Evidence-based practice of photopheresis 1987-2001: a report of a workshop of the..., Mckenna [/bib_ref] which looked at the use of ECP in a variety of conditions. They concluded that there was: 'fair' evidence that ECP has clinical benefit in erythrodermic MF/SS (stage III/IVA/B1/0), with a strength of recommendation of B (on a scale from A to E), based on level II-i evidence (i.e. from well-designed controlled trials without randomization); 'fair' evidence to support the use of TSEB with ECP for erythrodermic MF/SS [strength of recommendation B, quality of evidence II-ii (well-designed cohort or case-control studies)]; and poor evidence to support the use of IFN-a plus ECP for erythrodermic MF/SS (strength of recommendation C, quality of evidence II-ii). The authors described a typical protocol of two ECP treatments on two consecutive days per month, continued for up to 6 months, followed by tapering or maintenance treatment in those patients who have respondedthe frequency of treatment can be increased to fortnightly in poor responders, or ECP can be combined with other therapeutic agents such as IFN-a. Recommended patient assessments and appropriate efficacy parameters were also listed. The National Cancer Institute in the USA guidance on treatment of MF and SS 68 listed appropriate treatments at each CTCL disease stage. ECP was included as an option for the treatment of stage III MF/SS and, either alone or with TSEB, for the treatment of stage IV MF/SS. For patients with recurrent MF/SS, it was noted that ECP has produced tumour regression in those who are resistant to other therapies. No information was given on the appropriate monitoring of therapy or of outcomes. The NCCN clinical guidelines on MF/SS (2012) state that their recommendations are all based on category 2A evidence (lower level evidence but with NCCN consensus). ECP was recommended as first line for stage IV SS, alone or in combination with interferon or bexarotene. ECP was also recommended in relapsed or refractory stage III disease and in IA, IB-IIA disease refractory to skin-directed therapy.The United States Cutaneous Lymphoma Consortium (US-CLC) reviewed the therapeutic options for SS.ECP was recommended as a category A systemic monotherapy, based on level II-2 evidence (i.e. obtained from at least one prospective, welldesigned cohort or case-control study, preferably from more than one centre or research group). In addition, recommended category A combination therapies included TSEB plus ECP alone or in combination with IFN-a, IFN-c or bexarotene, and ECP plus bexarotene, IFN-a, IFN-c or low-dose methotrexate singly or in combination. The NORth Trent COMmissioners (NORCOM) policy on ECP for cancer and disease (reviewed in 2008)was developed to provide guidance to five UK Primary Care Trusts on when ECP therapy should be funded. It concluded that, based on case series studies alone (i.e. lower quality evidence than randomized controlled trials), the evidence supports the use of ECP for erythrodermic MF/SS. They recommended that, to be eligible for treatment, patients with CTCL should fulfil all the following criteria: erythroderma, biopsy-proven diagnosis of CTCL, evidence of circulating clonal disease and evidence of circulating S ezary cells (10% of lymphocytes present). The recommended treatment was two consecutive days of ECP per month for a minimum of 6 months. Recommendations were also provided on monitoring of therapy, response assessment criteria and tapering of treatment in responders. Finally, the Association of the Scientific Medical Societies of Germany recently provided guidance on the staging, assessment, diagnosis and therapy of cutaneous lymphomas.ECP was recommended as first-line treatment for erythrodermic MF stage III and for SS. The guidelines stated that ECP could be combined with IFN-a, methotrexate, bexarotene or PUVA, and they also commented on the good safety profile of ECP. No rating of the grade of recommendation or level of evidence was given, and no information was provided on how the guidelines were prepared. ## Recommendations Patient selection ECP should be considered as first-line therapy for the following CTCL patients. - Erythrodermic stage IIIA or IIIB (i.e. with B0 or B1 score according to the revised International Society for Cutaneous Lymphomas [ISCL]/EORTC classification). [bib_ref] Revisions to the staging and classification of mycosis fungoides and Sezary syndrome:..., Olsen [/bib_ref] Even though a series of papers (see the recent study by Talpur et al. [bib_ref] Multicenter photopheresis intervention trial in early-stage mycosis fungoides, Talpur [/bib_ref] have suggested that there is a potential benefit of ECP in patients with early-stage disease (stage IA, IB, IIA), the consensus decision was that this indication should be considered only for clinical trial purposes, as a variety of other safe, effective and easily accessible treatment options are available for use at this stage. - Stage IVA1 (i.e. patients with B2 score) and a T score of T1, T2 or T4. - Stage IVA2 (i.e. patients with N3 score) and a T score of T4. ## Treatment schedule - Initial recommended schedule should be one cycle (i.e. two consecutive days) every 2 weeks for the first 3 months, then once monthly or every 3 weeks. However, there is no clear optimal therapy, and other published guidelines have recommended one cycle every 2-4 weeks, followed by tapering after maximum response. [bib_ref] consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous..., Scarisbrick [/bib_ref] There are no controlled data in the literature that clearly support higher clinical activity associated with more frequent ECP courses. On the basis of clinical experience, it was recognized that an initial increased frequency of treatment courses could give a potentially significant benefit, particularly in patients with strong subjective symptoms (itchiness) and those with B2 score. However, based on patient compliance, a standard monthly treatment could also be performed, according to the policies and possibilities at each centre. - Treatment should be continued for a time period of not less than 6 months, and ranging between 6 and 12 months to evaluate for a positive response. - At maximal response, treatment should be slowly tapered to one treatment every 4-8 weeks for maintenance therapy. - In patients with a response or disease stabilization and good quality of life, ECP treatment should not be stopped and should be prolonged for even more than 2 years, with a progressive extension of treatment intervals up to 8 weeks. - Patients who do not respond to ECP as first-line therapy should be considered for combination therapies (i.e. ECP plus other drugs). - The agents that should be associated with ECP on the basis of their known immunomodulatory mechanisms are IFN and/or bexarotene. Skin care and topical medications need to be included from the start of ECP. In addition, topical steroids applied on selected parts of the body skin surface are allowed in association with ECP, particularly in patients with strong subjective symptoms. In patients with a frank 'leukaemic' involvement with high white blood cell counts (i.e. >20 000 mm À3 ), cytoreductive treatment (debulking chemotherapy or alemtuzumab) can be performed before ECP to decrease the extent of peripheral blood involvement. Also, local radiotherapy can be performed either before or during ECP to treat localized infiltrated lesions. While the association of ECP with histone deacetylase inhibitors appears potentially useful, at present there are no published data available to support this combination. - Systemic concurrent therapies can be initiated at any time point at the discretion of each centre; however, it is suggested to wait for at least 3 months of ECP monotherapy before starting an associated drug. If patients are already on other therapies (bexarotene and/or IFN), then ECP can be added without the withdrawal of the previous treatment. ## Response assessment - Response assessment should be performed every 3 months and made on the basis of the ISCL/USCLC/EORTC consensus statement. [bib_ref] Clinical end points and response criteria in mycosis fungoides and Sezary syndrome:..., Olsen [/bib_ref] It is recommended to wait for at least 6 months of treatment before concluding that ECP is not effective. Based on clinical experience, responses usually do not develop early and can also be observed a considerable period of time after starting ECP. It was agreed that the minimum time for evaluation of response to ECP should be after at least 6 months of treatment before it is concluded that ECP is not effective. - In the presence of a CR, treatment should not be stopped and prolonged for a long period of time, with a progressive extension of treatment intervals up to 8 weeks. - In the presence of PR/stable disease, it is suggested to evaluate for combination treatments or to increase the frequency of treatments. - In the presence of progressive disease, it is suggested to evaluate for combination treatments, to increase the frequency of treatments, or to stop ECP in favour of alternative anti-CTCL therapy. Chronic graft-versus-host disease cGVHD is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT), associated with substantial morbidity and mortality, mainly due to infectious complications. [bib_ref] Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects..., Socie [/bib_ref] [bib_ref] Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse, Lee [/bib_ref] [bib_ref] Chronic graft versus host disease, Higman [/bib_ref] First-line therapy of cGVHD consists of corticosteroids, 82-84 whereas many therapeutic options have been reported for salvage therapy. [bib_ref] Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic..., Wolff [/bib_ref] [bib_ref] Treatment of chronic graft-versus-host disease: past, present and future, Martin [/bib_ref] However, no single class of immunosuppressive agent has consistently achieved a steroid-sparing effect in patients with cGVHD. ECP represents a frequently used therapeutic approach for the treatment of cGVHD. Recently, Martin and colleagues, performing a comprehensive review of both retrospective and prospective trials of cGVHD therapy, reported on 60 studies evaluating 17 different agents. [bib_ref] Treatment of chronic graft-versus-host disease: past, present and future, Martin [/bib_ref] Interestingly, ECP was the most frequently studied therapy. Tables 4 87-98 and 5 99-108 provide a summary of studies with ECP in paediatric and adult patients with cGVHD. Owsianowski and colleagues reported the first use of ECP in cGVHD in 1994, [bib_ref] Successful treatment of chronic graft-versus-host disease with extracorporeal photopheresis, Owsianowski [/bib_ref] and it is now a widely recognized secondline therapy for cGVHD patients failing on corticosteroids. [bib_ref] Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic..., Wolff [/bib_ref] [bib_ref] Diagnosis and management of chronic graft-versus-host disease, Dignan [/bib_ref] The safety profile of ECP is excellent, with minimal side-effects and no long-term complications, particularly in comparison with other immunosuppressive therapies currently available for cGVHD (including mycophenolate mofetil, tacrolimus, inhibitors of the mammalian target of rapamycin, hydroxychloroquine and rituximab), which are known to be associated with increased organ toxicities, susceptibility for opportunistic infections and relapse of original disease. [bib_ref] Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic..., Wolff [/bib_ref] Most of the evidence on the use of ECP in cGVHD comes from patients with steroid-refractory disease and there are very few data currently available for the use of ECP as a first-line therapy of cGVHD. [bib_ref] Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and..., Wolff [/bib_ref] Due to the excellent safety profile of ECP and frequently reported evidence that the graft-versus-leukaemia effect seems not to be impaired by ECP, leading experts in the field of allogeneic HSCT recommend the use of ECP earlier in the course of cGVHD. [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] [bib_ref] Assessing the potential role of photopheresis in hematopoietic stem cell transplant, Greinix [/bib_ref] [bib_ref] Update on extracorporeal photochemotherapy for graft-versus-host disease treatment, Kanold [/bib_ref] Most countries perform ECP in specialized centres and offer it as a second-or subsequent-line therapy for patients with steroid-refractory, -dependent or -intolerant cGVHD in need of systemic therapy. [bib_ref] Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic..., Wolff [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood, Salvaneschi [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the..., Perotti [/bib_ref] [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] [bib_ref] Extracorporeal photopheresis therapy in the management of steroid-refractory or steroiddependent cutaneous chronic..., Apisarnthanarax [/bib_ref] [bib_ref] Influence of extracorporeal photopheresis on clinical and laboratory parameters in chronic graft-versus-host..., Seaton [/bib_ref] [bib_ref] Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host..., Foss [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD, Couriel [/bib_ref] [bib_ref] Assessing the potential role of photopheresis in hematopoietic stem cell transplant, Greinix [/bib_ref] [bib_ref] A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment..., Flowers [/bib_ref] [bib_ref] Efficacy of bimonthly extracorporeal photopheresis in refractory chronic mucocutaneous GVHD, Dignan [/bib_ref] [bib_ref] Technology insight: ECP for the treatment of GvHD-can we offer selective immune..., Marshall [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease, Smith [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for graft versus host disease in pediatric patients, Kanold [/bib_ref] Flowers and colleagues published the first multicentre, randomized, controlled, prospective phase II trial of ECP in 95 patients with steroidrefractory/-dependent/-intolerant cGVHD. [bib_ref] A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment..., Flowers [/bib_ref] The primary efficacy end-point of the study was a blinded quantitative comparison of percentage change from baseline in Total Skin Score (TSS) of 10 body regions at week 12. The median percentage improvement in TSS at week 12 was 15% for the ECP arm compared with 9% for the control arm, a non-significant difference. However, significantly more patients in the ECP arm had a complete or partial skin response, as assessed by the clinical investigators (P < 0.001). At week 12, the proportion of patients who had at least a 50% reduction in steroid dose and at least a 25% decrease in TSS was 8% in the ECP arm vs. 0% in the control arm (P = 0.04). A steroid-sparing effect of ECP has also been reported by other investigators. [bib_ref] Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood, Salvaneschi [/bib_ref] [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] [bib_ref] Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host..., Foss [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD, Couriel [/bib_ref] [bib_ref] Assessing the potential role of photopheresis in hematopoietic stem cell transplant, Greinix [/bib_ref] [bib_ref] Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week..., Greinix [/bib_ref] [bib_ref] Classic and overlap chronic graft-versus-host disease (cGVHD) is associated with superior outcome..., Jagasia [/bib_ref] In a subsequent prospective clinical study, 29 patients in the control group not responding to conventional immunosuppressive treatment in the initial randomized study were eligible for open-label ECP in case of progression of cutaneous cGVHD or less than 15% improvement in the TSS by week 12. [bib_ref] Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week..., Greinix [/bib_ref] Besides achieving a complete or partial skin response at week 24 of ECP treatment in nine patients (31%), response in extracutaneous manifestations of cGVHD, including oral mucosa, eyes, liver and lung, was observed in 70%, 47%, 50% and 50% of patients by week 24 respectively. Organ involvement is a main parameter predicting response to ECP. Investigators consistently report best responses in skin (both lichenoid and sclerodermoid), mucous membrane and liver manifestations of cGVHD. In 2007, Scarisbrick and colleagues reviewed 23 individual studies including 633 patients with cGVHD given ECP between 1987 and 2001. [bib_ref] consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous..., Scarisbrick [/bib_ref] The response rates were recorded according to involved organ. The mean response rate in cutaneous cGVHD, as reported in 18 studies, was 68% (range 29-100%), including CRs in some patients. The mean response rate in patients with hepatic involvement, as reported in 10 studies, was 63%. The mean response rate in patients with mucosal involvement, as reported in 9 studies, was also 63%. Experience is limited with ECP in other manifestations of cGVHD, such as lung involvement, with 100 reported patients achieving a response rate of 51%, including 14 CRs, 20 PRs and 17 improvements. [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD, Couriel [/bib_ref] [bib_ref] A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment..., Flowers [/bib_ref] [bib_ref] Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week..., Greinix [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for the treatment of graft-versus-host disease, Dall'amico [/bib_ref] [bib_ref] Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT, Lucid [/bib_ref] In view of the dismal prognosis of pulmonary cGVHD and the limited therapeutic options for these patients, results of ECP in pulmonary cGVHD are encouraging. Nonetheless, the efficacy of ECP in lung manifestations of cGVHD needs to be determined in prospective studies with a larger patient cohort. Considering its excellent safety profile, ECP should be administered earlier in the course of cGVHD to avoid irreversible tissue damage and patient mortality due to infections during immunodeficiency. ECP has steroid-sparing properties and may prevent adverse effects from prolonged immunosuppression. [bib_ref] A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment..., Flowers [/bib_ref] Of note, ECP reportedly does not cause generalized immunosuppression, [bib_ref] Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience..., Suchin [/bib_ref] and no increase in infectious complications has been reported during ECP therapy. [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] [bib_ref] Assessing the potential role of photopheresis in hematopoietic stem cell transplant, Greinix [/bib_ref] [bib_ref] A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment..., Flowers [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versushost disease: a..., Greinix [/bib_ref] Many investigators administer ECP in patients with cGVHD according to the original publication by Edelson and colleagues. [bib_ref] Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy preliminary results, Edelson [/bib_ref] This consists of two ECP treatments on consecutive days every 2-4 weeks. Typically, therefore, cGVHD has been treated with 4-8 treatments per month, usually for 12-24 weeks. [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] [bib_ref] Assessing the potential role of photopheresis in hematopoietic stem cell transplant, Greinix [/bib_ref] [bib_ref] Technology insight: ECP for the treatment of GvHD-can we offer selective immune..., Marshall [/bib_ref] There is little evidence as to the value of increased ECP treatments in this initial phase. In a prospective, phase II study, Foss and colleagues found no advantage for patients initially treated with a more intensive weekly schedule compared with those receiving biweekly treatment. [bib_ref] Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host..., Foss [/bib_ref] Subsequent prolongation of the interval between ECP treatments is typically performed by many centres. However, only limited data are currently available on the advantages and disadvantages of ECP tapering, and thus no recommendations can be provided. Tapering is influenced in most series by the ability to reduce concurrent immunosuppressive therapy, regarded as a significant risk factor for infectionrelated morbidity and mortality. Progression of cGVHD under treatment is an indication for discontinuation of ECP, whereas recurrence of cGVHD during tapering or after discontinuation of therapy may be controlled by restarting ECP or intensification of the treatment schedule with a subsequently slower weaning regime. [bib_ref] consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous..., Scarisbrick [/bib_ref] The length of therapy required for individual patients is difficult to predict from current published literature, in view of the diversity of treatment schedules applied and the difficulty in comparing heterogeneous patient populations. [bib_ref] Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood, Salvaneschi [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] [bib_ref] Extracorporeal photopheresis therapy in the management of steroid-refractory or steroiddependent cutaneous chronic..., Apisarnthanarax [/bib_ref] [bib_ref] Influence of extracorporeal photopheresis on clinical and laboratory parameters in chronic graft-versus-host..., Seaton [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD, Couriel [/bib_ref] [bib_ref] Assessing the potential role of photopheresis in hematopoietic stem cell transplant, Greinix [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease, Smith [/bib_ref] Dignan and colleagues reported on 82 patients who received a bimonthly regimen of two ECP treatments on consecutive days (one cycle), which was subsequently tapered to a monthly regimen depending on response. [bib_ref] Efficacy of bimonthly extracorporeal photopheresis in refractory chronic mucocutaneous GVHD, Dignan [/bib_ref] The median duration of treatment was 330 (range 42-987) days and the median number of ECP cycles received was 15 (range 1.5-32) cycles. Eighty-four per cent of patients completed a minimum of 6 months of treatment. Among those receiving immunosuppressive drugs at the start of ECP treatment, 77% had a dose reduction after 6 months of treatment and 80% had reduced their steroid dose. However, in the largest retrospective study published to date, from the MD Anderson Cancer Centre, the median number of ECP treatments administered was 32 (range 1-259) over a median of 14.5 (range 1-333) weeks. [bib_ref] Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD, Couriel [/bib_ref] Foss and colleagues observed an OR rate of 64%, defined as response in at least one site of disease, when ECP was given to 25 patients with extensive steroid-refractory cGVHD. [bib_ref] Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host..., Foss [/bib_ref] The median duration of therapy was 9 (range 3-24) months. In line with these findings, Greinix and colleagues reported complete resolution of cutaneous features in 12 of 15 patients (80%) with steroid-refractory extensive cGVDH who were given ECP for a median of 12 (range 4-31) months. [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] In the recently published prospective study in 29 patients with steroid-refractory cGVHD, progressive improvement in the TSS during weeks 16 and 24 of open-label ECP treatment was observed, suggesting a cumulative response over time. [bib_ref] Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week..., Greinix [/bib_ref] These findings and the higher response rates reported in other studies with prolonged treatment with ECP 99,100,102 suggest that continuation of ECP beyond 24 weeks may result in further benefit in patients with longer duration of cGVHD. Of note, longer treatment duration may also be necessary to obtain best responses to ECP in patients with sclerodermatous manifestations. [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] [bib_ref] Extracorporeal photopheresis therapy in the management of steroid-refractory or steroiddependent cutaneous chronic..., Apisarnthanarax [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD, Couriel [/bib_ref] [bib_ref] Treatment of extensive chronic graft-versus-host disease with extracorporeal photochemotherapy, Bisaccia [/bib_ref] Survival rates are variable among reports in the literature. Significantly improved survival rates and improvements in quality of life in ECP responders have been reported by Greinix and colleagues 99,105 and Messina and colleagues. [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] In the prospective, randomized study on steroid-refractory/-dependent/-intolerant cGVHD patients, ECP treatment was significantly associated with improved quality of life, demonstrated by a 19% improvement in the median targeted symptom assessment scores in the ECP arm compared with a 3% improvement in the control arm (P = 0.01). [bib_ref] A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment..., Flowers [/bib_ref] Kanold and colleagues treated 15 paediatric patients with steroid-refractory cGVHD, achieving high response rates in those with cutaneous (75%), hepatic (82%) and mucosal (86%) involvement. [bib_ref] Extracorporeal photochemotherapy for graft versus host disease in pediatric patients, Kanold [/bib_ref] Steroids could be tapered by 50% after a median of 12 (range 4-23) procedures, and could be discontinued during ECP in three patients. After a median follow-up of 52 (range 6-108) months, 10 of the 15 patients (67%) were alive. Tolerance of ECP was generally good, the main limiting factors being vascular access and the psychological impact of repeated apheresis procedures. Furthermore, children weighing less than 25 kg were not any more susceptible to side-effects compared with patients weighing more than 25 kg. In summary, ECP is a safe and efficacious form of cGVHD therapy, with steroid-sparing capacity. A venous access for therapy is required and peripheral veins should be used preferentially to avoid central line-associated infections. Further prospective clinical studies are warranted to assess the efficacy of ECP in homogeneous cohorts of cGVHD patients treated earlier in the course of disease. ## Existing clinical guidelines In 2008, Scarisbrick and colleagues 50 published a UK consensus statement on the use of ECP for the treatment of cGVHD. In this statement, it was decided that ECP should be considered for patients with cGVHD who are refractory to, dependent on, or intolerant of corticosteroids. Recently, recommendations of a joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT) have been published, based on review of the available literature. [bib_ref] Diagnosis and management of chronic graft-versus-host disease, Dignan [/bib_ref] In these guidelines, ECP was strongly recommended (grade 1b) as second-line therapy for skin, oral and liver manifestations of cGVHD, with a schedule of fortnightly paired treatments for a minimum assessment period of 3 months. Grade 1 recommendation means that there is confidence about the benefits of ECP, and no other immunosuppressive therapeutic modality received a stronger recommendation for second-line therapy of cGVHD. Furthermore, ECP was recommended as a third-line treatment option in cGVHD involving other organs (grade 2C). It was observed that infections requiring systemic antibiotics may be halved in patients receiving ECP. The German/Austrian/Swiss consensus conference on secondline treatment of cGVHD in daily clinical practice recommended ECP with a strength of recommendation of C-I, meaning use in second-line treatment is justified, based on grade II evidence. [bib_ref] Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic..., Wolff [/bib_ref] Of note, ECP was considered superior to other novel immunosuppressive agents, due to its excellent safety profile and steroidsparing effect. These recommendations were based on the fact that numerous investigators had reported high response rates in skin, liver and oral manifestations of steroid-refractory cGVHD and improved survival rates both in children and in adults. Considering the use of ECP in the first-line treatment of cGVHD, the German/Austrian/Swiss consensus conference stated that, while ECP has been found to be associated with a steroid-sparing capacity and favourable side effect profile, there are currently insufficient data to support the use of ECP in first-line treatment but that further studies are highly warranted. [bib_ref] Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic..., Wolff [/bib_ref] In 2007, Kanold and colleagues published clinical practice guidelines on the use of ECP in children with cGVHD after allogeneic marrow transplantation, based on field experience and a review of the literature. [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] In these guidelines, ECP was recommended in paediatric patients with cGVHD not responding to steroids, defined as stable disease after 1 month of steroid treatment, PR after 2 months of steroids, or progression of cGVHD after 2 weeks of steroid treatment. Thus, ECP was recommended as second-line therapy of cGVHD not responding to corticosteroids. Furthermore, ECP was recommended in paediatric patients with severe cGVHD with steroid-intolerance, and in steroidrefractory or steroid-dependent paediatric patients after more than three lines of immunosuppressive therapies. In view of the excellent safety profile of ECP, Kanold and colleagues considered ECP as first-line therapy for paediatric patients with limited cGVHD regardless of other therapies administered. ## Recommendations Patient selection Patients with moderate or severe cGVHD according to National Institutes of Health (NIH)-defined criteria [bib_ref] National Institutes of Health consensus development project on criteria for clinical trials..., Filipovich [/bib_ref] should receive systemic therapy. Mild manifestations of cGVHD that cannot be treated sufficiently by topical agents, such as hepatic manifestations or fasciitis, may also be treated with systemic corticosteroids for first-line therapy. Currently, no uniformly accepted definition of steroid-refractory cGVHD is available and generally accepted criteria include progression on prednisone at 1 mg/kg/day for 2 weeks, stable disease on at least 0.5 mg/kg/day for 4-8 weeks and inability to taper steroids below 0.5 mg/kg/day. [bib_ref] Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic..., Wolff [/bib_ref] For second-line therapy of steroid-refractory cGVHD, all patients are eligible to receive ECP, except those with total leucocyte counts below 1.0 G/L, intolerance to methoxsalen, heparin or citrate products, and hemodynamic instability due to ongoing life-threatening infections or severe bleeding events. Treatment schedule No general recommendation can be made on treatment schedule, due to missing evidence. Typically, patients would receive one cycle of two ECP treatments every 1-2 weeks for weeks 0-12. After week 12, treatment intervals could possibly be increased by 1 week every 3 months, depending on the type of lesions, extent of cGVHD and clinical response. If cGVHD progresses, a change in treatment strategy should be considered. [bib_ref] Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and..., Wolff [/bib_ref] [bib_ref] Consensus conference on clinical practice in chronic GVHD: second-line treatment of chronic..., Wolff [/bib_ref] Response assessment Response should be assessed according to the NIH guidelines. [bib_ref] Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus..., Pavletic [/bib_ref] Acute graft-versus-host disease aGVHD, like cGVHD, is a serious complication of allogeneic HSCT, and a key cause of transplant-related morbidity and mortality, mainly due to severe infections and organ toxicities. [bib_ref] First and second-line systemic treatment of acute graft-versus-host disease: recommendations of the..., Martin [/bib_ref] Furthermore, aGVHD is an important risk factor for the later development of cGVHD. Currently, standard first-line therapy consists of corticosteroids; however, only up to 50% of all patients respond to therapy and thus a substantial proportion of patients with aGVHD require salvage treatment. [bib_ref] First and second-line systemic treatment of acute graft-versus-host disease: recommendations of the..., Martin [/bib_ref] [bib_ref] A retrospective analysis of therapy for acute graft-versus-host disease: initial treatment, Martin [/bib_ref] [bib_ref] Glucocorticoid-refractory acute graft-versus-host disease, Pidala [/bib_ref] [bib_ref] Diagnosis and management of acute graft-versus-host disease, Dignan [/bib_ref] So far, no immunosuppressive agents have been approved for the treatment of steroid-refractory aGVHD. Despite many studies, practices vary considerably regarding the selection of agents for treatment of steroid-refractory aGVHD. Recently, Martin and colleagues published recommendations of the American Society of Blood and Marrow Transplantation for the treatment of aGVHD based on a comprehensive and critical review of published reports. [bib_ref] First and second-line systemic treatment of acute graft-versus-host disease: recommendations of the..., Martin [/bib_ref] Across the 67 studies selected with welldefined evaluation criteria, 19 different agents were investigated. Besides horse antithymocyte globulin (ATG), ECP was the most frequently studied therapeutic option. Approximately, 300 patients with steroid-refractory aGVHD given ECP have, so far, been reported in numerous publications, with an increasing number during recent years. [bib_ref] Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood, Salvaneschi [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for steroid-refractory graft-versus-host disease in low-weight pediatric patients. Immunomodulatory effects..., Gonzalez-Vicent [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the..., Perotti [/bib_ref] [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease, Smith [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for graft versus host disease in pediatric patients, Kanold [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for the treatment of graft-versus-host disease, Dall'amico [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versushost disease: a..., Greinix [/bib_ref] [bib_ref] Extracorporeal photochemotherapy as a challenging treatment for cutaneous T-cell lymphoma, acute and..., Perseghin [/bib_ref] [bib_ref] Role of extracorporeal photopheresis (ECP) in treatment of steroid-refractory acute graft-verus-host disease, Greinix [/bib_ref] [bib_ref] The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with..., Greinix [/bib_ref] [bib_ref] Extracorporeal chemophototherapy for the treatment of graft-versus-host disease: hematologic consequences of short-term,..., Garban [/bib_ref] [bib_ref] Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD, Perfetti [/bib_ref] [bib_ref] Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients:..., Berger [/bib_ref] [bib_ref] Extracorporeal photochemotherapy may improve outcome in children with acute GVHD, Calore [/bib_ref] [bib_ref] The use of fluid boluses to safely perform extracorporeal photopheresis (ECP) in..., Schneiderman [/bib_ref] [bib_ref] A single centre experience of the efficacy of extracorporeal photopheresis in the..., Das-Gupta [/bib_ref] Overall, CR and PR of cutaneous manifestations were observed in a median of 75% (range 50-100%) of patients, CR and PR of hepatic involvement were observed in a median of 47% (range 0-100%) of patients, and CR and PR of GI manifestations were observed in a median of 58% (range 0-100%) of patients. ECP was tolerated excellently and side-effects were mild, consisting mainly of reversible drops in peripheral blood cell counts after the first courses of ECP. The results of studies with ECP in the second-line treatment of aGVHD are summarized in [fig_ref] Table 6: Summary of studies using extracorporeal photopheresis in the second-line treatment of acute... [/fig_ref]. [bib_ref] Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood, Salvaneschi [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for steroid-refractory graft-versus-host disease in low-weight pediatric patients. Immunomodulatory effects..., Gonzalez-Vicent [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the..., Perotti [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for the treatment of graft-versus-host disease, Dall'amico [/bib_ref] [bib_ref] The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with..., Greinix [/bib_ref] [bib_ref] Extracorporeal chemophototherapy for the treatment of graft-versus-host disease: hematologic consequences of short-term,..., Garban [/bib_ref] [bib_ref] Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD, Perfetti [/bib_ref] [bib_ref] Extracorporeal photochemotherapy may improve outcome in children with acute GVHD, Calore [/bib_ref] Following promising results in preliminary investigations, [bib_ref] Successful use of extracorporeal photochemotherapy in the treatment of severe acute and..., Greinix [/bib_ref] then in a pilot study of 21 patients, [bib_ref] Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versushost disease: a..., Greinix [/bib_ref] Greinix and colleagues conducted a phase II study of ECP in 59 adult patients with severe aGVHD (both steroid-refractory and steroid-dependent). [bib_ref] The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with..., Greinix [/bib_ref] CR rates for individual organs were 82% for skin involvement and 61% each for GI and liver involvement. Responses were highest in patients with cutaneous symptoms only (87%), and lower for those who had two organ systems involved (62% for skin and liver involvement, 40% for skin and GI involvement), or those who had all three organs affected (25%). Response rates were also higher for patients with less severe grades of aGVHD at the start of treatment (CR rate 86% for grade II, 55% for grade III and 30% for grade IV aGVHD). In contrast to the pilot study, [bib_ref] Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versushost disease: a..., Greinix [/bib_ref] an intensified schedule of ECP was administered in the phase II study, consisting of two to three treatments per week on a weekly basis until maximum response. This strategy led to improvements in CR rates in patients with grade IV aGVHD (60% vs. 12%) and GI involvement (73% vs. 25%) using the intensified ECP schedule compared with the pilot study. [bib_ref] Role of extracorporeal photopheresis (ECP) in treatment of steroid-refractory acute graft-verus-host disease, Greinix [/bib_ref] [bib_ref] The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with..., Greinix [/bib_ref] Best response to ECP was observed after a median of 1.3 (range 0.5-6) months of treatment and no flare-ups were seen after tapering and discontinuation of corticosteroids. In ECP-responding patients, corticosteroids could be discontinued after a median of 55 (range 17-284) days after the start of ECP. In univariate analysis, a lower grade of aGVHD and fewer organs involved at the start of firstline therapy with corticosteroids as well as at the start of ECP, and a lower cumulative corticosteroid dose prior to ECP, significantly increased the probability of CR of steroid-refractory aG-VHD with ECP. However, in logistic regression analysis, only a lower grade of aGVHD at the start of ECP and later onset of corticosteroid medication after HSCT were variables significantly favouring the achievement of CR by ECP. The cumulative incidence of transplant-related mortality at 4 years was 14% in patients achieving a CR of steroid-refractory aGVHD, compared with 73% in patients without CR, 3 months after the start of ECP (P < 0.0001). Patients with a CR of steroid-refractory aGVHD with ECP had a significantly improved OS of 59%, compared with 11% in patients without a CR (P < 0.0001). The cumulative incidence of relapse at 4 years was 28%, which was thus not increased when compared with HSCT patients not receiving ECP. Treatment with ECP was well tolerated and no increase in rates of infection was observed. Perotti and colleagues recently reported excellent response rates in 50 patients with steroid-refractory aGVHD and confirmed the corticosteroid-sparing effect of ECP. [bib_ref] Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the..., Perotti [/bib_ref] There was a policy of early intervention in patients with aGVHD, so the median time from onset of symptoms to start of ECP therapy was 9 days. The OR rate was 68% (32% CR and 36% PR), with similar response rates for the different organ systems (83% skin, 67% liver, 73% GI system). Furthermore, ECP-responders had a significantly improved survival of 62%, compared with 6% in aGVHD patients not responding to ECP (P < 0.001). Ability to decrease the corticosteroid dose 30 days after the start of ECP was associated with significantly decreased mortality, confirming the importance of corticosteroid-sparing in aGVHD. Other authors have also noted that the possibility of reducing or discontinuing immunosuppressive therapies, and particularly ongoing corticosteroids, is a major advantage for ECP in preventing long-term complications in children. [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] Several studies of ECP have been conducted in paediatric patients with aGVHD and have shown similar results to those obtained in adults. A large, multicentre, retrospective study of 33 paediatric patients with steroid-refractory aGVHD showed, overall, 54% CR and 21% PR. [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] The CR for skin symptoms was 76%, for GI manifestations was 75%, and for liver involvement was 60%. The five-year OS rate was significantly better for responders (69%) than non-responders (12%; P = 0.001). As a result of ECP, immunosuppressive therapy could be discontinued in eight patients of 19 surviving patients (42%) and reduced in seven (36%). The median Karnofsky performance score improved significantly from 60% before ECP to 100% (range 80-100%) after completing ECP therapy. Supporting data come from subsequent small studies using the twice-weekly ECP treatment regimen. [bib_ref] Extracorporeal photochemotherapy for steroid-refractory graft-versus-host disease in low-weight pediatric patients. Immunomodulatory effects..., Gonzalez-Vicent [/bib_ref] [bib_ref] Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients:..., Berger [/bib_ref] In 15 paediatric patients with steroid-refractory aGVHD, the strongest predictor of response to treatment was disease stage: there was a 100% response rate for stage II, 75% for stage III and 0% for stage IV, 132 with stage of GVHD and response to ECP both being significant predictors of transplant-related mortality. A comparison of ECP and steroid therapy in paediatric patients also showed somewhat better results for ECP. [bib_ref] Extracorporeal photochemotherapy may improve outcome in children with acute GVHD, Calore [/bib_ref] Following ECP treatment, 73% of the 15 patients showed a CR, and the remaining 27% showed a PR; a CR was recorded in 92% of patients with skin manifestations, 71% with GI manifestations, and 100% with liver disease. In comparison, 56% of 16 patients receiving steroid therapy showed a CR, and 31% a PR; two patients had persistent cGVHD after 1 year. CR rates for different organs were 46% for skin, 57% for GI system and 67% for liver. Transplant-related mortality at day 100 of treatment was 6% for steroid therapy, but no patients had died in the ECP group, and the 2-year OS rates were numerically, but not significantly, higher for ECP (85%) than for steroid therapy (57%). [bib_ref] Extracorporeal photochemotherapy may improve outcome in children with acute GVHD, Calore [/bib_ref] Several authors have pointed out that the use of ECP in children presents specific challenges, such as low bodyweight, vascular access, extracorporeal volume, metabolic and haematological problems, and psychological tolerance [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] [bib_ref] The use of fluid boluses to safely perform extracorporeal photopheresis (ECP) in..., Schneiderman [/bib_ref] Nevertheless, Messina and colleagues were able to treat patients with a bodyweight as low as 10 kg without significant side-effects. [bib_ref] Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell..., Messina [/bib_ref] Kanold and colleagues reported the follow-up of paediatric patients with GVHD, with a particular emphasis on the technical aspects of ECP therapy. [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] Their efficacy results were similar to those from other studies [7/12 patients (58%) with aGVHD showed a CR and 3/12 (25%) a PR]. They observed good treatment tolerability in patients with low bodyweight, and emphasized the importance of a dedicated paediatric environment and care team to manage challenges such as vascular access and psychological tolerance that might be particularly prominent in the paediatric setting. [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] The challenge of treating low-bodyweight paediatric patients (as low as 15 kg) was also addressed in a study of patients with both aGVHD and cGVHD. [bib_ref] The use of fluid boluses to safely perform extracorporeal photopheresis (ECP) in..., Schneiderman [/bib_ref] In contrast to many groups that have used an 'offline', two-stage technique for mononuclear cell collection and irradiation, [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for steroid-refractory graft-versus-host disease in low-weight pediatric patients. Immunomodulatory effects..., Gonzalez-Vicent [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the..., Perotti [/bib_ref] this group reported the use of a sterile, closed-loop procedure, in which patients received fluid boluses of normal saline or 5% albumin to boost blood volume before, and if needed during, ECP procedures. The process was well tolerated by patients, and therefore could extend the use of continuous-flow ECP to these patients with low body weight. In addition to these studies of treatment of aGVHD, preliminary studies have investigated the use of ECP as part of the myeloablative conditioning regimen, prior to HSCT, in an attempt to reduce the incidence of aGVHD. Miller and colleagues showed a lower than expected incidence of severe aG-VHD when ECP was used as part of a novel reduced-intensity conditioning regimen, with no negative effects on engraftment or disease relapse. [bib_ref] A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated..., Miller [/bib_ref] However, in a phase II study of the addition of ECP to cyclosporine and methotrexate (all as aGVHD prophylaxis) in a standard myeloablative regimen, the incidence of aGVHD was similar to that found in other studies. [bib_ref] Extracorporeal photopheresis for the prevention of acute GVHD in patients undergoing standard..., Shaughnessy [/bib_ref] Comparison of the ECP-treated group with historical controls did appear to indicate a somewhat lower incidence of grades II-IV aGVHD and a longer OS for patients when ECP was included in conditioning. [bib_ref] Extracorporeal photopheresis for the prevention of acute GVHD in patients undergoing standard..., Shaughnessy [/bib_ref] Therefore, this preventive use of ECP may have some benefits, but data from more patients with a longer duration of follow-up are needed to assess this. In conclusion, ECP is well tolerated, with an excellent safety profile in children and adults and is highly efficacious in aG-VHD. Early start of ECP in steroid-refractory patients, with an intensified ECP schedule consisting of two to three treatments per week and rapid tapering of corticosteroids during ECP, are important variables significantly impacting on the response to ECP and patients' survival. Further prospective studies are warranted, including the use of ECP in upfront therapeutic or prophylactic strategies. ## Existing clinical guidelines The American Society for Apheresis (ASFA) reviewed the data available on ECP in aGVHD up to early 2013. [bib_ref] Clinical applications of therapeutic apheresis: an evidence based approach, 6th edition, Schwartz [/bib_ref] They concluded that OR rates for steroid-refractory aGVHD in paediatric and adult patients range from 52% to 100%, with responses in skin, GI tract and liver ranging from 66% to 100%, from 40% to 83% and from 27% to 71%, respectively, and that CRs outnumber PRs. The ASFA recommended that ECP should be used on two consecutive days (one series) performed weekly until disease response and then tapered to every other week before discontinuation. The recent BCSH/BSBMT guidelines for the diagnosis and management of aGVHD recommended ECP as a second-line therapy for the treatment of steroid refractory aGVHD, based on level 2C evidence. [bib_ref] Diagnosis and management of acute graft-versus-host disease, Dignan [/bib_ref] They commented on the good tolerability of ECP, but concluded that the optimal treatment schedule and duration of treatment have yet to be established. However, Das Gupta and colleagues reported a regimen of weekly cycles for a minimum of 8 weeks continued until maximal response or CR. [bib_ref] A single centre experience of the efficacy of extracorporeal photopheresis in the..., Das-Gupta [/bib_ref] Of note, no other immunosuppressive agent was recommended with a higher level of evidence by the BCSH/BSBMT. In 2007, Kanold and colleagues published clinical practice guidelines for physicians caring for children with aGVHD, based on expert opinion, analysis of current practice and some published results. [bib_ref] Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines..., Kanold [/bib_ref] In these guidelines, ECP was recommended in paediatric patients with aGVHD not responding to corticosteroids, defined as absence of clinical and biological improvement after 1 week of corticosteroid therapy (up to 2-5 mg/kg/day). However, the authors commented that the tendency to start ECP earlier in the event of severe aGVHD, led them to consider ECP as early as 48 hours after the initiation of corticosteroid therapy in cases of insufficient efficacy. Thus, ECP was recommended as second-line therapy of aGVHD not responding to corticosteroids. In addition, ECP was recommended in paediatric patients with severe aGVHD with steroid-intolerance, and steroid-refractory or steroid-dependent paediatric patients after more than three lines of immunosuppressive therapies, as well as for grade IV aGVHD, in association with first-line immunosuppressive therapy. In view of the excellent safety profile of ECP, Kanold and colleagues considered ECP as first-line therapy for paediatric patients with grade IV aGVHD (in association with conventional immunosuppressive approaches) and as secondline therapy in steroid-refractory aGVHD of grades II-III. Recommendations were provided on vascular access and ECP technique in children, and the recommended schedule was to start with ECP at three times weekly until maximal response was achieved, followed by individual progressive tapering of therapy. ## Recently, martin and colleagues published recommendations of the american society of blood and marrow transplantation (ASBMT) for the treatment of aGVHD based on a comprehensive and critical review of published reports. [bib_ref] First and second-line systemic treatment of acute graft-versus-host disease: recommendations of the..., Martin [/bib_ref] Data on 6-month survival and CR and PR of aGVHD in 67 reports summarizing results of secondary systemic treatment did not support the choice of any specific agent for second-line therapy. The results also provided no evidence that any specific agent should be avoided for secondary therapy of steroid-refractory aGVHD. Among the five studies with outliers in 6-month survival, the clinical trial on ECP by Messina and colleagues was cited with an outlier high survival. Since only children were treated, with a median age of 9.6 years, Martin and colleagues concluded that these outliers could reflect age differences between patient cohorts, as the benchmark study using horse ATG included a patient cohort with a median age of 27 years. [bib_ref] Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host..., Macmillan [/bib_ref] The ASBMT described the limited toxicity of ECP, including blood loss from the extracorporeal circuit, hypocalcaemia due to anticoagulant, mild cytopenia and catheter-associated bacteraemia, but no increased risk for infections beyond standard therapy, and they specifically mentioned no concerns for increased viral reactivations during ECP treatment. A typical ECP schedule of three times weekly during the first week, followed by twice weekly on a weekly basis, was described. According to the ASBMT recommendations, choice of second-line regimen should be guided by considerations of potential toxicity, interactions with other agents, familiarity of the physician with the agent, prior experience of the physician with the agent, convenience and costs. Due to the excellent safety profile of ECP and the lack of interactions with other agents, ECP compares favourably with other immunosuppressive strategies, supporting its increasingly frequent use as second-line therapy of steroid-refractory aGVHD. ## Recommendations Patient selection Patients with aGVHD not responding to first-line therapy with corticosteroids at 2 mg/kg/day, defined as progression of aGVHD after ≥3 days of corticosteroid treatment or lack of response after ≥7 days of corticosteroids, should receive adjunct ECP as second-line therapy. Treatment schedule Patients should be treated on a weekly basis, with two to three treatments per week. There is currently no evidence that maintenance ECP is beneficial. Thus, as soon as patients achieve a CR, ECP can be discontinued. Response assessment Activity of aGVHD should be assessed every 7 days with staging according to published criteria. [bib_ref] Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched..., Glucksberg [/bib_ref] Assessments should relate to organ involvement. Quality of life data are important in this group with multiple morbidities. ## Scleroderma Scleroderma [systemic sclerosis (SSc)] is a multisystemic connective tissue disease characterized by humoral and cellular immune abnormalities and fibroblast activation. These changes are associated with excessive deposition of collagen, and obliterative vasculopathy primarily within the skin and frequently within visceral organs such as the kidneys, heart, lungs and digestive tract.The prognosis of SSc has been shown to vary depending on both the extent of skin thickening and its rate of progression. Cases restricted to the hands have a 10-year survival above 70%, whereas cases with proximal involvement including the trunk have a 10-year survival rate of only approximately 20%. [bib_ref] A survival study of patients with scleroderma diagnosed over 30 years (1953-1983):..., Barnett [/bib_ref] Although the aetiology and pathogenesis of SSc are at present unknown, evidence suggests that certain environmental agents (organic solvents, specific tryptophan-containing products, adulterated oils), genetic backgrounds (specific human leucocyte antigen alleles such as DR-5) and/or viruses [retroviruses, cytomegalovirus (CMV)] may be associated with the development of disease. Interestingly, it has been shown that fetal CD3 + T cells from prior pregnancies could be detected in the blood and lesional skin of a significant proportion (>50%) of females with SSc, [bib_ref] New perspectives on the etiology of systemic sclerosis, Artlett [/bib_ref] suggesting that, in certain cases, T-cell microchimerism may be directly involved in the pathogenesis of SSc by initiating a graftversus-host-like response. Furthermore, clonal T-cell populations have been identified in the blood and skin of patients with SSc. [bib_ref] Identification of amplified clonal T cell populations in the blood of patients..., French [/bib_ref] [bib_ref] Clonal T cells in the blood of patients with systemic sclerosis, Marie [/bib_ref] [bib_ref] Clonal T-cell populations are frequent in the skin and blood of patients..., Kreuter [/bib_ref] Therapeutic management of SSc is challenging. Both the low prevalence (240 cases per million population) and the variable prognosis of SSc make the evaluation of therapeutic responses difficult and explain why many of the treatments currently used have not been formally evaluated within randomized, controlled trials. Skin thickening can be treated in various manners (methotrexate, cyclophosphamide, ECP, allogeneic bone marrow transplantation), but the US Food and Drug Administration has to date not approved any therapies for SSc. No placebo-controlled clinical trials exist showing clear superiority of one therapy. ECP has been evaluated in SSc in two randomized clinical trials, one crossover trial, and two open trials. In the first multicentre trial, 79 patients with SSc of recent onset (mean symptom duration 1.83 years) and progressive skin involvement entered a randomized, parallel-group, single-blinded clinical trial comparing ECP treatments given on two consecutive days monthly with treatment using D-penicillamine at a maximum dose of 750 mg/ day. [bib_ref] Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial, Rook [/bib_ref] At both the six-and ten-month evaluation points, the mean skin severity score, mean percentage skin involvement and mean oral aperture measurements were significantly improved from baseline among those who received ECP. By comparison, among the patients treated with D-penicillamine, none of the parameters of cutaneous disease had improved significantly after 6 months of therapy, although for those individuals in whom treatment was continued the mean skin severity score and mean percentage skin involvement had improved by 10 months. In a randomized, double-blind, placebo-controlled, multicentre clinical trial reported by Knobler and colleagues in 2006, 64 patients with SSc were randomized to receive either active or sham ECP on two consecutive days monthly for 12 months, and severity of skin and joint involvement were assessed. [bib_ref] A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis, Knobler [/bib_ref] A statistically significant improvement in skin scores compared with baseline was observed at 6 (P = 0.0024) and 12 months (P = 0.008) among patients who had active ECP, but not those on sham ECP. Comparison of skin scores between the two study arms did not achieve statistical significance because of the small sample size. Joint involvement was also significantly improved after 6 (P = 0.002) and 12 months (P = 0.001) of active ECP when compared with baseline. However, the study lacked sufficient statistical power to reveal a significant difference in skin and joint manifestations between the active and sham ECP arms. In a crossover trial reported by Enomoto in 1999, 19 patients with progressive SSc of less than 5 years' duration were randomized into two groups: group A received ECP according to the standard protocol for 1 year, and group B received no treatment. [bib_ref] Treatment of patients with systemic sclerosis with extracorporeal photochemotherapy (photopheresis), Enomoto [/bib_ref] The main outcome parameter was the skin score after 1 year of treatment compared with that of the control group. The results obtained could not show a statistically significant effect of ECP in this relatively small patient population, although the average skin score improved by 5% [standard error (SE) 21%] in group A (ECP) and deteriorated by 5% (SE 14%) in group B (sham; not significant; P = 0.71). Approximately 1 year after crossover, the skin scores reversed to what would have been expected, with an average increase of 5% per year. A single-centre, open trial of ECP in 11 women with progressive SSc of recent onset, who were treated for a period of 16-57 months, revealed an overall improvement and/or stabilization of skin changes and physical performance in 5 of the 11 patients (45%). [bib_ref] Extended extracorporeal photochemotherapy with extracorporeal administration of 8-methoxypsoralen in systemic sclerosis. An..., Muellegger [/bib_ref] Extracutaneous manifestations deteriorated in 10 of the 11 patients (91%; P < 0.05) and quality of life deteriorated in 9 of the 11 patients (82%; P < 0.05). This small, open, single-centre trial suggested that ECP provides minor improvement of skin changes in a subset of SSc patients without improving extracutaneous manifestations or quality of life. Finally, a recent study in 16 patients with diffuse cutaneous SSc, who each received a total of 12 ECP treatments, reported a reduction in dermal thickness and an improvement in joint mobility, while internal organ involvement remained stable. [bib_ref] Immunomodulatory effects of extracorporeal photochemotherapy in systemic sclerosis, Papp [/bib_ref] This study also investigated the immunomodulatory effects of ECP in the patients, which demonstrated an increase in Tr1 and Treg cells as early as post-second cycle of ECP treatment and a concomitant decrease in Th17 cells. In addition, there was a shift from pro-to anti-inflammatory and anti-fibrotic cytokines, with an increase in IL-10, IL-1Ra and HGF and a decrease in TGFbeta and CCL2. Furthermore, there was a direct positive correlation between the reduction of IL-17 levels and skin thickness. Taken together, ECP performed on two consecutive days every month is well tolerated in SSc and may have beneficial therapeutic effects on skin involvement that may not be detectable in small trials. Two controlled trials report beneficial effects of ECP on skin, whereas one of three smaller studies suggests there is no significant benefit. It may be that there is an effect in specific subtypes but this remains to be determined by appropriate clinical studies. For example, for localised scleroderma refractory to PUVA, there are reports that use of ECP can be associated with clinical responses. [bib_ref] Extracorporeal photochemotherapy for generalized deep morphea, Neustadter [/bib_ref] Existing clinical guidelines None. ## Recommendations Patient selection On the basis of its safety profile, ECP should be used in SSc as second-line or adjuvant therapy in mono-or combination therapy, and it is recommended that it should be applied in early progressive disease. In case of aggressive advancement of the disease, ECP should be considered as an approach to treat skin, but not organ, involvement. Treatment schedule In the randomized, double-blind, placebo-controlled trial of ECP in SSc published by Knobler and colleagues, [bib_ref] A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis, Knobler [/bib_ref] ECP treatment was performed on two consecutive days (one treatment cycle) every 4 weeks for 12 months. There is evidence to support an increase in the frequency of treatments, which may have a positive effect, and the group of experts considered that there will be a benefit with two treatments per month. Maintenance should consist of one treatment cycle per month for skin symptoms of SSc only. To stop ECP, treatment intervals should be increased by 1-2 weeks every 3 months. Based on the clinical course over a reasonable significant period of time, individual centres must make a clinical judgement on whether a patient is responding to ECP therapy or not. If no response is noted, then the ECP treatment intervals should be increased, or a pause introduced to follow the course of the disease without ECP. Response assessment Clinically and photographically, using validated scoring systems. ## Solid organ transplantation ## Lung transplantation Based on recent International Society of Heart and Lung Transplantation (ISHLT) registry data, more than 2700 lung transplantation procedures were performed in 2010.Despite a shift towards more potent immunosuppressive regimens, the development of acute and chronic allograft rejection continues to impact negatively the long-term survival of lung transplant recipients. It is estimated that acute rejection of the transplanted lung occurs in more than 30-50% of recipients and is one of the major risk factors for chronic rejection, which remains the most common cause of death after the first year. Bronchiolitis obliterans syndrome (BOS) represents chronic allograft rejection and occurs in more than 60% of lung transplant survivors 5-10 years after the transplant. [bib_ref] Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria, Estenne [/bib_ref] Bronchiolitis obliterans is a pathological process that affects small airways. It can be difficult to diagnose by transbronchial biopsy and thus diagnosis is made on the basis of graft deterioration due to persistent airflow obstruction rather than by histological confirmation. BOS is characterized clinically by progressive dyspnoea and airflow limitation with declining forced expiratory volume in 1 second (FEV1) that cannot be explained by other causes such as acute rejection or infection. According to the ISHLT staging system for BOS, stage 0 signifies no significant abnormality and an FEV1 of >90% of the best postoperative value, whereas stage 3 signifies severe BOS with an FEV1 of ≤50%. [bib_ref] Post-transplant bronchiolitis obliterans, Boehler [/bib_ref] Potential BOS (0-p), defined as an FEV1 of 81-90%, was added to detect early changes in graft function that might predict the onset of stage 1. BOS is a major factor limiting long-term survival after lung transplantation, which is approximately 50% at 5 years. The most precipitous decline in airflow typically occurs in the first 6 months following a diagnosis of BOS, although the time of onset of BOS and rate of decline of FEV1 are highly variable. At the time of transplantation, many transplant centres now employ an induction regimen that includes infusion of an antibody that targets activated host lymphocytes. Such agents include polyclonal anti-T-cell preparations such as ATG, or monoclonal agents aimed at lymphocyte surface molecules such as IL-2 receptor/CD25 (daclizumab, basiliximab) or, less commonly, CD52 (alemtuzumab). [bib_ref] A randomized, controlled trial of daclizumab vs anti-thymocyte globulin induction for lung..., Mullen [/bib_ref] Maintenance immunosuppressive therapy after lung transplantation typically comprises of a three-drug regimen consisting of a calcineurin inhibitor (cyclosporine or tacrolimus), an antimetabolite (azathioprine or mycophenolate mofetil) and steroids. Short courses of intravenously pulsed corticosteroids, followed by a temporary increase in maintenance doses for a few weeks, are the preferred treatment for uncomplicated acute rejection. The initial treatment of BOS usually consists of repeated pulses of high-dose methylprednisolone. Additional therapeutic options are augmentation of existing regimens, and/or switching within classes of drugs. Successful treatment of BOS is usually defined as 'stabilization' or 'slowing' of FEV1 decline rather than true improvement or normalization of airflow. For patients with unresponsive BOS, salvage immunosuppressive regimens have included ATG, OKT3, alemtuzumab, as well as addition of other agents or interventions including methotrexate, cyclophosphamide, inhaled cyclosporine, sirolimus, total lymphoid irradiation and surgical treatment of gastro-oesophageal reflux disease if present. More recently, the macrolide antibiotic azithromycin has shown efficacy in improving FEV1 in lung transplant recipients suffering from BOS. [bib_ref] Long-term azithromycin for bronchiolitis obliterans syndrome after lung transplantation, Gottlieb [/bib_ref] ECP has been utilized as a salvage therapy for the treatment of lung transplant rejection when conventional therapies have not produced an adequate response. [bib_ref] Immunosuppression for lung transplantation, Bhorade [/bib_ref] Importantly, ECP is not associated with an increased risk of infection, which is common with immunosuppressant drugs. [bib_ref] Clinical applications of therapeutic apheresis: an evidence based approach, 6th edition, Schwartz [/bib_ref] The first introduction of ECP in human lung transplantation was performed in 1995 for an acute rejection episode occurring in severely infected patients, [bib_ref] Extracorporeal photochemotherapy treatment for acute lung rejection episode, Andreu [/bib_ref] who improved clinically after 3 weeks and histologically after 4 weeks. During the same year, ECP was used in three patients with chronic lung rejection that was refractory to steroid treatment, allowing stabilization of the degradation of their pulmonary function. [bib_ref] Photopheresis for chronic rejection of lung allografts, Slovis [/bib_ref] ECP was performed at monthly intervals without significant complication. ECP was then implemented for refractory BOS, with stabilization of pulmonary function and improvement in survival after monthly treatments performed on two consecutive days. [bib_ref] Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation, O'hagan [/bib_ref] [bib_ref] Extracorporeal photopheresis for the treatment of lung allograft rejection, Villanueva [/bib_ref] Villanueva and colleagues reported their experiences with ECP in 14 lung transplant patients all diagnosed with BOS, who received 3-13 (median 6) ECP treatments. [bib_ref] Extracorporeal photopheresis for the treatment of lung allograft rejection, Villanueva [/bib_ref] In the three patients with a concurrent acute rejection, ECP led to the resolution of this. Of the eight patients with BOS grade 1, four improved or remained stable, while two progressed to grade 2 and the last died of lung cancer. Those with grade 2-3 BOS did not improve on ECP (five died and one was retransplanted). [bib_ref] Extracorporeal photopheresis for the treatment of lung allograft rejection, Villanueva [/bib_ref] O'Hagan and colleagues described five patients with severe BOS refractory to augmented immunosuppression such as methotrexate, ATG and OKT3. A temporary stabilization of the airflow obstruction was observed in three patients during ECP. However, a high rate of complications was reported as a consequence of the total augmented immunosuppression: one patient developed a lymphoproliferative disease and there were three opportunistic infections that resulted in two deaths. [bib_ref] Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation, O'hagan [/bib_ref] A similar experience was reported by Salerno and colleagues in eight patients, including seven with BOS: five patients improved on ECP, with a histological reversal of rejection in two patients. After a follow-up of 36 months, four patients remained in a stable condition without any complication related to ECP. [bib_ref] Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis, Salerno [/bib_ref] Benden and colleagues reviewed a single-centre experience with ECP for BOS and recurrent acute rejection after lung transplantation, with 12 patients in each group treated. [bib_ref] Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience, Benden [/bib_ref] In transplant recipients with BOS, the decline in FEV1 was 112 mL/ month before the start of ECP and 12 mL/month after 12 ECP cycles (P = 0.011), with a mean (95% confidence interval) change in rate of decline of 100 (28-171 mL/month). ECP thus reduced the rate of decline in lung function in recipients with BOS and was well tolerated. Furthermore, recipients with recurrent acute rejection experienced clinical stabilization. In another single-centre study, Morrell and colleagues analysed the efficacy and safety of ECP for progressive chronic rejection. [bib_ref] The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation, Morrell [/bib_ref] A total of 60 lung allograft recipients were treated with ECP for BOS and showed a significant reduction in the rate of decline in lung function. Jaksch and colleagues performed a prospective interventional study that included 51 patients with BOS who were treated with ECP between 2001 and 2011. [bib_ref] A prospective interventional study on the use of extracorporeal photopheresis in patients..., Jaksch [/bib_ref] A total of 31 (61%) responded to the therapy and showed sustained stabilization of lung function (FEV1 range -5% to +5% compared with baseline at the start of ECP) over 6 months. Responders to ECP showed significantly greater survival and less need for re-transplantation than non-responders (P = 0.0001). Factors associated with an inferior treatment response were cystic fibrosis as an underlying lung disease and a longer time between transplantation and development of BOS. Compared with non-ECP-treated patients, those responding to ECP showed an improved graft survival (P = 0.05). In a very recent study, Greer et al. performed a single centre, retrospective analysis of all patients treated with ECP for chronic lung allograft dysfunction (CLAD) during a contemporary four year period, with the primary goals being to identify factors predicting treatment response and the prognostic implications. [bib_ref] Phenotyping established chronic lung allograft dysfunction predicts extracorporeal photopheresis response in lung..., Greer [/bib_ref] Of a total of 65 patients treated with ECP, 64 had deteriorated despite treatment with azithromycin. Median follow-up after starting ECP was 503 days. At the start of ECP, all patients were categorized into the following clinical phenotypes: restrictive allograft syndrome (RAS), neutrophilic CLAD (nCLAD) and rapid decliners. At follow-up, 12.3% had a ≥ 10% improvement in FEV1, 41.5% stabilized, and 46.2% had a ≥ 10% decline in FEV1. Patients meeting the criteria of rapid decliner (32.3%, P = 0.005), RAS (33.8%, P = 0.002) and those not exhibiting neutrophilia in bronchoalveolar lavage (67.7%, P = 0.01) exhibited poorer outcomes. ECP was an effective treatment in approximately 54% of patients with CLAD who had failed azithromycin, and those who responded were found to have a statistically improved progression-free survival (median 401 vs. 133 days). A possible marker for ECP response could be the level of Treg-cells, which increase after photopheresis. It is interesting to note that after ECP for lung transplantation the levels of Tregcells did not correlate with the number of ECP treatments, but rather with lung function itself. [bib_ref] Peripheral CD4(+)CD25(+) TREG cell counts and the response to extracorporeal photopheresis in..., Meloni [/bib_ref] In summary, there have been a few retrospective papers and one prospective study on the use of ECP in lung transplant recipients. In most reports, ECP was used in patients with BOS, but there are a small number of cases with acute and/or recurrent/ongoing rejection episodes. Furthermore, in several case series reports with ECP, lung transplant recipients who were unresponsive to standard immunosuppressive therapy and who had deterioration of graft function due to refractory BOS or persistent acute rejection experienced stabilization of lung function and/or symptoms. [bib_ref] Photopheresis for chronic rejection of lung allografts, Slovis [/bib_ref] [bib_ref] Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation, O'hagan [/bib_ref] [bib_ref] Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience, Benden [/bib_ref] [bib_ref] Peripheral CD4(+)CD25(+) TREG cell counts and the response to extracorporeal photopheresis in..., Meloni [/bib_ref] [bib_ref] Extracorporeal photopheresis in lung transplantation, Astor [/bib_ref] There are no studies to date addressing the prophylactic effect of ECP for lung transplantation. ## Cardiac transplantation Based on recent ISHLT registry data, more than 3700 cardiac transplantation procedures were performed in 2010. It is estimated that acute rejection of the transplanted heart occurs in more than 25-40% of recipients within the first year and approximately 5% will result in severe hemodynamic compromise. [bib_ref] Scientific Registry of the International Society for Heart and Lung Transplantation: introduction..., Hertz [/bib_ref] [bib_ref] The Registry of the International Society for Heart and Lung Transplantation: twenty-seventh..., Stehlik [/bib_ref] [bib_ref] The Registry of the International Society for Heart and Lung Transplantation: thirteenth..., Kirk [/bib_ref] [bib_ref] The Registry of the International Society for Heart and Lung Transplantation: thirteenth..., Aurora [/bib_ref] Although major improvements have been made in the prevention and treatment of acute transplant rejection, accelerated cardiac allograft vasculopathy (CAV) still limits the long-term success of heart transplantation. [bib_ref] Cardiac allograft vasculopathy: recent developments, Schmauss [/bib_ref] After the first year, CAV is the second most common cause of death, after malignancy. Its pathogenesis, although not fully understood, is characterized by a fibroproliferative process affecting all cardiac arteries and resulting in concentric narrowing, obliteration and, ultimately, allograft failure. [bib_ref] Cardiac allograft vasculopathy: recent developments, Schmauss [/bib_ref] CAV is detectable by angiography in 5% of survivors within the first year and in over 27% within the first 5 years. [bib_ref] Scientific Registry of the International Society for Heart and Lung Transplantation: introduction..., Hertz [/bib_ref] [bib_ref] The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth..., Stehlik [/bib_ref] [bib_ref] The Registry of the International Society for Heart and Lung Transplantation: fourteenth..., Kirk [/bib_ref] [bib_ref] The Registry of the International Society for Heart and Lung Transplantation: twenty-eighth..., Christie [/bib_ref] [bib_ref] The Registry of the International Society for Heart and Lung Transplantation: fourteenth..., Benden [/bib_ref] Patient survival is diminished significantly after the detection of CAV, and CAV and graft failure (most likely undetected CAV) are, in addition to malignancy, the most important causes of death in patients who survive the first year after transplantation. [bib_ref] Cardiac allograft vasculopathy: recent developments, Schmauss [/bib_ref] The first reports of ECP therapy for cardiac transplant rejection surfaced in 1992. These early reports showed rapid biopsyproven reversal of acute cardiac rejection after 2-4 ECP treatments. By 1998, the first multicentre, randomized clinical trial was published. [bib_ref] Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study..., Barr [/bib_ref] In this study, 60 cardiac transplant recipients were randomized post-transplant to receive standard triple immunosuppressive therapy vs. standard triple immunosuppressive therapy plus ECP started within 30 hours of the transplant surgery. After 6 months of follow-up it was clear that the addition of ECP (10 treatments in month 1, four treatments in months 2 and 3, and two treatments in months 4, 5 and 6) resulted in significantly fewer cardiac rejection episodes (P = 0.03). There were no significant differences in the time to a first episode of rejection, the incidence of rejection associated with hemodynamic compromise or survival at 6 and 12 months. Interestingly, detection of cytomegalovirus DNA in the plasma by PCR was reduced significantly in the ECP cohort (P = 0.036). [bib_ref] Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study..., Barr [/bib_ref] Shortly thereafter, a pilot, prospective, randomized study was published to determine whether the addition of prophylactic ECP to a triple immunosuppressive regimen in cardiac transplant recipients resulted in decreased levels of panel reactive antibodies (PRA) and CAV. [bib_ref] Prophylactic photopheresis and chronic rejection: effects on graft intimal hyperplasia in cardiac..., Barr [/bib_ref] Twenty-three cardiac transplant recipients were randomized to receive standard triple immunosuppressive therapy vs. standard triple immunosuppressive therapy plus ECP started within the first month after transplantation (2 treatments per month 9 12, 2 treatments every 6-8 weeks during months [bib_ref] Effect of UVA and 8-methoxypsoralen, 4, 6, 4'-trimethylangelicin or chlorpromazine on apoptosis..., Wolnicka-Glubisz [/bib_ref] [bib_ref] Transimmunization, a novel approach for tumor immunotherapy, Berger [/bib_ref] [bib_ref] Photochemotherapy induces the apoptosis of monocytes without impairing their function, Hannani [/bib_ref] [bib_ref] Maturation state of dendritic cells during the extracorporeal photopheresis and its relevance..., Spisek [/bib_ref] [bib_ref] Transimmunization for cutaneous T cell lymphoma: a Phase I study, Girardi [/bib_ref] [bib_ref] Extracorporeal photochemotherapy induces a significant increase in CD36 + circulating monocytes in..., Fimiani [/bib_ref] [bib_ref] Extracorporeal photochemotherapy restores Th1/Th2 imbalance in patients with early stage cutaneous T-cell..., Renzo [/bib_ref] [bib_ref] Extracorporeal photopheresis: a focus on apoptosis and cytokines, Bladon [/bib_ref] [bib_ref] Extracorporeal photochemotherapy induces arginase 1 in patients with graft versus host disease, Merlin [/bib_ref] [bib_ref] Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T..., Maeda [/bib_ref] [bib_ref] Phenotypic and functional characterization of ultraviolet radiation-induced regulatory T cells, Maeda [/bib_ref] [bib_ref] Experimental extracorporeal photopheresis inhibits the sensitization and effector phases of contact hypersensitivity..., Maeda [/bib_ref] [bib_ref] Circulating B-cell activating factor level predicts clinical response of chronic graft-versus-host disease..., Whittle [/bib_ref]. Although there were no differences between the two groups in the incidences of infection or acute rejection, the ECP group had a significant reduction in PRA levels and intimal proliferation by intravascular ultrasound (a surrogate for CAV) at 12 and 24 months. [bib_ref] Prophylactic photopheresis and chronic rejection: effects on graft intimal hyperplasia in cardiac..., Barr [/bib_ref] In 2006, Kirklin and colleagues published a retrospective review of 13 years' experience of managing cardiac transplant rejection. [bib_ref] Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis, Kirklin [/bib_ref] The group compared the fate of 36 patients who received at least 3 months of ECP for hemodynamically compromised (HC) or recalcitrant rejection with that of 307 patients who did not receive ECP. Survival and risk factors were examined by analysis using multivariate hazard function modulated renewal function. After 3 months of ECP, rejection risk was decreased (P = 0.04) and the hazard for subsequent HC rejection or rejection death was significantly reduced towards the risk-adjusted level of lower risk non-ECP patients (P = 0.006). This study was the first to suggest that ECP reduces the risk of subsequent HC rejection and death in patients with high rejection risk. [bib_ref] Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis, Kirklin [/bib_ref] Despite the evidence from some studies showing that ECP might be a valuable adjunct to standard immunosuppression in cardiac transplantation, there are no clear guidelines or recommendations on the use of ECP in this indication. Furthermore, there are still several unanswered questions such as the identification of responders, the best timing for ECP (when to start, when to stop), how to monitor response and whether ECP can replace the use of drugs. Although studies report a benefit, the protocols used varied considerably and there are scarce data to provide guidance on which patients should be treated with ECP and when. In addition, adjuvant immunosuppressive protocols used in the studies vary significantly and may have had a considerable impact on the outcome. It will therefore be essential to conduct a prospective, randomized, multi-centre trial to answer the question of whether there is a role for ECP in cardiac transplantation. [bib_ref] Update on extracorporeal photopheresis in heart and lung transplantation, Marques [/bib_ref] Other organ transplantation ECP has, over the years, been used to control rejection following face, 186 liver [bib_ref] Successful reversal of recalcitrant hepatic allograft rejection by photopheresis, Lehrer [/bib_ref] [bib_ref] The use of extracorporeal photopheresis for allograft rejection in liver transplant recipients, Urbani [/bib_ref] [bib_ref] A novel immunosuppressive strategy combined with preemptive antiviral therapy improves the eighteen-month..., Urbani [/bib_ref] [bib_ref] Potential applications of extracorporeal photopheresis in liver transplantation, Urbani [/bib_ref] and kidney [bib_ref] Successful treatment of recurrent rejection in renal transplant patients with photopheresis, Dall'amico [/bib_ref] [bib_ref] Immunomodulatory effect of extracorporeal photopheresis after successful treatment of resistant renal allograft..., Baron [/bib_ref] [bib_ref] Reversal of acute renal allograft rejection by extracorporeal photopheresis: a case presentation..., Wolfe [/bib_ref] [bib_ref] Refractory acute renal allograft rejection successfully treated with photopheresis, Genberg [/bib_ref] [bib_ref] Photopheresis for the treatment of refractory renal graft rejection, Kumlien [/bib_ref] [bib_ref] Induction of regulatory T cells after prophylactic treatment with photopheresis in renal..., Lamioni [/bib_ref] [bib_ref] Photopheresis therapy for problematic renal allograft rejection, Jardine [/bib_ref] [bib_ref] Multimodal therapy with combined plasmapheresis, photoapheresis, and intravenous immunoglobulin for acute antibody-mediated..., Lai [/bib_ref] transplantation. In 2007, Urbani et al. published a prospective study in 36 liver transplant patients with ECP to delay calcineurin inhibitor use in patients felt to be at high risk of renal and neurological complication post-transplantation. [bib_ref] Avoiding calcineurin inhibitors in the early post-operative course in high-risk liver transplant..., Urbani [/bib_ref] The ECP treatment schedule was at days 2 and 6 post-transplant, then weekly in the first month, followed by weekly or monthly treatments depending on liver function test results. No significant difference was seen between the two groups with regard to rates of biopsy-proven acute rejection, time to rejection, nephrotoxicity, neurotoxicity or mean duration of hospitalization. There was a statistically significant higher survival rate in the ECP cohort. Recently, Kusztal et al. evaluated the biological responses of ECP combined with conventional immunosuppressive therapy as prophylactic treatment in a prospective randomized study of 10 kidney transplant patients compared with a control group of 10 patients only receiving a calcineurin inhibitor, mycophenolate, and steroids. [bib_ref] Extracorporeal photopheresis as an antirejection prophylaxis in kidney transplant recipients: preliminary results, Kusztal [/bib_ref] A total of 12-16 ECP treatments were performed over 2.5 months. The ECP group showed a positive trend to a higher estimated glomerular filtration rate (eGFR) at 3 months (53 AE 11 vs. 47.1 AE 9; P = 0.17) and was statistically significant at 6 months (67.5 AE 10 vs. 53.6 AE 3; P = 0.03, Wilcoxon test). An increased percentage of Treg (CD3 + CD4 + CD25 + ) among the total CD3 cell count (4.9 AE 1% to 9.4 AE 15%) as well as inducible Treg (CD3 + CD8 + CD28 À ) was observed among CD3 cells (3.3 AE 3% to 11.8 AE 8%, P = 0.025) within 3 months of ECP treatment. A significant difference in the percentage of Treg was noted at month 3 between the ECP and the control groups (9.4 AE 15% vs. 3 AE 1%; P = 0.01). ## Existing clinical guidelines The British Photodermatology Group and the UK Skin Lymphoma Group 74 noted that there was good evidence to support the use of ECP for the treatment of acute and recurrent acute cardiac rejection, prophylaxis of cardiac rejection and chronic cardiac rejection. At that time, there was poor evidence to support the use of ECP for the management of renal or lung allograft rejection. More recently, in 2013, ASFA published guidelines on the use of therapeutic apheresis in clinical practice. [bib_ref] Clinical applications of therapeutic apheresis: an evidence based approach, 6th edition, Schwartz [/bib_ref] The guidelines suggested that ECP may be appropriate for the treatment of lung transplant rejection in selected individuals with persistent acute rejection and early BOS. For cardiac allograft rejection, ECP prophylaxis was rated category I, evidence 1A (strong recommendation, high-quality evidence) and ECP treatment of cardiac allograft rejection was rated category II, evidence 1B (strong recommendation, moderate-quality evidence). ## Recommendations ## Patient selection - After lung transplantation, the main indication for ECP is currently in patients with chronic allograft dysfunction (BOS). As mentioned above, patients with early onset of BOS (within the first 3-year post-transplant) seem to respond better to the treatment. ECP should be started as soon as possible after a diagnosis of BOS is established. In other indications (as a form of induction therapy, as a rescue therapy in cases of recurrent or ongoing acute cellular rejection), ECP has been used with promising results but there are, as yet, no recommendations published or available. - For patients undergoing cardiac transplantation there are some studies that support ECP as a valuable addition to immunosuppressive regimens, but the protocols vary considerably in both the ECP and immunosuppressive regimens used. It remains unclear whether routine use of ECP in cardiac transplantation would be beneficial and ECP cannot be fully recommended until a prospective, randomized, multi-centre trial is conducted to provide a final answer. Nevertheless, ECP appears to be a promising strategy for patients with either treatment-resistant or recurrent rejection episodes. Treatment schedule One treatment cycle consists of ECP on two consecutive days. A common regimen includes one cycle every 2 weeks for the first 2 months, followed by once monthly for 2 months (total of six). The optimal duration remains unanswered, and the number of treatment cycles ranges from 6 to 24. If clinical stabilization occurs with ECP, long-term continuation might be warranted to maintain the clinical response. In a recent, 10-year, single-centre experience, 12 cycles was the initial 'dose' and long-term continuation was recommended for responders. Response assessment Efficacy of ECP is routinely monitored using the pulmonary function test, with the FEV1 value a surrogate-marker for grade of BOS and response to therapy. Successful treatment of BOS is usually defined as 'stabilization' or 'slowing' of FEV1 decline instead of true improvement or normalization of airflow. ## Crohn's disease Crohn's disease is a chronic progressive inflammatory disorder of the GI tractit can affect any segment of the tract, but mostly involves the terminal ileum and colon. Stricturing and penetrating complications arise as sequelae of inflammation, necessitating intestinal surgery in the majority of patients. [bib_ref] Long-term evolution of disease behavior of Crohn's disease, Cosnes [/bib_ref] Evidence suggests that Crohn's disease derives from perturbations at the interface between the intestinal microbiota and the innate immune system, based on genetic predisposition, which result in mucosal hyperimmunity and inflammation. [bib_ref] Homeostasis and inflammation in the intestine, Garrett [/bib_ref] Thus, current treatment strategies almost exclusively harness immunosuppressive mechanisms of action, and include steroids, thiopurines, methotrexate and anti-TNF-a agents. Such treatment strategies are associated with an increased risk of infection, however, and recently advocated strategies combining thiopurines and anti-TNF-a agents may increase this risk further. [bib_ref] The second European evidence-based Consensus on the diagnosis and management of Crohn's..., Dignass [/bib_ref] Data on the use of ECP in Crohn's disease remain scarce and uncontrolled. A small single-centre study evaluated the use of ECP in patients with prospectively evaluated steroid-dependent Crohn's disease. [bib_ref] Extracorporeal photochemotherapy in patients with steroid-dependent Crohn's disease: a prospective pilot study, Reinisch [/bib_ref] ECP was administered as two treatments every 2 weeks, for a total of 24 weeks. In four out of nine patients (44%), steroid therapy could be completely withdrawn during ECP, without relapse of symptoms; in another four patients, the dose of steroid could be reduced by at least 50%; only one patient, with long disease duration and a high baseline steroid dose, experienced therapeutic failure. In a subsequent multi-centre study (CD1 study), patients with steroid-dependent Crohn's disease received two treatments every other week, for a 24-week steroid-tapering period, and underwent a forced steroid-tapering protocol. [bib_ref] Extracorporeal photopheresis in patients with steroid-dependent Crohn's disease: an open-label, multicenter, prospective..., Reinisch [/bib_ref] Steroid-free remission was achieved in seven out of 31 patients (23%). In general, steroid-free remission is an endpoint which is difficult to achieve in patients with steroid-dependent Crohn's disease that is refractory to, or intolerant of, other therapies, including immunosuppressants or anti-TNF-a agents. From the literature, a steroid-free remission rate of a maximum of 25% is expected to be achieved by a switch to a second-line anti-TNF-a agent, whereas the placebo steroid-free remission rate is close to 0%. [bib_ref] Review article: causative factors and the clinical management of patients with Crohn's..., Danese [/bib_ref] The CD2 study followed a different approach. Patients with moderate-to-severe active Crohn's disease refractory to immunomodulators and/or anti-TNF-a agents received ECP twice weekly for 4 weeks, tapering to twice every other week for another 6 weeks. [bib_ref] Extracorporeal photopheresis for the treatment of refractory Crohn's disease: results of an..., Abreu [/bib_ref] Among the 28 patients included, there was a marked reduction in the Crohn's Disease Activity Index score during the 12-week treatment period, with 14 patients (50%) being classified as responders, and seven patients (25%) achieving remission. Existing data show some promise for the use of ECP in Crohn's disease. To date, two indications have been investigated in open-label trials, namely steroid-dependent Crohn's disease and moderate-to-severe active Crohn's disease. Most patients included in these trials had shown no benefit following previous exposure to the available standard care, including immunosuppressants and anti-TNF-a agents, and data are lacking on a patient population less progressed in disease and therefore possibly more sensitive to a tolerogenic response. Thus, a clear demarcation of patients who could gain most from ECP is currently impossible. We are still waiting for proof of the efficacy of ECP in Crohn's disease outside of clinical trials, and it should therefore be used primarily for patients with Crohn's disease not responding to, or intolerant of, standard care. ## Existing clinical guidelines None. ## Recommendations Based on published literature, ECP is generally well tolerated in patients with Crohn's disease and may help to control disease progression in selected patients. However, at the present time, no treatment recommendations can be made. ## Atopic dermatitis Atopic dermatitis (AD; atopic eczema) is a common, inflammatory, chronically relapsing skin disease characterized by itchy eczematous skin lesions which can affect the entire body surface in severe cases. [bib_ref] ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of..., Darsow [/bib_ref] [bib_ref] Guidelines for management of atopic dermatitis, Saeki [/bib_ref] [bib_ref] Atopic dermatitis: S2 guidelines, Werfel [/bib_ref] Histologically, the lesions of AD show epidermal changes, including spongiosis and epidermal hyperplasia with slight hyperkeratosis and some parakeratosis (depending on the disease stage), and dermal infiltrates composed of T lymphocytes, monocytes and eosinophils. The exact pathogenesis of AD remains unclear. A multifactorial trait involving numerous gene loci on different chromosomes has been proposed and the highest correlations have been shown with mutations in the filaggrin gene associated with a disturbed epidermal barrier function. [bib_ref] ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of..., Darsow [/bib_ref] A functional failure of Tregcells [bib_ref] T regulatory cells in atopic dermatitis and subversion of their activity by..., Ou [/bib_ref] [bib_ref] Relation of CD4 + CD25 + regulatory T-cell suppression of allergen-driven T-cell..., Ling [/bib_ref] and an abnormal Th2/Th17-driven immune response to exogenous and/or endogenous antigens seem to be the main driving force in the genetically predisposed patients, leading to the skin changes in AD. [bib_ref] A role for Th17 cells in the immunopathogenesis of atopic dermatitis?, Di Cesare [/bib_ref] [bib_ref] Development and function of TH17 cells in health and disease, Louten [/bib_ref] Clinical studies have demonstrated a correlation between disease severity and levels of immunoglobulin (Ig)E, and surrogate markers such as eosinophil cationic protein, soluble IL-2 receptor (sIL-2R) and soluble E-selectin. [bib_ref] Soluble interleukin 2 receptor in atopic eczema, Colver [/bib_ref] [bib_ref] Soluble E-selectin and eosinophil cationic protein are distinct serum markers that differentially..., Furue [/bib_ref] In adults, AD typically has a chronic relapsing course associated with significant physical and psychological disability. The disease usually responds adequately to emollients, topical corticosteroids, calcineurin emollients, or phototherapy such as UVA-1, 311 nm UVB or PUVA. [bib_ref] ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of..., Darsow [/bib_ref] [bib_ref] Guidelines for management of atopic dermatitis, Saeki [/bib_ref] [bib_ref] Atopic dermatitis: S2 guidelines, Werfel [/bib_ref] [bib_ref] Narrowband UV-B vs medium-dose UV-A1 phototherapy in chronic atopic dermatitis, Legat [/bib_ref] [bib_ref] 5-Methoxypsoralen plus ultraviolet (UV) A is superior to medium-dose UVA1 in the..., Tzaneva [/bib_ref] In some patients, however, standard therapy remains unsatisfactory. These patients often require immunosuppression with systemic corticosteroids, azathioprine, methotrexate or cyclosporine to prevent severe disability. More recently, third-line approaches leading to diminished T-cell activation, including alefacept, efalizumab, rituximab or intravenous IgG, have been found to be effective in severe cases of AD. [bib_ref] ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of..., Darsow [/bib_ref] Treatment with the anti-IgE antibody omalizumab or the anti-IL-5 mepolizumab has also revealed promising results in moderate-to-severe cases of AD. These systemic therapies, however, are associated with a significant risk of adverse effects. In contrast, ECP has been used as a very safe treatment modality in severe cases of AD. [bib_ref] Treatment of severe atopic dermatitis with extracorporeal photopheresis, Prinz [/bib_ref] [bib_ref] A retrospective study of six cases of severe recalcitrant atopic dermatitis treated..., Hjuler [/bib_ref] [bib_ref] Quality of life improvement in a patient with severe atopic dermatitis treated..., Mohla [/bib_ref] [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] [bib_ref] Long-term application of extracorporeal photochemotherapy in severe atopic dermatitis, Prinz [/bib_ref] [bib_ref] Bicentre experience in the treatment of severe generalised atopic dermatitis with extracorporeal..., Radenhausen [/bib_ref] [bib_ref] Activation markers in severe atopic dermatitis following extracorporeal photochemotherapy, Radenhausen [/bib_ref] [bib_ref] Successful monotherapy of severe and intractable atopic dermatitis by photopheresis, Richter [/bib_ref] [bib_ref] Extracorporeal photopheresis as a treatment for patients with severe, refractory atopic dermatitis, Sand [/bib_ref] Prinz and colleagues first described, in 1994, the successful administration of ECP in the treatment of three severe cases of AD. [bib_ref] Treatment of severe atopic dermatitis with extracorporeal photopheresis, Prinz [/bib_ref] Thereafter, several open clinical trials [bib_ref] A retrospective study of six cases of severe recalcitrant atopic dermatitis treated..., Hjuler [/bib_ref] [bib_ref] Quality of life improvement in a patient with severe atopic dermatitis treated..., Mohla [/bib_ref] [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] [bib_ref] Long-term application of extracorporeal photochemotherapy in severe atopic dermatitis, Prinz [/bib_ref] [bib_ref] Bicentre experience in the treatment of severe generalised atopic dermatitis with extracorporeal..., Radenhausen [/bib_ref] [bib_ref] Activation markers in severe atopic dermatitis following extracorporeal photochemotherapy, Radenhausen [/bib_ref] [bib_ref] Successful monotherapy of severe and intractable atopic dermatitis by photopheresis, Richter [/bib_ref] [bib_ref] Extracorporeal photopheresis as a treatment for patients with severe, refractory atopic dermatitis, Sand [/bib_ref] [bib_ref] Long term follow-up results on severe recalcitrant atopic dermatitis treated with extracorporeal..., Rubegni [/bib_ref] with mostly small numbers of patients have corroborated that ECP may be effective in severe cases of AD that are resistant to standard treatment. In most studies, ECP cycles were administered in biweekly intervals for at least 12 weeks and continued thereafter depending on the individual patient response. In the largest study so far reported, Radenhausen and colleagues 222 administered ECP to 35 patients with severe generalized AD over a period of 6-10 cycles. ECP led to a significant decrease (P < 0.05) in SCORing Atopic Dermatitis (SCORAD) score from 74.4 before to 36.8 after ECP therapy (after a mean of 10 cycles). Approximately, 70% of patients had a favourable response to ECP, requiring at least six cycles. The results of all studies of ECP in AD are summarized in [fig_ref] Table 7: Summary of studies using extracorporeal photopheresis as systemic monotherapy for the treatment... [/fig_ref]. [bib_ref] Treatment of severe atopic dermatitis with extracorporeal photopheresis, Prinz [/bib_ref] [bib_ref] A retrospective study of six cases of severe recalcitrant atopic dermatitis treated..., Hjuler [/bib_ref] [bib_ref] Quality of life improvement in a patient with severe atopic dermatitis treated..., Mohla [/bib_ref] [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] [bib_ref] Long-term application of extracorporeal photochemotherapy in severe atopic dermatitis, Prinz [/bib_ref] [bib_ref] Bicentre experience in the treatment of severe generalised atopic dermatitis with extracorporeal..., Radenhausen [/bib_ref] [bib_ref] Activation markers in severe atopic dermatitis following extracorporeal photochemotherapy, Radenhausen [/bib_ref] [bib_ref] Successful monotherapy of severe and intractable atopic dermatitis by photopheresis, Richter [/bib_ref] [bib_ref] Extracorporeal photopheresis as a treatment for patients with severe, refractory atopic dermatitis, Sand [/bib_ref] [bib_ref] Long term follow-up results on severe recalcitrant atopic dermatitis treated with extracorporeal..., Rubegni [/bib_ref] In an attempt to categorize the patient response in order to be able to compare the different studies the rates were as follows: CR 13%, PR 39%, minor response 22%, no response 25% in the pooled data of 67 patients with AD from those studies. The reported percentages of SCORAD reduction ranged from 16% to 99%. ECP seems to be particularly effective in patients with first-line-therapy-refractory erythrodermic AD when an intensified treatment regimen is administered and maintained with treatment cycles given over longer periods of timeand/or in combination with other systemic treatments. [bib_ref] Long term follow-up results on severe recalcitrant atopic dermatitis treated with extracorporeal..., Rubegni [/bib_ref] In the most recent trial of ECP in AD, 220 a prospective study set-up revealed that a defined 20-week ECP protocol led to a SCORAD reduction of greater than 25% in only three of 10 patients. In all patients together, the authors observed on average a small but significant reduction in SCORAD from 64.8 at baseline to 54.5 at week 20 (i.e. a reduction of 15.9%). However, improvement in quality of life measured by different scores, including SKINDEX, SF-36 or FACT, did not reach statistical significance. [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] It is intriguing to note that ECP has also been shown to be effective in erythroderma of other origin, such as red man syndrome, 228,229 erythrodermic pityriasis rubra pilaris 230 or photoaccentuated erythroderma associated with CD4 + T-lymphocytopenia. [bib_ref] Photoaccentuated erythroderma associated with CD4 + T lymphocytopenia: successful treatment with 5-methoxypsoralen..., Wolf [/bib_ref] ECP has also been found to improve laboratory correlates of active AD including elevated levels of IgE, eosinophilic cationic protein, sIL-2R and/or soluble E-selectin. [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] [bib_ref] Long-term application of extracorporeal photochemotherapy in severe atopic dermatitis, Prinz [/bib_ref] [bib_ref] Bicentre experience in the treatment of severe generalised atopic dermatitis with extracorporeal..., Radenhausen [/bib_ref] [bib_ref] Activation markers in severe atopic dermatitis following extracorporeal photochemotherapy, Radenhausen [/bib_ref] Radenhausen and colleagues reported no significant correlation between a decrease in these levels and values of blood eosinophils. [bib_ref] Bicentre experience in the treatment of severe generalised atopic dermatitis with extracorporeal..., Radenhausen [/bib_ref] In comparison with ECP responders, most non-responders were characterized by very high levels of total IgE before and during therapy. [bib_ref] Bicentre experience in the treatment of severe generalised atopic dermatitis with extracorporeal..., Radenhausen [/bib_ref] No serious side-effects have been reported in AD patients treated with ECP. [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] In summary, several open clinical trials with small numbers of patients have suggested that ECP is safe and may be effective in severe cases of AD (including erythrodermic variants) that exhibit resistance to standard treatment. Based on the existing data and given the relative safety of ECP, it would be worthwhile investigating its use in the treatment schedule of earlier phases of AD. ## Existing clinical guidelines According to existing EDF guidelines it appears that ECP has an effect in patients with AD.The level of evidence is not high but, given the safety profile of ECP, further clinical studies should be encouraged. ## Recommendations Patient selection According to the inclusion criteria of a prospective, multi-centre, investigator-initiated study, 220 ECP may be considered in a patient with AD who fulfils the following criteria: a diagnosis of severe atopic dermatitis: (i) of at least 12 months' duration; (ii) SCORAD >45; (iii) resistance in the last 12 months to all first-line therapies used to treat AD, including topical steroids, topical calcineurin inhibitors, and one form of phototherapy (UVA, UVB or PUVA) or resistance to either systemic steroids or cyclosporine as second-line therapy. Treatment schedule The initial ECP treatment for AD should be one cycle (i.e. two consecutive treatment days) every 2 weeks for 12 weeks, a schedule that has been applied in most previous studies on the use of ECP in AD. Thereafter, ECP cycles may be given in intervals depending on the individual response of a patient, for example, every 4 weeks for another 3 months; at maximal response, treatment should be tapered to one treatment cycle every 6-12 weeks before stopping. Relapse can be treated by returning to the interval frequency of the previously effective treatment schedule. Response assessment Primary endpoints. The primary efficacy outcome determination can be the response of the patient as determined by SCORAD assessment. [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] [bib_ref] Bicentre experience in the treatment of severe generalised atopic dermatitis with extracorporeal..., Radenhausen [/bib_ref] [bib_ref] Activation markers in severe atopic dermatitis following extracorporeal photochemotherapy, Radenhausen [/bib_ref] [bib_ref] Extracorporeal photopheresis as a treatment for patients with severe, refractory atopic dermatitis, Sand [/bib_ref] [bib_ref] Long term follow-up results on severe recalcitrant atopic dermatitis treated with extracorporeal..., Rubegni [/bib_ref] A response may be judged as a CR (defined as ≥95% reduction of SCORAD), PR (≥50% reduction of SCORAD), minor response (≥25% reduction of SCORAD); or no response (<25% reduction in SCORAD). SCORAD assessment should be performed at baseline, at each 2-week visit during the treatment period for the first 12 weeks, and thereafter every 4 weeks or at longer intervals depending on the individual ECP treatment schedule. Together with SCORAD, the quality of life of patients should be assessed using tools such as the Dermatological Life Quality Index [bib_ref] Dermatology Life Quality Index (DLQI)-a simple practical measure for routine clinical use, Finlay [/bib_ref] [bib_ref] Life quality assessment among patients with atopic eczema, Holm [/bib_ref] [bib_ref] Health outcome measures in atopic dermatitis: a systematic review of trends in..., Rehal [/bib_ref] or SKINDEX, SF-36 or FACT scores. [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] Secondary endpoints. The extent of topical steroid sparing and/ or reductions in serum IgE, eosinophilic cationic protein and sIL-2R from the start may be considered as secondary endpoints of response to ECP treatment. [bib_ref] Soluble interleukin 2 receptor in atopic eczema, Colver [/bib_ref] [bib_ref] Soluble E-selectin and eosinophil cationic protein are distinct serum markers that differentially..., Furue [/bib_ref] [bib_ref] Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from..., Wolf [/bib_ref] The assessment of levels and function of circulating CD4 + CD25 + bright Treg-cells 29 may be of additional help to predict, identify and/or monitor AD patients who respond to ECP. ## Type 1 diabetes T1D is a common and serious disease with an increasing incidence worldwide. It is regarded as an autoimmune disease, mediated by self-reactive T cells against pancreatic insulin-producing b-cells. Despite the use of intensive treatment with multiple daily injections of insulin and self-monitoring of blood glucose, T1D produces substantial morbidity and mortality. [bib_ref] Declining incidence of nephropathy in insulin-dependent diabetes mellitus, Bojestig [/bib_ref] Residual insulin secretion facilitates metabolic control and reduces the risk of ketoacidosis, [bib_ref] Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes, Madsbad [/bib_ref] and even modest b-cell function has been reported to reduce long-term complications. [bib_ref] Beta-cell function and the development of diabetes-related complications in the diabetes control..., Steffes [/bib_ref] Moreover, the drive to save b-cells and improve their function has become even more pertinent since some studies have indicated that b-cells may regenerate. [bib_ref] The replication of beta cells in normal physiology, in disease and for..., Butler [/bib_ref] If so, there is new hope for the prevention and treatment of this disease. It is not known what precipitates or stimulates the autoimmune process against b-cells. Viral infections may be important †Numbers in parentheses indicate treatment cycles that were given only to a portion of the patients. ‡Five patients were not evaluated (due to short treatment course) and were not included in the further analysis, including the calculation of male/female ratio. §Inclusion criteria: severe, refractory AD; SCORAD >45; during last 12 months refractory to first-line therapies, including topical steroids, calcineurin inhibitors and phototherapy or refractory to one-second-line therapy, including systemic steroids or cyclosporine. #In the 12 months before ECP, patients were refractory to all three-first-line therapies, that is, topical steroids, topical calcineurin inhibitors and one form of phototherapy (UVA, UVB or PUVA). +Standard therapies included photo(chemo)therapy, externally and internally administered corticosteroids and other immunosuppressive drugs (e.g. cyclosporine). AD, atopic dermatitis; CR, complete response; ECP, extracorporeal photopheresis; MR, minor response (>25% improvement in skin lesions/scores); NK, not known; NR, no response; PR, partial response (>50% improvement in skin lesions/scores); PUVA, psoralen plus UVA; SCORAD, SCORing Atopic Dermatitis; SD, standard deviation; UV, ultraviolet. (e.g. coxsackie virus, CMV, Epstein-Barr virus, rota virus) as well as nutritional agents from cow's milk proteins or gluten. Another hypothesis suggests that increased demand for insulin (because of, e.g. increased weight, reduced physical exercise, increased psychological stress), and a consequent burden on bcells, leads to the presentation of autoantigens and possibly heat shock proteins, which may precipitate an autoimmune reaction leading to insulitis in genetically predisposed individuals whose immune system has lost balance. Causes of a less well-balanced immune system could include increased hygiene and/or abnormal gut flora. Autoreactive T cells (CD4 + and CD8 + cells) are implicated as active players in b-cell destruction, while autoantibodies, often detected prior to clinical disease, are considered as markers of an ongoing disease process in the pancreatic islets. The autoantibodies react against either the islet cells, specific autoantigens such as insulin autoantibodies against insulin, glutamic acid decarboxylase, tyrosine phosphatase or zinc transport antigen. [bib_ref] Autoimmune markers in diabetes, Winter [/bib_ref] Several immune interventions have been tested, with the aim of preserving residual b-cell function, but to date these have been associated with insufficient efficacy and/or unacceptable adverse effects. [bib_ref] Disappearance and reappearance of islet cell cytoplasmic antibodies in cyclosporin-treated insulin-dependent diabetics, Mandrup-Poulsen [/bib_ref] [bib_ref] Factors associated with early remission of type I diabetes in children treated..., Bougneres [/bib_ref] [bib_ref] Low dose linomide in Type I juvenile diabetes of recent onset: a..., Coutant [/bib_ref] [bib_ref] A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in..., Herold [/bib_ref] [bib_ref] Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes, Keymeulen [/bib_ref] [bib_ref] B-lymphocyte depletion, and preservation of beta-cell function, Pescovitz [/bib_ref] There is a need for interventions that do not suppress, but rather modulate and rebalance, the immune system, or that create tolerance to the autoantigens involved in the autoimmune process. In the non-obese diabetic mouse model of T1D, delivery of ECP-treated cells significantly delayed the development of T1D. The combination of ECP-treated cells with b-cell antigens appeared to improve the efficacy of ECP cell therapy. ECP induced FoxP3 + Treg-cells, suggesting that it may provide protection from T1D through the promotion of immune regulation. ECP-treated spleen-cell therapy also induced suppression of the immune response to b-cell antigens. Furthermore, in contrast to ECP-treated cells alone, the combination of ECP-treated cells with b-cell antigens appeared to improve the protective effect, as shown by the marked reduction in insulitis in the islets. These results indicate that the protective effects of ECP against T1D include suppression of T-cell responses to autoantigens and production of Treg-cells. They also suggest that combined therapy may be required to optimize ECP therapy for T1D. For instance, combination of ECP with b-cell antigens might provide a more potent protective effect. [bib_ref] Experimental extracorporeal photopheresis therapy significantly delays the development of diabetes in non-obese..., Xia [/bib_ref] To date, there is only one reported well-designed study in which ECP has been used in newly diagnosed patients with T1D. [bib_ref] Photopheresis at onset of type 1 diabetes: a randomised, double blind, placebo..., Ludvigsson [/bib_ref] This was a double-blind, controlled study, using placebo tablets and sham ECP in the control group. A total of 49 children, aged 10-18 years at diagnosis of T1D were included; 40 patients completed the study, five double ECP/placebo treatments were given over a 3-month period and patients were then followed up for 3 years (19 received active treatment with ECP and 21 received placebo treatment). The ECP-treated children secreted significantly more C-peptide in the urine during follow-up than the control group. C-peptide values in serum showed corresponding differences between the two groups. The insulin dose/ kg bodyweight required to reach HbA1c targets was always lower in the ECP group, although there was no difference in HbA1c values between the groups during follow-up. ECP was well tolerated. In conclusion, clinical and experimental findings suggest that ECP might influence and delay the disease process in T1D by enhancing the production of Treg-cells and having an immunosuppressive effect. The efficacy of autoantigen treatment may be increased by ECP, which might be regarded as a sort of vaccination of transformed autoreactive T cells. ## Existing clinical guidelines None. ## Recommendations Experience is very limited and, at present, ECP should only be used in the treatment of T1D in well-designed clinical trials, which is an opinion supported by previously published guidelines. [bib_ref] Evidence-based practice of photopheresis 1987-2001: a report of a workshop of the..., Mckenna [/bib_ref] Pemphigus Eleven patients with drug-resistant, severe pemphigus (nine with pemphigus vulgaris and two with pemphigus foliaceus), who had cutaneous and mucous membrane involvement, underwent ECP. [bib_ref] Extracorporeal photochemotherapy for drug-resistant pemphigus vulgaris, Rook [/bib_ref] [bib_ref] Unresponsive severe generalized pemphigus vulgaris successfully controlled by extracorporeal photopheresis, Gollnick [/bib_ref] [bib_ref] Short-time extracorporeal photochemotherapy in the treatment of drug-resistant autoimmune bullous diseases, Wollina [/bib_ref] [bib_ref] Pemphigus vulgaris treated with photopheresis, Liang [/bib_ref] [bib_ref] Severe pemphigus foliaceus treated with extracorporeal photochemotherapy, Azana [/bib_ref] OR was 91% (10/11 patients), with 73% (8/11) having a CR, 18% (2/11) having a PR and 9% (1/11) having stable disease. A retrospective analysis of eight patients with PV treated with ECP on two consecutive days at 4-week intervals reported a CR in all but one patient after 2-6 (mean 4.5) cycles. Prednisolone doses could be tapered in all patients. [bib_ref] Remission of severe autoimmune bullous disorders induced by long-term extracorporeal photochemotherapy, Sanli [/bib_ref] Three patients with recalcitrant foliaceus pemphigus who received ECP achieved one CR and two PRs. [bib_ref] Short-time extracorporeal photochemotherapy in the treatment of drug-resistant autoimmune bullous diseases, Wollina [/bib_ref] [bib_ref] Severe pemphigus foliaceus treated with extracorporeal photochemotherapy, Azana [/bib_ref] [bib_ref] Extracorporeal photochemotherapy of therapy-refractory cases of systemic lupus erythematosus with urticarial vasculitis..., Licht-Mbalyohere [/bib_ref] ECP was performed every 2-4 weeks for a minimum of two cycles, allowing the doses of combined therapies, including corticosteroids and immunosuppressants, to be tapered. Decreased levels of circulating anti-intercellular substance autoantibodies have been reported. ## Existing clinical guidelines The British Association of Dermatologists' guidelines, published in 2003, concluded that ECP could be considered in recalcitrant cases of PV for which more conventional therapy had failed. [bib_ref] British Association of Dermatologists. Guidelines for the management of pemphigus vulgaris, Harman [/bib_ref] The strength of the recommendation was B (fair evidence to support the use of the procedure) based on quality of evidence III (opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees). ## Recommendations Patient selection ECP can be considered for those patients with recalcitrant PV or foliaceus pemphigus, in whom conventional therapy and second-line interventions (such as immunoabsorption, rituximab and intravenous immunoglobulins) fail. ## Treatment schedule - Initial treatment during weeks 0-12 should be one cycle of two treatments every 2-4 weeks, followed by one cycle of two treatments every 4 weeks during weeks 12-24 until complete remission. - After 24 weeks, treatment should be tapered according to clinical response (e.g. increasing the treatment intervals by 1 week every 3 months). Response assessment The clinical response should be monitored by two currently accepted clinical scores: the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and the Pemphigus Disease Activity Index (PDAI). [bib_ref] Severity score indexes for blistering diseases, Daniel [/bib_ref] In addition, the determination of autoantibody titres should also be performed, at least in pemphigus vulgaris. ## Epidermolysis bullosa acquisita No series of epidermolysis bullosa acquisita (EBA) patients treated with ECP has been reported. Eight patients with very severe EBA, resistant to several systemic immunosuppressive or immunomodulatory agents that caused severe adverse effects, have been described. [bib_ref] Remission of severe autoimmune bullous disorders induced by long-term extracorporeal photochemotherapy, Sanli [/bib_ref] [bib_ref] Remission of severe epidermolysis bullosa acquisita induced by extracorporeal photochemotherapy, Miller [/bib_ref] [bib_ref] Treatment of refractory epidermolysis bullosa acquisita with extracorporeal photochemotherapy, Gordon [/bib_ref] [bib_ref] Resistant acquired bullous epidermolysis with severe ocular involvement: the success of extracorporeal..., Camara [/bib_ref] The number of ECP sessions ranged from 3 to 32, given at 3-to 4-week intervals. The OR was 88% (7/8 patients), with 50% (4/8) of patients achieving a CR. The time to CR was short: 6-8 weeks of ECP. It is worth noting that two patients were able stop ECP-combined drugs and did not relapse after ECP tapering, unlike the patients reported by Sanli and colleagues. [bib_ref] Remission of severe autoimmune bullous disorders induced by long-term extracorporeal photochemotherapy, Sanli [/bib_ref] After ECP, circulating antibasement membrane zone autoantibodies were no longer detected in the four patients with positive tests at the start of ECP. The only major adverse events were observed in a patient who developed herpes zoster and pneumococcal sepsis during steroid tapering and idiopathic cardiomyopathy 14 months after the last cycle. Reported followup lasted 11-24 months for five patients. ## Existing clinical guidelines None. ## Recommendations Patient selection ECP could be a therapeutic option for severe EBA recalcitrant to conventional systemic therapy [according to local guidelines (e.g. cyclosporine, mycophenolate mofetil, immunoadsorption, rituximab and intravenous immunoglobulins)]. ## Treatment schedule - Start treatment 3 months after initiation of conventional therapy; no wash-out period is required. - Initial treatment during weeks 0-12 should be one cycle of two treatments every 2 weeks, followed by one cycle of two treatments every 4 weeks during weeks 12-24 until CR. - After 24 weeks, treatment should be tapered according to clinical response (e.g. increasing the treatment intervals by 1 week every 3 months). Response assessment The clinical response should be monitored by two currently accepted clinical scores (ABSIS and PDAI). [bib_ref] Severity score indexes for blistering diseases, Daniel [/bib_ref] Erosive oral lichen planus The first series of seven patients with severe, multiresistant, histologically proven chronic erosive oral lichen planus (EOL) were treated successfully with ECP. [bib_ref] Extracorporeal photochemotherapy for chronic erosive lichen planus, Becherel [/bib_ref] Time to improvement was rapid: 1.5 months on average, with all patients having a CR after a mean of 12 ECP sessions. No recurrence was observed after ECP discontinuation, with the longest follow-up of 24 months thereafter. Other studies have tested the efficacy of ECP for EOL, including case reports [bib_ref] Treatment of therapy-resistant erosive oral lichen planus with extracorporeal photopheresis (ECP), Kunte [/bib_ref] [bib_ref] Photopheresis: an alternative therapeutic approach in corticoresistant erosive oral lichen planus, Marchesseau-Merlin [/bib_ref] [bib_ref] Recalcitrant severe erosive cutaneous lichen planus treated with extracorporeal photopheresis monotherapy, Elewa [/bib_ref] [bib_ref] Effectiveness of extracorporeal photochemotherapy in the treatment of a case of refractory..., Zingoni [/bib_ref] and one open study on 12 patients, [bib_ref] Treatment of refractory erosive oral lichen planus with extracorporeal photochemotherapy: 12 cases, Guyot [/bib_ref] in a total of 26 patients. In all those reports, ECP regimens differed widely, from one cycle every week to one cycle every month. OR was 100%, with 77% CR and 23% PR. Healing of the genital and cutaneous lesions in nine and five patients, respectively, paralleled that of their oral lesions. [bib_ref] Recalcitrant severe erosive cutaneous lichen planus treated with extracorporeal photopheresis monotherapy, Elewa [/bib_ref] [bib_ref] Treatment of refractory erosive oral lichen planus with extracorporeal photochemotherapy: 12 cases, Guyot [/bib_ref] Clinical improvement could be seen as early as 1.5 months, and almost 1 year of ECP sessions could be required to achieve CR. Although no relapse was mentioned in the initial article with brief follow-up, ECP had a palliative effect, as EOL recurred in 12 out of 13 patients during either ECP therapy or long-term follow-up, at a mean of 8.3 months after ECP withdrawal. [bib_ref] Recalcitrant severe erosive cutaneous lichen planus treated with extracorporeal photopheresis monotherapy, Elewa [/bib_ref] [bib_ref] Treatment of refractory erosive oral lichen planus with extracorporeal photochemotherapy: 12 cases, Guyot [/bib_ref] However, relapses were sensitive to ECP reintroduction. ECP was extremely well tolerated, with lower lymphocyte counts observed in a few patients. [bib_ref] Recalcitrant severe erosive cutaneous lichen planus treated with extracorporeal photopheresis monotherapy, Elewa [/bib_ref] [bib_ref] Treatment of refractory erosive oral lichen planus with extracorporeal photochemotherapy: 12 cases, Guyot [/bib_ref] Existing clinical guidelines None. ## Recommendations Patient selection ECP could represent an alternative therapy for recalcitrant EOL, when previous classical treatments, including topical and/or systemic therapies, have failed. ## Treatment schedule - Initial treatment during weeks 0-12 should be one cycle of two treatments every 2 weeks, followed by one cycle of two treatments every 4 weeks during weeks 12-24, until CR. - After 24 weeks, treatment should be tapered according to clinical response (e.g. increasing the treatment intervals by 1 week every 3 months). Response assessment Disappearance of the oral lesions. ## Lupus erythematosus Non-specific anti-inflammatory and immunosuppressive drugs, such as non-steroidal anti-inflammatory drugs, corticosteroids, thalidomide, antimalarial and cytotoxic agents, are the standard treatments to control lupus erythematosus (LE). These drugs, however, have a hazard of serious side-effects and poor tolerability. Recently, advances in molecular biology and immunology have allowed a greater understanding of the mechanisms involved in LE pathogenesis, [bib_ref] Extracorporeal photopheresis: a review on the immunological aspects and clinical applications, Chiesa-Fuxench [/bib_ref] and have supported the development of biological agents targeting a variety of pathologic pathways. These new drugs have given promising results in experimental clinical trials, but are unapproved as yet. [bib_ref] Report of a Task Force of the EULAR Standing Committee for International..., Bertsias [/bib_ref] [bib_ref] Advances in drug therapy for systemic lupus erythematosus, Wallace [/bib_ref] Although ignored by international guidelines [bib_ref] Report of a Task Force of the EULAR Standing Committee for International..., Bertsias [/bib_ref] and expert reviews, [bib_ref] Advances in drug therapy for systemic lupus erythematosus, Wallace [/bib_ref] preliminary results indicate that ECP could represent an innovative effective and safe therapeutic option for the treatment of LE. Eighteen female patients with LE have been treated with ECP to date. [bib_ref] Extracorporeal photochemotherapy for the treatment of systemic lupus erythematosus. A pilot study, Knobler [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in cutaneous lupus erythematosus, Wollina [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in therapy-refractory subacute lupus, Richard [/bib_ref] [bib_ref] Extracorporeal photopheresis in recalcitrant lupus erythematosus, Boeckler [/bib_ref] [bib_ref] Four cases of photopheresis treatment for cutaneous lupus erythematosus refractory to standard..., Morruzzi [/bib_ref] All had mild-to-moderate disease activity that was not adequately controlled with standard treatment options and/ or they had a flare of disease activity upon attempted reduction and/or elimination of these drugs. Eight patients were affected by systemic LE (SLE), six by subacute cutaneous LE (one was affected by lupus tumidus too) and three by disseminated discoid LE. One patient had lupus tumidus, lupus panniculitis and chilblain lupus. Ten patients reported photosensitivity. In all but one report, [bib_ref] Extracorporeal photochemotherapy in therapy-refractory subacute lupus, Richard [/bib_ref] ECP cycles consisted of two ECP sessions on consecutive days at monthly [bib_ref] Extracorporeal photochemotherapy for the treatment of systemic lupus erythematosus. A pilot study, Knobler [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in cutaneous lupus erythematosus, Wollina [/bib_ref] [bib_ref] Extracorporeal photopheresis in therapy-refractory disseminated discoid lupus erythematosus, Richter [/bib_ref] or bi-monthly 273,274 intervals until remission. Afterwards, the treatment was interrupted or performed with longer intervals to maintain remission, if any. A marked remission or CR leading to withdrawal (or a substantial decrease of dosage) of corticosteroid and cytotoxic drugs was seen in 16 patients. In the case series reported by Knobler and colleagues, 270 some patients had other LE lesions (i.e. arthritis, arthralgias and myalgias) that improved as well. Of note was the fact that ECP sessions did not induce exacerbation of other SLE symptoms, regardless of whether or not the patients were photosensitive. [bib_ref] Extracorporeal photochemotherapy for the treatment of systemic lupus erythematosus. A pilot study, Knobler [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in cutaneous lupus erythematosus, Wollina [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in therapy-refractory subacute lupus, Richard [/bib_ref] [bib_ref] Extracorporeal photopheresis in recalcitrant lupus erythematosus, Boeckler [/bib_ref] [bib_ref] Four cases of photopheresis treatment for cutaneous lupus erythematosus refractory to standard..., Morruzzi [/bib_ref] Remission was prolonged (up to 4 years) in many patients, even without maintenance ECP cycles. [bib_ref] Extracorporeal photochemotherapy in cutaneous lupus erythematosus, Wollina [/bib_ref] [bib_ref] Extracorporeal photopheresis in recalcitrant lupus erythematosus, Boeckler [/bib_ref] In one patient, an early relapse was seen, but lesions were amenable to another treatment cycle. [bib_ref] Extracorporeal photochemotherapy in cutaneous lupus erythematosus, Wollina [/bib_ref] Marked changes in specific routine laboratory parameters and autoantibody levels were never registered. [bib_ref] Extracorporeal photochemotherapy for the treatment of systemic lupus erythematosus. A pilot study, Knobler [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in cutaneous lupus erythematosus, Wollina [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in therapy-refractory subacute lupus, Richard [/bib_ref] [bib_ref] Extracorporeal photopheresis in recalcitrant lupus erythematosus, Boeckler [/bib_ref] [bib_ref] Four cases of photopheresis treatment for cutaneous lupus erythematosus refractory to standard..., Morruzzi [/bib_ref] In the case series reported by Knobler and colleagues, 270 hypovolaemic hypotension was documented in one patient during the ECP procedure and three patients were found to develop nausea after ingestion of the 8-MOP capsules. One patient died 6 months after initiation of the ECP programme, with death occurring 10 days post-ECP, so a relationship to ECP treatment could not be ruled out, although autopsy did not demonstrate pulmonary embolism or occluded arteries. [bib_ref] Extracorporeal photochemotherapy for the treatment of systemic lupus erythematosus. A pilot study, Knobler [/bib_ref] ECP cycles were without unwanted side-effects and well tolerated in the remaining patients. [bib_ref] Extracorporeal photochemotherapy in cutaneous lupus erythematosus, Wollina [/bib_ref] [bib_ref] Extracorporeal photochemotherapy in therapy-refractory subacute lupus, Richard [/bib_ref] [bib_ref] Extracorporeal photopheresis in recalcitrant lupus erythematosus, Boeckler [/bib_ref] [bib_ref] Four cases of photopheresis treatment for cutaneous lupus erythematosus refractory to standard..., Morruzzi [/bib_ref] In summary, the use of ECP in LE is supported by poor clinical evidence (i.e. results from individual case reports or small case series with different treatment protocols and short followup). Therefore, it must be considered only at an exploratory stage. However, the preliminary clinical results are positive and future randomized, controlled clinical trials should be encouraged to assess therapeutic efficacy and cost-effectiveness. In addition, length of therapy, design of specific protocols, concomitant use of immunosuppressive therapy, patient characteristics and long-term side-effects should be assessed. ## Other indications ECP has also been used in prospective studies in a number of other disease areas, including psoriasis, 276 rheumatoid arthritis, 277-279 multiple sclerosis, [bib_ref] Photopheresis-a possible treatment of multiple sclerosis?: report of two cases, Poehlau [/bib_ref] [bib_ref] A double-blind, placebo-controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis, Rostami [/bib_ref] [bib_ref] Extracorporeal photochemotherapy for secondary chronic progressive multiple sclerosis: a pilot study, Besnier [/bib_ref] [bib_ref] Extracorporeal photochemotherapy: a safety and tolerability pilot study with preliminary efficacy results..., Cavaletti [/bib_ref] nephrogenic fibrosing dermopathy, [bib_ref] Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis, Gilliet [/bib_ref] [bib_ref] Extracorporeal photopheresis improves nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: three case reports and..., Mathur [/bib_ref] [bib_ref] Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis, Lauchli [/bib_ref] and scleromyxoedema, 287,288 with inconclusive evidence. # Summary/conclusions It is now 25 years since the results of the first prospective, multicentre, international clinical study on the use of ECP for treatment of CTCL were published by Edelson and colleagues, leading to FDA approval of ECP as the first cellular immunotherapy for cancer. Since then, ECP has been investigated for prevention and treatment of a variety of T-cell mediated diseases as described in this publication. In many of these diseases there are now sufficient data from retrospective and, increasingly, prospective single and multi-centre clinical trials with ECP to enable recommendations to be made on which patients should be treated, the ECP treatment regimen to be used and how treatment should be monitored. Our recommendations are summarized in [fig_ref] Table 8: Synopsis of recommendations on use of ECP in different diseases [/fig_ref]. ECP is a well-tolerated therapy with an excellent safety profile. No significant side-effects have been reported in any of the conditions reviewed here, except for the short-term effects of oral 8-MOP when this was used in early studies. Unlike other immunosuppressive therapies, ECP has not been associated with an increased incidence of infections. New technical developments allow it to be used in children and have also substantially shortened treatment times. Furthermore, whereas ECP has, in the past, been used empirically within the clinic, recent preclinical and clinical research is now throwing light on the complexities of its mechanism of action. In addition, promising data are also emerging on the identification of biomarkers predicting response to ECP, which are urgently needed in an environment where there is a rising demand for efficient use of limited resources. The advances during recent years have established ECP as a recognized and accepted immunomodulatory therapy with the potential to induce tolerance. It seems likely that greater understanding of how ECP works and extension of its clinical use will enable the value of ECP to be extended into the future. [fig] © 2013: The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. JEADV 2014, 28 (Suppl. 1), 1-37 [/fig] [table] Table 1: ECP approaches in current use in adults and children (adapted from Wong and Jacobsohn 7 ). [/table] [table] Table 2: European CE mark and FDA approval status of the 'one-step', closed photopheresis systems and the various cell separation and drug photo activation systems used in the 'two step' photopheresis procedures.Suitable for low body weight patients.© 2013 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology. [/table] [table] Table 3: Summary of studies using extracorporeal photopheresis as monotherapy or in combination with other therapies for the treatment of cutaneous T-cell lymphoma (adapted fromScarisbrick et al. 2008 50 ). [/table] [table] Table 4: Summary of studies using extracorporeal photopheresis in paediatric patients with chronic graft-versus-host disease. CR, complete response; OS, overall survival; PR, partial response. [/table] [table] Table 5: Summary of studies using extracorporeal photopheresis in adult patients with chronic graft-versus-host disease.CR, complete response; NK, not known; OR, overall response; PR, partial response. [/table] [table] Table 6: Summary of studies using extracorporeal photopheresis in the second-line treatment of acute graft-versus-host disease. year †Combined CR and PR. CR, complete response; OS, overall survival; PR, partial response. [/table] [table] Table 7: Summary of studies using extracorporeal photopheresis as systemic monotherapy for the treatment of severe atopic dermatitis. *From a total of 34 patients of four studies 223,225-227 a categorized response was not available, resulting in a total number of 67 patients as the base for the percentage calculation of the response rates. [/table] [table] Table 8: Synopsis of recommendations on use of ECP in different diseases. CR, complete response; ECP, extracorporeal photopheresis; FEV1, forced expiratory volume in 1 s; NIH, National Institutes of Health; SCORAD, SCORing Atopic Dermatitis; TNF, tumour necrosis factor. [/table]	None	https://europepmc.org/articles/pmc4291097?pdf=render	After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease.
2bbfdc2e3b6a088dd86fded7fb276cd5eb48c6eb	pubmed	None	In 2014 the International Endohernia Society (IEHS) published the first international "Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias". Guidelines reflect the currently best available evidence in diagnostics and therapy and give recommendations to help surgeons to standardize their techniques and to improve their results. However, science is a dynamic field which is continuously developing. Therefore, guidelines require regular updates to keep pace with the evolving literature. Methods For the development of the original guidelines all relevant literature published up to year 2012 was analyzed using the ranking of the Oxford Centre for Evidence-Based-Medicine. For the present update all of the previous authors were asked to evaluate the literature published during the recent years from 2012 to 2017 and revise their statements and recommendations given in the initial guidelines accordingly. In two Consensus Conferences (October 2017 Beijing, March 2018 Cologne) the updates were presented, discussed, and confirmed. To avoid redundancy, only new statements or recommendations are included in this paper. Therefore, for full understanding both of the guidelines, the original and the current, must be read. In addition, the new developments in repair of abdominal wall hernias like surgical techniques within the abdominal wall, release operations (transversus muscle release, component separation), Botox application, and robot-assisted repair methods were included. Results Due to an increase of the number of patients and further development of surgical techniques, repair of primary and secondary abdominal wall hernias attracts increasing interests of many surgeons. Whereas up to three decades ago herniarelated publications did not exceed 20 per year, currently this number is about 10-fold higher. Recent years are characterized by the advent of new techniques-minimal invasive techniques using robotics and laparoscopy, totally extraperitoneal repairs, novel myofascial release techniques for optimal closure of large defects, and Botox for relaxing the abdominal wall. Furthermore, a concomitant rectus diastasis was recognized as a significant risk factor for recurrence. Despite still insufficient evidence with respect to these new techniques it seemed to us necessary to include them in the update to stimulate surgeons to do research in these fields. Conclusion Guidelines are recommendations based on best available evidence intended to help the surgeon to improve the quality of his daily work. However, science is a continuously evolving process, and as such guidelines should be updated about every 3 years. For a comprehensive reference, however, it is suggested to read both the initially guidelines published in 2014 together with the update. Moreover, the presented update includes also techniques which were not known 3 years before. # Introduction Treatment of abdominal wall hernias is a rapidly evolving field of surgery. Correspondingly there is a dramatic increase of publications. There are many reasons for this development: rise of the number of laparotomies and the number of major surgeries being performed, progress in anesthesiology, increase of older patients with weak connective tissue, increase of patients with risk factors for hernias, and significant increase of patients managed with an open abdomen in a damage-control situation. Worldwide as many as two million patients are operated on every year. A variety of new repair techniques came up, recently even robot-assisted operations. The surgical approach may be open, laparoscopic, endoscopically within the abdominal wall, or hybrid approaches combining these modalities. The volume of literature, often with low levels of evidence and conflicting results, can be difficult to interpret in a meaningful way to assist the surgeon in appropriate management of the hernia patient. Therefore, there is a need for evidence-based guidelines to help the surgeon in his daily decision making process. "Guidelines are the bridge between science and clinical practice (Eccles M, Mason J.Health Technol Assess. 2001; 5(16):1-69. Review.). In 2014 this same group (IEHS) published the first international "Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias" . It is generally accepted that guidelines require an update every 3 years to reflect the rapid evolution of techniques, materials and data available. The current update follows the same methodology as described in the original guidelines. The authors were encouraged to avoid redundancy and concentrate on the new studies showing a level of evidence 1, 2 and 3, and which were published between 2012 and 2017. Statements and recommendations which are still valid are not repeated. As such, this update should be read in the context and in conjunction with the initially published guidelines. New topics included in this update are: In which patient group is a component separation indicated? Should the component separation be done open or endoscopically? Is an anterior component separation better than the posterior one? Is preliminary treatment with Botox indicated in patients in whom a component separation is planned? Should TAR be done open or endoscopically? In patients presenting with a ventral hernia in combination with a rectus diastasis which is the best treatment option? Does robot-assisted surgery have a future in repair of primary and secondary ventral hernias? What is the optimal treatment of lateral primary or incisional hernias? We are well aware that with respect to these innovations the evidence is not yet strong enough to give valuable statements or recommendations, however, the guidelines should inform the surgical community and stimulate further studies to gain more knowledge in the coming years. ## Included publications Covering the period from 2003 to February 2018, using the search terms "abdominal wall hernia", "ventral hernia", and "incisional hernia" identified 12,507, 9971, and 3806 articles, respectively. One hundred and forty-three articles were identified for "rectus diastasis". These were refined to 89 studies. In total, 30 studies were found to be relevant. Twenty-three were included in formulating these guidelines while 7 were excluded for language , open technique (2), or low quality . Total Extraperitoneal Preperitoneal (TEP) ventral hernia repair may be used to correct small and medium size ventral hernias. ## Level 4 Endoscopic-assisted Linea Alba ReconstrucƟon (ELAR) with mesh augmentaƟon may be used to correct ventral hernias and coexisiƟng diastasis with wide extraperitoneal mesh augmentaƟon and favorable outcomes regarding recurrence, complicaƟons, and pain. ## Level 4 Laparoscopic transabdominal preperitoneal and retromuscular ventral hernia repair (ventral TAPP and TARM = RMVH) may be used to correct small and medium size ventral hernias and coexisiƟng diastasis with wide extraperitoneal mesh augmentaƟon, minimal fixaƟon, and favorable outcomes regarding recurrence, infecƟon, and pain. With large ventral hernias, ventral TAPP and RMVH operaƟons can be combined with posterior component separaƟon (TAR). ## Level 4 Enhanced-view Total Extraperitoneal Preperitoneal (eTEP) ventral hernia repair may be used to correct ventral hernias and coexisƟng diastasis with wide extraperitoneal mesh augmentaƟon, minimal fixaƟon, and favorable early outcomes regarding recurrence, infecƟon, and pain. With large ventral hernias, eTEP operaƟons can be combined with posterior component separaƟon (TAR). ## Level 2b Minimally invasive Less Open Sublay (MILOS) and its endoscopic variants (EMILOS) effecƟvely repair ventral hernias and coexisiƟng diastasis with wide extraperitoneal mesh augmentaƟon, minimal fixaƟon, and favorable outcomes regarding recurrence, infecƟon, and pain. With large ventral hernias, MILOS and EMILOS operaƟons can be combined with posterior component separaƟon (TAR). ## Level 3 RoboƟc Retromuscular Hernia Repair (RRVHR) may be used to repair ventral hernias and coexisiƟng diastasis with wide extraperitoneal mesh augmentaƟon, minimal fixaƟon, and favorable outcomes regarding fascial closure, recurrence, and length of stay but greater seroma rates and uƟlizaƟon of myofascial release. With large ventral hernias, RRVHR operaƟons can be combined with posterior component separaƟon (TAR). ## Level 4 Linear cuƫng staplers may simplify and speed the creaƟon of the retromuscular pocket and plicate a coexisƟng diastasis during extraperitoneal hernia and rectus diastasis repairs (MILOS, EMILOS, eTEP, TAPP). ## 3 RecommendaƟon: Grade C Several minimally invasive laparoendoscopic and roboƟc opƟons for extraperitoneal mesh repair of ventral hernia with favorable short term outcomes can be offered. Ongoing evaluaƟon regarding long term outcomes, operaƟve Ɵme, cost, and clinical benefit are needed. The new techniques should only be adopted aŌer adequate training. ## Key question In patients presenting with a ventral hernia in combination with a rectus diastasis, which is the best treatment option-IPOM plus, ELAR, MILOS, EMILOS, LIRA, eTEP, Stapler Abdominoplasty? # Statements: level 2a With regards to isolated Rectus Diastasis, no clear disƟncƟon in recurrence rate, postoperaƟve complicaƟons, or paƟent reported outcomes can be made regarding plicaƟon as compared to hernia repair methods. ## Level 3 CoexisƟng Rectus diastasis significantly increases hernia recurrence rate (31 vs 8%) while closure with non-absorbable sutures and mesh repair decrease recurrence. ## Level 3 Mesh reinforcement is safe and durable for repair of large rectus diastases and those with concomitant hernia. Level 2B PlicaƟon of the Linea Alba during concurrent hernia and rectus diastasis repair reduces the average distance between the rectus muscles and may provide a funcƟonal and aestheƟc benefits. Level 2A Laparoscopic IPOM ventral hernia and rectus diastasis repair with midline mesh augmentaƟon and defect closure (IPOM plus) results in less recurrence, seroma and bulging. ## Level 3 Laparoscopic intracorporeal rectus aponeuroplasty (LIRA) with mesh augmentaƟon may be used to correct ventral hernias with coexisiƟng diastasis with favorable outcomes regarding recurrence and pain. ## Level 3 Novel extraperitoneal ventral hernia repair techniques with mesh augmentaƟon (MILOS, eMILOS, eTEP, ventral TAPP, roboƟc eTEP, roboƟc TAPP, roboƟc RRVHR) may be uƟlized to repair ventral hernias with coexisƟng rectus diastasis. # Introduction Laparoscopic intraperitoneal onlay mesh (IPOM) repair and open sublay mesh repair are currently the most common techniques for the treatment of primary and recurrent abdominal wall hernias worldwide . A systematic review and two recently published meta-analyses concluded that laparoscopic IPOM and open abdominal wall hernia repairs are safe procedures with comparable short and longterm outcomes . Although the open techniques are burdened with higher infection rates, laparoscopic IPOM repairs carry an increased risk of intraoperative bowel injury, adhesions, and bowel obstruction . Despite progress in mesh technology and the development of coated meshes designed to lower the risk of adhesion formation, the potential risks associated with an intraperitoneal foreign body have not yet been eliminated . Traumatic mesh fixation increases the risk of adhesions, visceral damage, nerve injury, and acute and chronic pain. Reduction of the hernia sac with closure of the hernia defect is difficult with laparoscopic IPOM, and is often omitted leading to higher recurrence rates, eventrations (pseudorecurrences), and seroma formation . In larger hernias with a diameter of more than 15 cm, the laparoscopic IPOM repair can be very difficult . To address the limitations of traditional laparoscopic and open ventral hernia repair, several minimally invasive endoscopic, laparoscopic, and robotic extraperitoneal techniques have developed with the goal of combining the benefits of traditional open sublay repair removing prosthetics out of the visceral compartment with those of minimally invasive surgery. The new minimal invasive extraperitoneal techniques can be classified according to access, mesh location, modality of defect closure, and anatomic reconstruction of the abdominal wall. In all of these novel procedures, standard uncoated permanent synthetic meshes (Polypropylene, PVDF, Polyester) may be used. Analogous to the differentiation in laparoscopic inguinal hernia repair, laparoscopic transabdominal techniques (ventral preperitoneal TAPP, ventral transabdominal retromuscular TARM/RMVH) can be differentiated from endoscopic total extraperitoneal procedures (ventral TEP, eTEP, MILOS, EMILOS). Most of these novel extraperitoneal operations can be combined with posterior component separation (transversus abdominis release-TAR) as needed to address larger defects or accommodate larger prostheses. The first article on minimal invasive extraperitoneal mesh repair of ventral hernias was published by Miserez et al. . Subsequent development of transabdominal, total extraperitoneal, transhernial, and onlay techniques perfomed in mini-open, laparoscopic, and robotic fashion have expanded the minimally invasive extraperitoneal options for repair of ventral hernias and coexisting rectus diastasis. Classification details for these novel extraperitoneal repairs are shown in [fig_ref] Table 1: Classification of new techniques for minimal invasive extraperitoneal mesh repair of abdominal... [/fig_ref]. Patients with symptomatic umbilical, ventral, and incisional hernias and concomitant rectus abdominis diastasis represent a growing clinical problem and, as with isolated hernias, the ideal operative management of this complex hernia situation has not been defined. With regards to isolated rectus diastasis, defined as a thinning and widening of the linea alba, combined with laxity of the ventral abdominal wall musculature, controversy remains as to whether this pathology is cosmetic or functional due to the variation in severity, symptomatology, and the absence of strangulation risk found with hernias . While physiotherapy can achieve a limited benefit with regards to size and symptoms with isolated mild rectus diastasis, surgery significantly improves abdominal wall function and pain regardless of operative technique employed and should be considered with diastasis wider than 3 cm . Currently, both plication and hernia repair methods are used to repair isolated rectus abdominis diastasis with no clear distinction in recurrence rate, postoperative complications, or patient reported outcomes found in the literature . The presence of rectus abdominis diastasis and coexisting hernia presents a greater challenge as the weakened linea alba and ventral abdominal musculature increase the risk of hernia formation, compromise the integrity of the midline, and complicate the repair of ventral hernias. Köhler et al. demonstrated that a coexisting rectus diastasis significantly increases hernia recurrence rate with primary sutured closure (31 vs. 8%) . As such, well established principles from ventral hernia repair including primary closure with non-absorbable sutures and mesh repair should be utilized to decrease hernia and diastasis recurrence . Mesh repair of ventral hernias is well established as safe reducing the recurrence rate significantly compared to suture repair. Based on the volume of Level 1 studies studying ventral hernia, mesh reinforcement of ventral hernia repairs with a concomitant rectus diastasis is recommended while studies specifically evaluating ventral hernia and rectus diastasis corroborate these findings . While the role of defect closure with isolated ventral hernia is likely beneficial but still unestablished, mesh reinforcement with ventral hernia in the setting of a concurrent rectus diastasis is more clear . Multiple studies utilizing several different operative repair techniques demonstrate that restoration of the linea alba during concurrent hernia and rectus diastasis repair is feasible and reduces the average distance between the rectus muscles with potential functional and esthetic benefits [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] [bib_ref] A prospective randomized study comparing suture mesh fixation versus tacker mesh fixation..., Bansal [/bib_ref] [bib_ref] Surgical treatment of parietal defects with "da Vinci" surgical robot, Vasilescu [/bib_ref] [bib_ref] Outcomes after Robotic Ventral Hernia Repair: A Study of 21,565 Patients in..., Altieri [/bib_ref] [bib_ref] A nationwide evaluation of robotic ventral hernia surgery, Coakley [/bib_ref]. These studies include traditional laparoscopic intraperitoneal (IPOM) repair with defect closure, subcutaneous closure of the anterior sheath, endoscopic subaponeurotic closure of the anterior sheath, laparoscopic sutured linea alba closure, laparoscopic posterior sheath closure, and linear stapled closure techniques to address the separation of the linea alba prior to mesh hernia repair. Restoration of the midline with correction of the diastasis at the time of ventral hernia repair when possible may provide additional benefit with regards to abdominal wall function, pain, and cosmesis [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] [bib_ref] A prospective randomized study comparing suture mesh fixation versus tacker mesh fixation..., Bansal [/bib_ref] [bib_ref] Outcomes after Robotic Ventral Hernia Repair: A Study of 21,565 Patients in..., Altieri [/bib_ref]. With regard to specific technique, several of the new minimally invasive mini-open, endoscopic, laparoscopic, and robotic extraperitoneal ventral hernia repairs may simultaneously address a coexisting rectus diastasis. There is a paucity of data in the literature for many of these novel techniques and an absence of comparative data to establish superiority of any given technique. The current literature summarized in these guidelines support that these reported techniques are safe, feasible, and effective in shorter term studies but ongoing and future studies are need to establish a "best treatment option". Laparoscopic intraperitoneal onlay mesh (IPOM) repair is the best and longest studied minimally invasive ventral hernia repair technique. Palanivelu et al. described their "Venetian blind" technique in 2009 to address the cosmetic and functional implications of a coexisting rectus diastasis or bridged hernia defect demonstrating the feasibility and efficacy of closing the defect at the time of IPOM repair . Multiple primary studies, meta-analyses, and systematic reviews have subsequently been performed demonstrating the benefits of defect closure with midline mesh augmentation during IPOM repair with regards to recurrence, seroma, and "pseudorecurrence" or bulging . Extrapolating the data from these consistent level 2A studies to concurrent rectus diastasis and ventral hernia repair, reconstruction of linea alba with mesh augmentation, is recommended and should be performed when feasible. The minimally invasive Mini or Less Open Sublay Repair (MILOS) and its endoscopic variant (EMILOS) developed by Reinpold and colleagues utilize progressively smaller "mini (≤ 5 cm) or less open (6-12 cm)" incisions and laparoendoscopic transhernial approaches to replicate the traditional open Rives-Stoppa retrorectus or retromuscular sublay reconstruction for ventral hernia repair . This approach simultaneously addresses the midline linea alba correcting coexisting diastasis with wide midline mesh augmentation and minimal fixation. Reinpold et al. performed a prospective, propensity score matched study within the German Hernia Registry (Herniamed) comparing 615 MILOS incisional hernia operations to laparoscopic IPOM incisional hernia repair and open sublay repair . MILOS repair was associated with significantly fewer postoperative surgical complications, general complications, recurrences, and less chronic pain versus IPOM repair. Significantly fewer postoperative complications, reoperations, infections, general complications, recurrences, and less chronic pain were found compared to open sublay repair. The MILOS technique reproduces the functional and physiologic aspect of an open retromuscular repair with the benefits of minimally invasive techniques. Schwarz et al. and Bittner et al. demonstrated that this technique can be endoscopically modified (EMILOS) with similar feasibility, efficacy, and favorable outcomes for ventral hernia and rectus diastasis repair . In large defects, the MILOS technique can be combined with a posterior component separation (TAR). The Enhanced or Extended-view Total Extraperitoneal Preperitoneal (eTEP) approach developed by Daes has been used to perform midline and off midline ventral hernia repair augmenting the traditional preperitoneal space utilized in inguinal hernia repair to access almost any portion of the abdominal wall. With regards to ventral hernia with a coexisting rectus diastasis, this technique allows for midline closure of the linea alba and any diastasis with wide extraperitoneal mesh augmentation, minimal fixation, and may be combined with posterior component separation with release of the transversus abdominus muscle to access to the entire retromuscular plane. Belayansky et al. performed a retrospective multicenter review of 79 patients utilizing the eTEP approach demonstrating low complication rates, significantly improved pain and functionality scores using the Carolinas Comfort Scale, and low complication, infection, and recurrence rates [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref]. While the operative approach may differ slightly, the eTEP technique is anatomically and physiologically similar to the eMILOS technique demonstrating similar benefits and efficacy. The Endoscopic-assisted Linea Alba Reconstruction (ELAR) with mesh augmentation developed by Koeckerling is based on the principles of the MILOS technique and utilizes an endoscopic subcutaneous approach with subsequent mesh augmentation and reinforcement to address ventral hernia defects with concurrent rectus diastasis . This hybrid technique exposes the anterior layer of the rectus sheath from the xiphoid process to the subumbilical area, the medial segments of the anterior layer of both rectus sheaths are sutured to reconstruct the linea alba, and the resultant defect in the anterior layer of the rectus sheath is repaired by suturing a mesh to the anterior sheaths bilaterally to reconstruct the anterior abdominal wall. Koeckerling et al. reported low complication and reoperation rates (1.4%, 2 cases due to bleeding) with favorable early results regarding pain and recurrence in their series of 140 patients . Laparoscopic intracorporeal rectus aponeuroplasty (LIRA) with mesh augmentation described by Gómez-Menchero et al. was designed to address some of the challenges and limitations of closing the defect with the IPOM plus technique which may increase pain, recurrence, or require component separation to counteract the tension created by midline fascial reapproximation . The posterior rectus aponeurosis is laparoscopically opened lengthwise around the hernia defect to create two flaps. The flaps are then sutured closed and the repair reinforced with an IPOM mesh. In their series of 12 patients followed to 1 year, this novel technique achieves a reproducible, feasible, "tension-free" repair of ventral hernias with coexisting rectus diastasis with a low rate of postoperative pain and no reported recurrence, or bulging . Despite its benefits, minimally invasive laparoscopic ventral hernia repair can be technically challenging especially with complex procedures such as component separation, transversus abdominis release, and suturing of the ventral midline. The need for high technical skill, dexterity, and proficiency may lead to variability with regards to clinical outcomes, complication rates, and adoption. The use of the robotic platform for ventral hernia has progressively increased due to the benefits of improved optics and visualization, superior ergonomics, and improved degrees of freedom and range of motion needed to perform precise suturing, adhesiolysis, dissection, and mesh positioning and fixation necessary for abdominal wall reconstruction. With regards to ventral hernias and coexisting rectus diastasis, the Robotic Retromuscular Hernia Repair (RRVHR) utilizes the same operative plane as the open Rives-Stoppa, MILOS, eMILOS, and eTEP ventral hernia repairs. Warren et al. compared their robotic retromuscular repair (53 patients) to traditional laparoscopic ventral hernia repair (103 patients) utilizing registry data from the American Hernias Society Quality Collaborative. Robotic retromuscular repair facilitated facial closure and extraperitoneal mesh placement in the vast majority of cases (96.2 vs. 50.5%; p < 0.001). Hernia size was similar but robotic operations were longer and myofascial release was performed in 43% of robotic operations. Direct hospital costs were similar between both groups while length of stay was significantly shorter after RRVHR. Robotic retromuscular ventral hernia repair enables a true abdominal wall reconstruction and allows for simultaneous correction of coexisting rectus diastasis with wide extraperitoneal mesh augmentation, minimal fixation, and favorable outcomes regarding fascial closure and recurrence. The term "Stapler abdominoplasty" represents a technical modification of several extraperitoneal operative techniques for ventral hernia and rectus diastasis repair rather than a unique operative approach. Linear cutting staplers may be used to develop the retromuscular space and plicate a coexisting diastasis during extraperitoneal hernia and rectus diastasis repairs. Costa et al. introduced this technique using a laparoscopic transabdominal preperitoneal approach in 15 postbariatic patients with hernia and rectus diastasis demonstrating feasibility, simplicity, and low complication rates . Stapled plication of the anterior rectus sheath and division of the linea alba into an anterior and posterior component may be used in conjunction with open Rives-Stoppa, MILOS, EMILOS, eTEP, and laparoscopic retromuscular repairs [bib_ref] Surgical treatment of parietal defects with "da Vinci" surgical robot, Vasilescu [/bib_ref] [bib_ref] Outcomes after Robotic Ventral Hernia Repair: A Study of 21,565 Patients in..., Altieri [/bib_ref] [bib_ref] A nationwide evaluation of robotic ventral hernia surgery, Coakley [/bib_ref]. In general, the indication for repair of diastasis recti of the abdominal muscles is based upon cosmetic or functional impairment, as there is no risk of strangulation. However, the negative implication of a rectus diastasis on ventral hernias with regards to recurrence and complications warrants consideration of the optimal approach to address both disease processes simultaneously. In these cases, the morbidity and risk of larger, more complicated operations for typically smaller coexisting hernias must be considered. Currently, there are several novel minimally invasive endoscopic, laparoscopic, and robotic procedures to address ventral hernia with coexisting rectus diastasis that are feasible, safe, and effective. Future studies with long-term outcomes and comparative data will help to define optimal techniques for these coexisting pathologies. ## References ## Chapter 2. is there an indication for operative treatment of diastasis recti without hernia formation? Mazen Iskandar MD, Dimitri Ranev, MD, and George Ferzli, MD The following search terms were used: "diastasis recti" or "diastasis rectus" or "diastasis of the recti" or "diastasis of the rectus" or "rectus diastasis" or "rectus abdominis diastasis" or "divarication". A systemic review of the literature was done in September 2017. A total of 219 papers were found. After selecting relevant studies, 20 articles were used for this review. Level 2 There is a weak associaƟon between diastasis recƟ and pelvic organ prolapse. Diastasis recƟ may be associated with impaired healthrelated quality of life, impaired abdominal muscle strength and low back pain severity. ## Level 2 linea alba plicaɵon and retro-muscular mesh repair have equivalent results # Introduction Diastasis recti is a diagnosis that surgeons have to manage on a regular basis. It is simply described as bulging of the linea alba with increased intra-intra-abdominal pressure. Typically, women during pregnancy develop diastasis recti which regresses within a year after child birth. However, in a third of those patients, the diastasis persists . The width of the linea alba is measured at 2 reference points. The first is at 3 cm superior to the umbil-icus and the second is 2 cm inferior. A patient is considered to have diastasis if the width between the 2 medial edges of the recti is greater than 22 mm at the first reference point and greater than 16 mm at the second point . Nahas proposed a classification that included 4 types of "myofascial deformities" with a tailored treatment for each type . In addition to diastasis recti, these types took into consideration other factors such as the appearance of the waist line and the presence of lateral laxity. Most women with diastasis recti after pregnancy fall under type A and are treated with plication of the anterior rectus sheath. ## Indications for surgery Diastasis recti, even when associated with significant protrusion, does not represent a true hernia and poses no risk of incarceration or strangulation. Thus, the decision for surgery is based on functional and/or cosmetic impairment. In the majority of studies, repair is performed as part of abdominoplasty or ventral hernia repair . In order to identify predictive factors for successful surgery, Strigård et al. correlated preoperative Ventral Hernia Pain Questionnaire scores with postoperative improvement in abdominal muscle strength. Patients were predominantly female (55/57) with median age of 43 years and median BMI of 23 kg/m 2 . The study found that pain while being seated for longer than 30 min and pain limiting the ability to participate in sports are preoperative predictors for successful surgery . In another study by the same group of authors, patients were randomized between surgery and a training program supervised by a physiotherapist. Surgery resulted in significantly improved abdominal wall function compared to patients in the non-operative group . Because the rectus abdominis muscles help stabilize the spine, researchers were interested in finding an association between diastasis recti and low back pain . After conducting a systematic review, Benjamin et al. concluded that there was a small association between diastasis recti and pelvic organ prolapse, and that diastasis recti may be associated with impaired health-related quality of life, impaired abdominal muscle strength and low back pain severity . Wether there is an underlying connective tissue problem to explain the association remains unanswered. ## Surgical technique Surgical options for treatment of diastasis recti include linea alba plication, modified hernia repair techniques, minimally invasive techniques (endoscopic or laparoscopic), or a combination of open and minimally invasive (hybrid) techniques. A systematic review by Mommers et al. included 1591 patients and failed to demonstrate a difference in outcomes among different surgical approaches . Another two systematic reviews showed high patient satisfaction after surgery, but no difference between the different surgical options . The largest randomized-controlled trial on diastasis recti by Emanuelsson et al. included 89 patients with diastasis > 3 cm . Patients were randomized into three groups-plication in two layers using 2-0 barbed polydioxanone, repair with retromuscular polypropylene mesh or a supervised exercise program. The majority of patients (87/89) were female, with a median number of 2 prior pregnancies and a median BMI of 23. All patients were symptomatic and non-smokers. The study found no difference between the two surgical arms at 1 year follow-up, including improvement in abdominal wall function, quality of life, and complication rates. ## Choice of suture Gama et al. conducted a randomized-controlled trial comparing linea alba plication in two layers versus one layer using non-absorbable suture (nylon). The study included 30 patients aged 25-50 years with a BMI 18-30 kg/m 2 . Patients with pre-existing hernia, significant comorbidities or smoking were excluded. The study found no difference in outcomes and a shorter operating time for the single-layer plication (35 vs. 15 min). Of note, there was an unacceptably high recurrence rate of 33% in patients in whom a barbed suture was used . Another randomized study compared non-absorbable (nylon) with absorbable (polydioxanone) sutures for plication and found no difference in recurrence at 6 months. The study was limited by a small sample size-10 patients in each groupand the fact that it was sponsored by the company producing the absorbable sutures . Mestak et al. performed a linea alba plication in 51 patients using running, locked, #0 loop polydioxanone. In a case-control study using ultrasound, they compared the postoperative inter-recti distance between the study group and a control group of normal subjects. There was no difference between the inter-recti distances of the study group and healthy subjects at 21 months follow-up . Minimally invasive techniques In patients where excess skin removal and waist line definition are not needed, minimally invasive techniques become attractive. Endoscopic subcutaneous, laparoscopic, robotic, and hybrid approaches have been described as feasible and esthetically superior [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref]. Traditionally, these approaches have been applied to diastasis associated with a hernia and often these repairs use mesh with or without the need for a fascial release. Endoscopic-assisted linea alba reconstruction (ELAR) is a hybrid approach where subcutaneous dissection is utilized to expose the anterior rectus sheath [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref]. The anterior rectus sheath is released bilaterally and re-approximated to recreate the linea alba followed by augmentation with an onlay mesh. The endoscopic mini/ less open sublay (EMILOS) technique is a hybrid procedure where the retromuscular space is dissected, the line alba plicated followed by placement of a large mesh in the retromuscular space as in a Rives-Stoppa repair . The enhanced view totally extraperitoneal Rives-Stoppa (eTEP-RS) repair can be performed laparoscopically or robotically and, similar to the EMILOS approach, involves dissection of the retromuscular space, plication of line alba, and placement of a mesh . Totally endoscopic subcutaneous dissection has also been described utilizing 3 suprapubic trocars. Following dissection, the linea alba is recreated with or without placement of an onlay mesh. However, there are no prospective studies comparing open and minimally invasive techniques. Published systematic reviews report no difference in outcomes, but are limited by low-quality data and high heterogeneity . Since the indication for surgery in the majority of patients is cosmesis, a minimally invasive approach is the logical evolution in the surgical management of this condition when excess skin removal is not required. References (level of evidence in parentheses) ## Chapter 3. component separation techniques ## Frederik berrevoet, lars nannestad jorgensen Background Large ventral and incisional hernias, sometimes with loss of domain, remain a surgical challenge. Due to their relative rarity there is no exact estimate of their incidence. In 1951 Albanese et al. designed a first model of component separation of the abdominal wall, later elegantly refined by Ramirez in 1990 as a part of a study on human cadavers . The latter's initial results showed the possibility of translating the abdominal midline on average 10 cm per side at the umbilical level when releasing the external oblique muscle. Component separation has been applied increasingly and modifications trying to tackle the main issues of the technique have been made. Described limitations of this technique are complications involving the skin and subcutaneous tissue, most likely caused by surgical interruption of perforating vessels during exposure of the oblique muscle . To date, most commonly used techniques for releasing the various fascial components of the abdominal wall are the 'open anterior approach', the 'transversus abdominis release' (TAR), the 'endoscopic anterior release', and the 'open anterior perforator preserving approach' with their original description in the noted references . As the component separation techniques (CST) were not included in the former IEHS guidelines, a full literature search was performed. ## Key question 1. When is any type of component separation indicated? ## Search terms The following search terms were used: ((component* separation) OR (separation of components) OR (myofascial release)) AND (hernia OR (abdominal wall) OR ("Hernia, Ventral"[Mesh])) AND (indication OR use). ## Search machines PubMed, Medline, and the Cochrane Library as well as Google scholar were searched for relevant studies. Abstracts of resulted articles were reviewed for their relevance to component separation techniques and indications. In total 475 papers were analyzed, of which none specifically studied indications for CST. ## Indications for cst # Statements: Level 3 Based on heterogeneous data, CST seem indicated in paƟents with large hernia defects. ## Level 5 The hernia width diameter for which CST are indicated remains to be determined, (but 8-10 cm seems an acceptable value) Level 4 Contaminated fields might be an indicaƟon for CST to primarily close the abdominal wall. Level 3 CST are best combined with the use of mesh to reduce recurrence rates. ## Level 4 IndicaƟons for CST as compared to other approaches to treat large abdominal defects remain to be defined. ## Level 5 cst can be indicated in cases of open abdomen treatment. RecommendaƟons: Grade B CST should be used to obtain fascial closure in large midline hernias. Grade B CST should be used in combinaƟon with mesh reinforcement whenever possible. Grade C CST should be considered to obtain fascial closure in contaminated fields, when no mesh is used. Current literature on CST is heterogeneous in various aspects: indications for use, mesh augmentation versus primary fascial closure using CST, different surgical techniques, and different abdominal wall components to be separated. No well-designed randomized-controlled trials are available for most indications and comparative studies between CST other popular techniques to treat giant hernias with or without loss of domain, like the use of botoxulin A and progressive pneumoperitoneum are also non-existing. The majority of reported cases for CST involve large ventral hernia defects in which primary closure of the fascial edges is not possible and for which CST seems more efficient than bridging of the defect with mesh . However, the definition of 'large' defects also varies considerably among publications. Slater et al. defined a large defect as a hernia width of at least 10 cm , but failure of primary closure of the fascia might occur with smaller defect as well, mostly due to fibrosis, edema, or obesity. Among others, de Vries-Reilingh et al. and Hodgkinson et al. showed that CST might facilitate primary fascial closure in patients with contamination of the abdominal cavity, especially in case no mesh will be used . However, the same Dutch group of de Vries-Reilingh observed a high recurrence rate after CST without the use of mesh, which was confirmed by other groups . Another possible indication for the use of CST might be the open abdomen patient. Although the number of patients reported is very low, CST might increase the fascial closure rate in this specific subset of patients . ## References ## Key question Which type of anterior CST is preferred? ## Search terms The following search terms were used: ((component* separation) OR (separation of components) OR (myofascial release)) AND (hernia OR (abdominal wall) OR ("Hernia, Ventral"[Mesh])) AND (indication OR use). ## Search machines PubMed, Medline, and the Cochrane Library as well as Google scholar were searched for relevant studies. Abstracts of resulted articles were reviewed for their relevance to the different component separation techniques. From the total of 475 papers extracted, 7 reviews [1-7] and 12 case-control studies [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] were applicable to the key question. ## Level 3 IndicaƟons for EaCS as compared to MIaCS remain to be defined. ## Recommendaɵons: Grade B For fascial closure of large midline hernias, surgeons should consider EaCS or MIaCS, as an alternaƟve to OaCS, in order to reduce postoperaƟve wound morbidity . Various systematic reviews and meta-analyses have recently been reported to compare the different techniques of CST. The minimal invasive and endoscopic component separation have been suggested to reduce the postoperative wound morbidity as large subcutaneous dissection and skin flaps might be avoided achieving the same outcomes in terms of fascial closure rate. In 2014 Feretis et al. reported 13 studies in their metaanalysis including 220 patients . Overall they analyzed a wound complication rate of 17.5% versus 28% for endoscopic CST and Minimally Invasive CST respectively, resulting in a overall rate of 19.2%. However, when they only analyzed comparative studies, only 2 out of 5 studies showed a significantly lower incidence of wound morbidity in endoscopic and minimally invasive CST compared to open techniques, and the trend was clear in all studies . In total 5 retrospective cohort studies were observed with 163 patients, but again 43% versus 18% of wound morbidity was seen, in favor of the endoscopic CST . Cornette et al., although analyzing the various anterior CST versus the posterior CST (TAR), found 13 studies for laparoscopic/endoscopic CST, only 5 on minimally invasive perforator sparing techniques and 22 on open CST. Considering wound morbidity, a slight trend in favor of perforator sparing techniques was found, versus open and laparoscopic techniques (16% vs. 21.4% and 20.3% respectively). However, as this trend is consistent throughout all the available data, despite their moderate to low quality, surgeons should consider endoscopic or minimally invasive (perforator sparing) CST, as an alternative to open CST, in order to reduce postoperative wound morbidity. Regarding recurrence rates after these various modalities, no differences are observed in the current medical literature. Furthermore, it is difficult to draw any conclusions regarding this parameter, as many variables influence recurrence rate in these large hernias. ## References ## Key question Is a Transversus Abdominis Release (TAR) preferred over an anterior component separation technique? ## Search terms The following search terms were used: ((component* separation) OR (separation of components) OR (myofascial release)) AND (hernia OR (abdominal wall) OR ("Hernia, Ventral"[Mesh])) AND (anterior OR posterior). ## Search machines PubMed, Medline, and the Cochrane Library as well as Google scholar were searched for relevant studies. Abstracts of resulted articles were reviewed for their relevance to the different component separation techniques. From the total of 106 papers extracted, 3 reviews [1-3] and 3 case-control studies were applicable to the key question. # Statements: ## Level 3 EaCS and MIaCS result in a similar wound morbidity rate as a posterior Transversus Abdominis Release. ## Level 3 EaCS and MIaCS result in a comparable recurrence rate as a posterior Transversus Abdominis Release. ## Recommendaɵons: Grade B For intermediate to large defects, surgeons should consider EaCS, MIaCS or TAR as an alternaƟve to OaCS in order to reduce postoperaƟve wound morbidity. Grade C For lateral defects in need of a large mesh overlap, TAR should be preferred over anterior component separaƟon techniques. As a retromuscular mesh position in incisional hernia is still preferred over an onlay or intraperitoneal mesh repair, larger defects might be difficult to treat using this technique as the mesh overlap is limited by the lateral borders of the rectus sheet. Since the introduction of the posterior component separation technique using a transverses abdominis release (TAR), described by Novitsky et al., there is no need for large subcutaneous dissection to perform CST, and an extended wide overlap can be achieved for large defects and defects located lateral to the rectus muscles. Most of the literature involves retrospective observational cohort studies and not much comparative data are available. Recently, Hodgkinson et al. investigated the outcomes of posterior component separation and TAR with the open anterior CST. They report on 7 studies describing 281 cases of TAR for midline incisional hernia using a retromuscular mesh placement and compared those to 6 comparable studies describing 285 cases of open anterior CST and retromuscular mesh placement. Comparative analysis demonstrated no significant difference between hernia recurrence rate (p = 0.23) and no significant difference was found in wound complication rates between TAR and the open CST (p = 0.53). This finding was reported earlier already by Cornette et al. and again confirmed recently by Scheuerlein et al. . Therefore, surgeons are recommended to consider endoscopic, minimally invasive, or TAR as an alternative to OaCS in order to reduce postoperative wound morbidity. For lateral defects which may need a large mesh overlap, TAR should be preferred over anterior component separation techniques. ## References ## Chapter 4. key question: in which patient group is a transversus abdominis release (tar) indicated? ## G woeste, a de beaux The main goal of ventral hernia repair is reconstruction of the midline and bringing the rectus muscle together. The recurrence rate has shown to be significantly lower when a bridging of the gap with the used mesh can be avoided . A restoration of the midline is beneficial both in terms of functional results and recurrence rate. Whenever it is not possible to close the linea alba in midline ventral hernia repair, a component separation technique (CST) is indicated. The TAR technique can be used to achieve midline closure in most of the cases. With an advancement of 8 to 12 cm per side Novitsky et al. have reported a closure rate of 97.2% . When a recurrent hernia occurs after an anterior component separation (aCS) has been performed TAR has been shown to be an option for abdominal wall reconstruction in these complex cases . However, it is an import rule that aCS and TAR should never be performed simultaneously at the same side. Apart from midline incisional hernias TAR can be used for the repair of lateral hernias (L1-4). A case series of hernias after kidney transplantation has been published with low morbidity and low recurrence rate . Also a cohort of parastomal hernias has been successfully treated by stoma relocation and closure of the lateral hernia using TAR (5). Statements: TAR is effective in reconstruction of the abdominal wall in wide midline hernias (M1-5, W3) as well as in lateral hernias (L1-4). ## 3 Recommendations: Grade C TAR can be applied for abdominal wall reconstruction to achieve restoration of the midline in complex ventral hernias (M1-5, W3) Grade C TAR can be used for recurrent hernias following previous anterior component separation. ## Should the tar be done open or endoscopically? The open TAR technique has first been described by Novitsky in 42 patients with complex hernias with a mean defect size of 366 cm 2 . The largest series of open TAR (O-TAR) is published by the same author . In this retrospective series of 428 patients the incidence of surgical site events was 18.7% with 9.1% SSI and no mesh removal. The recurrence rate after 1 year was only 3.7%. Winder et al. described similar results in their retrospective review of 37 patients with 5.4% SSI and 2.7% recurrences at 2 years only in patients where a midline closure could not have been achieved . The laparoscopic technique of TAR has been published in 2016 with a cohort of 3 patients showing no complications . Also a robotic (rTAR) approach has been described . The published results of rTAR are very limited. A nationwide series of 6 patients in Brazil has been described . The authors conclude that this technique is feasible with two postoperative complications requiring reoperation. No randomized-controlled trials comparing open and laparoscopic or robotic TAR are published so far. Two retrospective studies compare the results of O-TAR and rTAR. The Cleveland group compared 38 patients who underwent rTAR with a matched historic cohort of 76 O-TAR cases . Comparing the patient characteristics, more ASA III patients were found in the O-TAR group. The robotic approach showed significant longer OR time (299 ± 95 vs. 211 ± 63, p < 0.001). The incidence of wound morbidity did not show any significant difference between the two techniques for both SSE and SSI. The rTAR group showed lower blood loss (49 ± 60 ml vs. 139 ± 149 ml, p < 0.001), less systemic complications (0 vs. 17.1%, p = 0.026), and a shorter hospital stay (1.3 ± 1.3 days vs. 6.0 ± 3.4 days, p < 0.001). A retrospective review of 102 patients, 26 rTAR and 76 O-TAR, were compared by Bittner et al. . Comparing the comorbidities, diabetes was more common in the O-TAR group (22.3% vs 0%, p = 0.01). The defect size was comparable (260 ± 209 cm 2 vs. 235 ± 107 cm 2 , p = 0.55). In this cohort the OR time was significantly longer with rTAR (287 ± 121 vs. 365 ± 78 min, p < 0.01). The surgical site events were the same in both groups (6.6% vs. 7.7%, p = 1.0). There was no significant difference in morbidity. The length of hospital stay was shorter after rTAR (3 vs. 6 days). Search items "Botox AND Hernia", "Botulinum Toxin A AND Hernia", "Component Separation AND Botulinum Toxin A", Component Separation" AND "Hernia", Progressive Pneumoperitoneum AND Hernia" A systematic search of the available literature was performed in September 2017 of Medline, PubMed, Cochrane Library, and relevant journals and reference lists using the above-listed search terms. The search found 38 articles; however, only 26 studies were suitable for this review in terms of content. ## Level 3 BTA administraƟon prior to VHR is associated with significantly less opioid analgesia use and significantly less pain. ## Level 4 Botulinum toxin A (BTA) prior to ventral hernia repair (VHR) facilitates a decrease in transverse hernia diameter, a significant reducƟon of lateral abdominal wall muscle thickness, and a significant elongaƟon of lateral abdominal wall muscles. In majority of paƟents with large ventral hernias BTA administraƟon alone enables direct fascial closure without addiƟonal component separaƟon techniques. BTA has shown to be effect when administered under ultrasound guidance between four to six weeks prior to VHR in either three or five injecƟon sites on each side. Despite BTA related side effect such as abdominal wall distension, impaired coughing and sneezing, BTA has been demonstrated to be safely administered prior to VHR without BTA related complicaƟons and adverse events. Before BTA administraƟon naƟonal medicaƟon regulaƟons should carefully be considered. Progressive pneumoperitoneum can increase the volume of the abdominal cavity by increasing the lateral abdominal wall muscle length, with the potenƟal of tension free primary fascial closure. However, PPP related complicaƟons must be considered. Tissue expander have a potenƟal as an adjunct in abdominal wall reconstrucƟon, but device related complicaƟons must be considered. # Statements ## Recommendaɵons Due to the low evidence of available data, no recommendaƟons regarding the use of Botulinum Toxin A, progressive pneumoperitoneum and Ɵssue expanders as adjunct intervenƟons in ventral hernia repair in can be made. # Introduction Techniques such as progressive pneumoperitoneum (PPP), tissue expander (TE), and-most recently-Botulinum Toxin A (BTA) have gained some interest as an adjunct in the surgical approach of large incisional hernias, to gain primary fascial closure (PFC). ## Botulinum toxin a Botulinum Toxin A (BTA) is a neurotoxic protein produced by clostridium botulinum. The paralyzing effect reaches a maximum 2 weeks after topical administration and declines gradually after 2-3 months . Several clinical studies investigated the effect of BTA on abdominal wall muscle parameters using CT scans. Ibarra-Hurtado et al. demonstrated a significant reduction of the transverse hernia defect in 12 patients. PFC was gained in six patients with BTA alone and with additional component separation (CS) in further six patients. In a subsequent study of 17 patients they demonstrated a significant reduction of lateral abdominal wall muscle thickness and the transverse hernia diameter, and a significant elongation of lateral abdominal wall muscles after BTA application . PFC was possible in all patients, of which nine needed additional CS. Farooque et al. reported a significant increase in mean length of the lateral abdominal muscles post-BTA in a case series of 8 patients achieving PFC in all cases . Also, Elstner et al. reported a significant increase in mean length of the lateral abdominal wall muscles in 27 patients, achieving PFC in all patients, with additional CS in six patients. Another study evaluated BTA administration in 56 consecutive patients undergoing VHR , of which 18 patients additionally underwent progressive pneumoperitoneum (PPP). They reported a significant increase in the lateral abdominal wall length. PFC was achieved in all patients, in 16% with additional CS. Another study from Elstner et al. investigated BTA and PPP administration in 16 patients with loss of domain undergoing VHR , achieving PFC in all patients without additional surgical dissection. Bueno-Lledó et al. performed a prospective observational study using BTA and PPP in 45 patients with loss of domain. They found a significant reduction of the VIH/VAC (volumes of the incisional hernia/volume of abdominal cavity) ratio by 14%. PFC was achieved in all patients with CS. There are seven clinical studies reporting the effect of BTA administration alone regarding avoidance of additional CS techniques . In total 150 patients were enrolled in these studies, achieving PFC with BTA alone in 78% (n = 117). Considering that BTA reaches its maximum paralyzing effect after 2 weeks , timing of BTA application seems of somewhat importance. The available clinical studies follow different timing concepts ranging from the day of surgery up to 6 weeks prior to surgery . Regarding supportive imaging guidance during BTA administration, majority of available studies report the use of ultrasound . Only on study used musculature electromyography . The injection volume, units, and concentration of BTA administration in VHR shows heterogeneity amongst available clinical studies. Three studies used 500 units of BTA in total . Six studies used a total dose of 300 units BTA . Regarding concentration and administered volume of BTA authors reported BTA concentration of 100 units/ml in 5 ml 0.9% saline solution , 10 units/ ml in 50 ml in 0.9% saline solution or 2 units/ml in 150 ml 0.9% saline solution . Regarding injections sites, authors either perform three or five injections per side. Only one study investigated the effect of BTA administration on postoperative pain in a prospective cohort of 22 patients with BTA administration prior to VHR compared with a historic matched control group (n = 66). Patients with BTA administration had significantly less pain when compared to controls . Since BTA is neurotoxic, potential complications or adverse events (AE) related to BTA application need to be addressed before injection. Only one study reported side effects of BTA administration such as abdominal wall distension, impaired coughing, and sneezing , while the majority of available clinical studies reported no BTA related adverse events or complications . There are three reviews investigating the effect of BTA in incisional hernia repair including 15 studies with 259 patients , 6 studies with 133 patients and 3 studies with 56 patients , respectively. The reviews reported PFC rates of 100% and 84% and decreases in the ventral hernia defect size . Due to the small sample sizes and heterogeneity of included studies and the lack of standardization of BTA administration the level of evidence remained low (3a). ## Progressive pneumoperitoneum The concept of progressive pneumoperitoneum (PPP) was first described 1947 by Goni Moreno and has been modified by other groups ever since. It consists of repeatedly inflating air into the abdominal cavity using sterile catheters over a few days, gaining an enlargement of the abdominal cavity to obtain hernia reduction and tension-free closure of large abdominal wall hernias. Since then a view case series and cohort studies with low number of patients have been published [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] [bib_ref] A prospective randomized study comparing suture mesh fixation versus tacker mesh fixation..., Bansal [/bib_ref] [bib_ref] Surgical treatment of parietal defects with "da Vinci" surgical robot, Vasilescu [/bib_ref] [bib_ref] Outcomes after Robotic Ventral Hernia Repair: A Study of 21,565 Patients in..., Altieri [/bib_ref]. All studies differ in terms of used gas for insufflation, patient population, timing, frequency, and volume of PPP insufflation. Investigated indications for PPP were giant incisional hernias [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] , large inguinal hernias or patients with loss of domain [bib_ref] A prospective randomized study comparing suture mesh fixation versus tacker mesh fixation..., Bansal [/bib_ref] [bib_ref] Surgical treatment of parietal defects with "da Vinci" surgical robot, Vasilescu [/bib_ref]. The timing of PPP insufflation showed differences among the available studies, starting at means between 5 and 15 days prior to surgery. PPP insufflation was repeated every day in some studies [bib_ref] A prospective randomized study comparing suture mesh fixation versus tacker mesh fixation..., Bansal [/bib_ref] , other studies had longer insufflation intervals of 2 days or more [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] [bib_ref] Surgical treatment of parietal defects with "da Vinci" surgical robot, Vasilescu [/bib_ref]. The totally applied PPP volume ranged at means from 12 to 23 l with insufflation volumes of 1000-4000 ml per session. Adverse events (AE) were reported in most studies. Most frequent AE was shoulder pain in up to 24% [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] , limiting the amount of insufflated air. Bleeding complications [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] , catheter misplacement [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] [bib_ref] A prospective randomized study comparing suture mesh fixation versus tacker mesh fixation..., Bansal [/bib_ref] , emphysema , and catheter infection [bib_ref] A prospective randomized study comparing suture mesh fixation versus tacker mesh fixation..., Bansal [/bib_ref] have also been reported. However, PPP has been demonstrated to increase the volume of the abdominal cavity [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref] [bib_ref] Surgical treatment of parietal defects with "da Vinci" surgical robot, Vasilescu [/bib_ref] by increasing the lateral abdominal wall muscle length. As highlighted in a recent review , tension-free PFC after PPP in large ventral hernias was achieved in 84% of cases with a reported recurrence rate of 7.2%. ## Tissue expanders The purpose of tissue expanders (TE) is to stretch skin or the underlying fascia allowing PFC in larger hernias. TE can be positioned subcutaneously in cases of skin loss, intermuscular between the external and internal oblique muscles in cases of large ventral hernias and intra-abdominal in cases of congenital abdominal wall defects [bib_ref] A nationwide evaluation of robotic ventral hernia surgery, Coakley [/bib_ref]. There is no consensus regarding indications, optimal technique, and TE associated risks. Recent reviews with large heterogeneity regarding study design, study population, number of patients, indication, and position of TE [bib_ref] A nationwide evaluation of robotic ventral hernia surgery, Coakley [/bib_ref] demonstrated PFC rates of 93% using TE. moperitoneum preparation (the Goni Moreno protocol) prior to large incisional hernia surgery: Volumetric, respiratory and clinical impacts. A prospective study. The following search terms were used to identify the relevant literature on robotic ventral hernia repair in July 2018. Abstracts of resulted articles were reviewed for their relevance to robotic ventral hernia repair. "Robotic ventral hernia" search identified 60 articles, 26 of which were relevant after review of the abstract. "Robotic incisional hernia" resulted in a total of 59 articles, with 3 additional relevant studies identified. Six additional articles were found using "robotic TAR," 2 of which were relevant and included. Search for "robotic transversus abdominis release" revealed no additional articles, nor did search for "robotic component separation." Finally, "robotic abdominal wall reconstruction" identified 1 additional relevant publication included in this review. # Introduction Though first described in 2003 , there has been relatively little interest in robotic surgery for hernia repair until the last several years. Of 32 relevant articles in the published literature, have been published in 2017-2018 alone. Technological interest, surgeon ergonomics, improved 3-dimensional visualization, and articulating instruments that greatly facilitate intracorporeal suturing and dissection are among the leading reasons for the exponential growth in robotic hernia repair. Disadvantages of the robotic platform are the loss of tactile feedback, relying entirely on visual cues, and intimate knowledge of tissue handling . Additionally, cost can be significant barrier to utilization and allocation of health care resources . Durability of various robotic repair techniques remains an unanswered clinical outcome. No studies to date have significantly long enough follow-up to determine hernia recurrence rates or other potential long-term complications. Several techniques have been described using the robot, including standard intraperitoneal onlay of mesh (rIPOM) similar to that of standard laparoscopic ventral hernia repair with intraperitoneal mesh (LVHR), transabdominal preperitoneal repair (rTAPP), retromuscular repair with or without transversus abdominis release (rRVHR or rTAR), and most recently a retromuscular repair using an extended totally extraperitoneal (eTEP) approach. ## Robotic intraperitoneal onlay of mesh (ripom) Statements: rIPOM ## Level 2c RoboƟc IPOM results in similar rates of surgical site occurrences and infecƟons compared to standard LVHR. ## Level 3 RoboƟc IPOM results in shorter length of stay compared to standard LVHR, with similar rates of readmission, reoperaƟon and other postoperaƟve complicaƟons. ## Level 3 RoboƟc IPOM reliably facilitates closure of the hernia defect. ## Level 3 OperaƟve Ɵme for rIPOM is significantly longer than standard LVHR. ## Level 5 RoboƟc IPOM may result in decreased post-operaƟve and chronic pain compared to standard LVHR with transfascial suture or tack fixaƟon. ## Recommendaɵons: ripom Grade B RoboƟc IPOM may be considered comparable to standard LVHR in most clinical outcomes at the expense of increased operaƟve Ɵme. Follow-up is insufficient, to adequately compare risk of hernia recurrence. Grade C RoboƟc IPOM improves the ability to close the hernia defect during minimally invasive hernia repair. Grade C Hospital LOS may be reduced with rIPOM compared to standard LVHR. Studies lack appropriate methodology and power, with significant heterogeneity in technique and perioperaƟve care, to clearly demonstrate the generalizability of this finding. The majority of reported cases involve the use of the robot to perform a standard laparoscopic approach with placement of mesh in an intraperitoneal position, with the addition of standard closure of the defect. The primary benefit of this approach over LVHR is the ability to reliably close the hernia defect. The benefits of defect closure have been demonstrated in a number of studies, primarily in reducing the rate of seroma formation, and possibly reduction in hernia recurrence . Abdominal wall tension required to close the hernia defect may be offset by additional transfascial suture fixation or use of myofascial release . Comparative series of rIPOM vs LVHR indicate higher rates of fascial closure for robotic repair, but all are retrospective series without a protocolized approach to defect closure [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref]. Operative time is significantly longer with rIPOM compared to LVHR in all four comparative trials [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref]. This is likely associated with the differences in technique, primarily in defect closure and suture fixation of the mesh rather than tacks, and the learning curve for robotic repair. Intracorporeal suture fixation of the mesh, rather than standard tack or transabdominal wall sutures, is often touted to reduce postoperative and chronic pain compared to LVHR . While there is some evidence that traditional fixation techniques, and the use of transfascial sutures in particular, may lead to greater postoperative pain [bib_ref] A prospective randomized study comparing suture mesh fixation versus tacker mesh fixation..., Bansal [/bib_ref] , data are lacking to support this finding. There is, however, a consistently demonstrated reduction in hospital length of stay, which may be a surrogate marker for decreased early postoperative pain following rIPOM. The only comparative study evaluating pain as a specific secondary outcome showed no difference in narcotic use between LVHR and rRVHR/rTAR . Rates of clinically significant wound complications are largely unaffected by rIPOM compared to LVHR. Rate of SSI is reported between 0.9 and 3.8%, with a single outlier study demonstrating a 9.1% rate of SSI (single patient in a case series of 11 patients) [bib_ref] Surgical treatment of parietal defects with "da Vinci" surgical robot, Vasilescu [/bib_ref]. Surgical site occurrences are similarly low with rIPOM (0.9-3.8%) [bib_ref] Surgical treatment of parietal defects with "da Vinci" surgical robot, Vasilescu [/bib_ref]. One study demonstrated a lower rate of SSO after rIPOM [bib_ref] Multicenter review of robotic versus laparoscopic ventral hernia repair: is there a..., Walker [/bib_ref]. No differences were seen in patients requiring procedural intervention in the treatment of SSO or SSI in these studies. Overall complications were procedures improving rates of readmission and LOS over OVHR [bib_ref] Robotic ventral hernia repair is not superior to laparoscopic: a national database..., Armijo [/bib_ref]. This study also cannot account for specific surgical technique. Hospital length of stay ranges from 0 to 2.5 days for rIPOM. Three of five comparative studies demonstrated a statistically significant difference in LOS . Prabhu et al. analyzed 186 rIPOM vs 452 LVHR in the Americas Hernia Society Quality Collaborative (AHSQC) database, demonstrating a reduction in LOS from 1 to 0 days with rIPOM (p < 0.001) . Alteiri et al. similarly demonstrated a shorter LOS after RVHR [bib_ref] Outcomes after Robotic Ventral Hernia Repair: A Study of 21,565 Patients in..., Altieri [/bib_ref]. Warren et al. demonstrated a shorter median LOS with rRVHR compared to IPOM LVHR . No inferences can be drawn regarding hernia recurrence due to lack of long-term follow-up. ## Robotic transabdominal preperitoneal repair (rtapp) reduced for rVHR compared to LVHR after propensity score analysis from the New York State Planning and Research Cooperative System [bib_ref] Outcomes after Robotic Ventral Hernia Repair: A Study of 21,565 Patients in..., Altieri [/bib_ref]. This study does not account for specific technique of RVHR, however. Similarly, evaluation of the National Inpatient Sample (NIS) demonstrates the safety and efficacy of rVHR, with similar rates of minor and major complications compared to LVHR [bib_ref] A nationwide evaluation of robotic ventral hernia surgery, Coakley [/bib_ref]. Interrogation of the Vizient database demonstrated no benefit of rVHR over LVHR in clinical outcomes, with both Statements: rTAPP Mesh placed in an extraperitoneal posiƟon reduces the potenƟal for long-term mesh-related complicaƟons, parƟcularly in the event of subsequent abdominal operaƟons. ## Level 4 RoboƟc TAPP is safe and technically feasible for repair of small ventral hernias. ## Level 5 RoboƟc TAPP may lessen the potenƟal for long-term mesh-related complicaƟons of intraperitoneal mesh. ## Recommendaɵons: rtapp Grade D RoboƟc TAPP is a safe and effecƟve alternaƟve to rIPOM or standard IPOM LVHR for small hernias. Grade D RoboƟc TAPP allows placement of mesh in an extraperitoneal posiƟon, which may reduce long-term mesh-related complicaƟons. Placement of mesh in an extraperitoneal position may reduce long-term mesh-related complications compared to standard IPOM, particularly in the event of subsequent abdominal operations [bib_ref] Risk of complications from enterotomy or unplanned bowel resection during elective hernia..., Gray [/bib_ref] [bib_ref] Intraperitoneal Polypropylene Mesh Hernia Repair Complicates Subsequent Abdominal Surgery, Halm [/bib_ref] [bib_ref] Risks of subsequent abdominal operations after laparoscopic ventral hernia repair, Patel [/bib_ref] [bib_ref] Prospective evaluation of adhesion characteristics to intraperitoneal mesh and adhesiolysis-related complications during..., Jenkins [/bib_ref] [bib_ref] Effect of mesh type and position on subsequent abdominal operations after incisional..., Snyder [/bib_ref] [bib_ref] Intraluminal migration of mesh following incisional hernia repair, Steinhagen [/bib_ref]. Laparoscopic TAPP repair of ventral hernia has been described, with favorable results [bib_ref] Laparoscopic transabdominal preperitoneal repair of ventral hernia: a step towards physiological repair, Prasad [/bib_ref]. The delicate dissection of the peritoneum may be facilitated by robotic instrumentation. Three studies have been published to date examining the rTAPP approach. Sugiyama et al. used an rTAPP approach for repair of ventral hernia in 1 3 three patients. Mean operative time was 164 min, with no reported operative or perioperative complications. Orthopoulos et al. reported rTAPP repair in 54 patients. Mean OR time was 73 min, with two reported complications; a seroma requiring percutaneous drainage and rectus sheath hematoma resulting in readmission and transfusion [bib_ref] Feasibility of Robotic-Assisted Transabdominal Preperitoneal Ventral Hernia Repair, Orthopoulos [/bib_ref]. Finally, Kennedy et al. compared 27 rIPOM to 36 rTAPP patients. Operative time was similar between groups, as were minor perioperative complications [bib_ref] Robotic TAPP Ventral Hernia Repair: Early Lessons Learned at an Inner City..., Kennedy [/bib_ref]. No inferences can be drawn regarding hernia recurrence due to lack of longterm follow-up. Robotic retromuscular ventral hernia repair (rRVHR), robotic transversus abdominis release (rTAR), and robotic extended totally extraperitoneal (eTEP) [formula] Statements: rRVHR / rTAR / eTEP Level 2C [/formula] RoboƟc retromuscular ventral hernia repair with or without TAR significantly reduces hospital length of stay compared to open VHR (OVHR). ## Level 3 OperaƟve Ɵme for rRVHR / rTAR is significantly longer than OVHR or standard LVHR. ## Level 3 Hernia defect closure and extraperitoneal mesh placement is reliably achieved with rRVHR / rTAR. ## Level 4 Incidence of SSI may be reduced for RRVHR / rTAR compared to OVHR. Incidence of SSO is similar, with the majority of cases involving seroma requiring no procedural intervenƟon. ## Recommendaɵons: rrvhr / rtar / etep Grade B Significant reducƟon is LOS is possible with rVHR / rTAR and should be considered in paƟents with ventral / incisional hernias. Grade C ReducƟon is SSI may be achieved with rVHR / rTAR / eTEP, but larger studies are necessary to clearly demonstrate the significance of this outcome. Grade C Recurrence rates appear similar to OVHR and LVHR. However, long-term follow-up is lacking. Grade D eTEP approach may reduce the need for addiƟonal myofascial release compared to rTAR, which more closely approximates the stepwise approach for myofascial release as performed in OVHR. Perhaps the greatest promise for robotic hernia repair is the capability of this platform to duplicate an open retromuscular hernia repair, widely considered to be the standard for OVHR. The first description of this approach was reported in 2012 [bib_ref] Procedimento de Rives/Stoppa modificado robô-assistido para correção de hérnias ventrais da linha..., Abdalla [/bib_ref]. The potential advantage of this approach is the ability to utilize the robot to perform myofascial release of the rectus abdominis and/or transversus abdominis to facilitate medialization of the hernia defect for closure under reduced tension and placement of mesh in the retromuscular (extraperitoneal) space. The first study reporting outcomes of rRVHR/rTAR demonstrated a reduction in LOS compared to standard LVHR (1 vs. 2 days; p = 0.004), with similar rates of SSI, SSO requiring procedural intervention (SSOPI), and reliable closure of the hernia defect. Operative time was significantly longer with robotic repair [bib_ref] Comparative analysis of open and robotic transversus abdominis release for ventral hernia..., Bittner [/bib_ref]. Operative time was significantly longer for rRVHR/rTAR in each of these studies. No inferences can be drawn regarding hernia recurrence due to lack of long-term follow-up. ## Costs # Statement: costs ## Level 3 RoboƟc requires significant capital expense, and is associated with higher cost compared to LVHR, and possibly higher direct cost than OVHR. ## Recommendaɵon: cost Grade D Cost calculaƟons are complex. Further study is needed to understand the cost of rVHR in its various forms and in relaƟon to potenƟal differences in clinical outcomes compared to laparoscopic and open repair. Cost is the factor most often used to critique robotic surgery across all disciplines. The capital cost of equipment alone often exceeds $2 million, with additional costs for service contracts, disposables, and instruments. In their review of the Vizient database, Armijo et al. found the cost of rVHR significantly greater than LVHR or OVHR [bib_ref] Robotic ventral hernia repair is not superior to laparoscopic: a national database..., Armijo [/bib_ref]. Charges for RVHR were significantly higher as reported by the National Inpatient Sample as well [bib_ref] A nationwide evaluation of robotic ventral hernia surgery, Coakley [/bib_ref]. However, charges and cost are different measures and cannot account for complexity of health care costs. Cost can vary greatly from hospital to hospital depending on payment contracts, Group Purchasing Organizations, type of procedure performed, coding, and reimbursement. Internationally, the diversity of health care organization is such that a single study will likely be unable to truly predict cost to any individual hospital or health system. ## Conflict of interest As with any new technology or technique, early literature must be interpreted in the context of the emerging technology itself, the larger changes in the given field of study, and the method of dissemination of the technique. Novel surgical techniques are quite often promulgated through industry, making author conflict of interest (COI) an important factor in interpreting the literature. In the case of rVHR, this is chiefly through Intuitive Surgical ® as this has been the only available robotic platform available for clinical use until recently. Patel et al. published an analysis of payments to published study authors from Intuitive Surgical ® , finding that only 20.8% of authors disclosed payments from Intuitive, and nearly 64% of studies had at least one author who received payment despite no COI indicated. These discrepancies between reported and actual payments correlated with a higher likelihood of recommending robotic surgery [bib_ref] Assessment of conflicts of interest in robotic surgical studies: validating author's declarations..., Patel [/bib_ref]. This study was not specific to VHR, many of the articles cited in this work include statements of payment received from Intuitive Surgical ® . While this does not automatically invalidate study findings, the discerning reader should carefully scrutinize study results. Author transparency is paramount. # Introduction Lateral abdominal wall hernias comprise primary and secondary defects of the lumbar, subcostal, flank, and iliac region (EHS classification). Compared to midline hernias (hernias of the rectus compartment) primary and incisional lateral abdominal wall hernias are rare. Consequently, the evidence guiding the surgical treatment of lateral abdominal wall hernias is scant. The lumbar region is divided into the superior and inferior lumbar space. Primary lumbar hernias of the superior space are denominated Grynfeltt hernia and those of the lower space Petit hernia. The boundaries of the inferior lumbar hernia are the latissimus dorsi muscle posteriorly, the external oblique muscle anteriorly, and the iliac crest inferiorly. The boundaries of the superior lumbar hernia are the 12th rib superiorly, the internal oblique muscle anteriorly, and the erector spinae muscle posteriorly. Lateral hernias often are located in more than one region of the lateral compartment. The first IEHS guidelines included 12 papers, 11 case series with more than five patients and one small RCT which included patients and compared open with laparoscopic repair. In total 123 patients were evaluated. The level of evidence of all trials was 4 and there were no reports on suture repair. The infection rate after open repair varied between 0 and 25% while no infections were reported after laparoscopic operations. The rate of intraoperative visceral damage was 0 to 4% in open and 0 to 15% in laparoscopic repair, respectively. One retrospective case series of 73 patients with laparoscopic repair of lateral incisional hernias with a medium follow-up of 62 months reported a total recurrence rate of 8% and 25% in the subgroup of subcostal incisional hernias . The authors concluded that a defect size of > 15 cm was a risk factor of recurrence. Only four case series reported on chronic pain . However, according to a systematic review chronic pain rates after open and laparoscopic lateral abdominal wall hernia repair seem to be comparable. Grade B For the treatment of Spieghelian hernias laparoendoscopic mesh repair should be preferred because of lower postoperaƟve morbidity and reduced length of hospital stay. The Spiegelian hernia first escribed anatomically by Adriaan van den Spieghel (1578-1625) is located at the level of the semicircular line where the fascias of the oblique and transversus muscles begin to split into separate layers of the abdominal musculature. Spiegelian hernias (SH) account for 1% to 2% of abdominal wall hernias. Since the advent of minimally invasive surgery laparoscopic methods have become increasingly popular with various techniques being described in the literature. Since 2012 thirtytwo case series with 5 or more patients were included in this review. No randomized-controlled trials on the treatment of SH were identified. One systematic review was published in 2016 which included 237 SHs that were repaired by various techniques. Intraperitoneal onlay mesh technique was the most popular repair method with minimal complications and recurrences reported in all techniques. # Conclusions There are a number of laparoscopic techniques available to the surgeon repairing a SH. Overall, laparoscopic repair of the SH is a safe and acceptable method. members, chief residents, fellows, and surgical residents . They commented that the traditional "see one, do one, teach one" method and prevalent methods of training is inadequate for learning hernia repair. In addition to supervised surgery, most trainees prefer new learning methods such as simulation, web-based training, hands on laboratory, and master videos. The consensus was that educational programs should be comprehensive, dynamic, and flexible to employ various media to address the deficits in hernia surgery training and patient care. D'Angelo et al., in their multi-center study, tried to evaluate effect of time away from clinical work on clinical skills during dedicated research rotations in surgical residency . Simulation-based training in LVHR, along with others procedures was used to assess improvements in perception of skill decay. They concluded that most residents during their research postings expect moderate skills decay in LVHR, and hence suggested to incorporate simulation-based training in the curriculum during dedicated research time or research fellowships to maintain trainees' surgical skills. Sonnadara et al. similarly suggested that competency-based training rather than time spent in training should be used to assess a surgeon's skill level . A Cochrane systemic review suggested that virtual reality training when compared to no training or box-trainer training reduces operating time and improves operative performance of surgical trainees with limited laparoscopic experience . In today's day and age, it is necessary for residency and fellowship training programs to incorporate simulationbased training and virtual reality training in the curriculum along with surgical training under supervision. Specific simulation training for ventral and incisional hernia repair will benefit the trainee to gain hernia specific skills and also prevent skill decay. [fig] 25: Moore AM, Anderson LN, Chen DC (2016) Laparoscopic Stapled Sublay Repair With Self-Gripping Mesh: A Simplified Technique for Minimally Invasive Extraperitoneal Ventral Hernia Repair. Surg Technol Int. 2016 Oct 26;29:131-139. (4) Statements Level 2 Surgical correcƟon of diastasis recƟ improves funcƟonal ability and quality of life compared to a supervised exercise program. [/fig] [fig] Level 3: Both open and minimally invasive TAR are safe procedures. rTAR is associated with longer operative time compared to O-TAR. rTAR can reduce postoperative length of hospital stay compared to O-TAR. O-TAR and rTAR show the same incidence of postoperative wound morbidity. Grade C TAR can be performed open, laparoscopic and robotic transversus abdominis release for ventral hernia repair. Surg Endosc 32:727-734. (4) Chapter 5. Key Question: The role of preoperative adjunct interventions in ventral hernia repair H. Hoffmann, P. Kirchhoff, J. Kukleta, W. Reinpold [/fig] [table] Table 1: Classification of new techniques for minimal invasive extraperitoneal mesh repair of abdominal wall ventral hernias [/table] [table] Table 2: Publications on laparoscopic lateral abdominal wall hernia repair 2012 to 2018[11][12][13][14] Level 2BLaparoendoscopic repair of Spieghelian hernias is superior to open repair because of reduced morbidity rates and length of hospital stayLevel 4 Comparable results are achieved with laparoscopic IPOM and laparoendoscopic preperitoneal techniques [/table]	None	None	None
3262d209a8ff28d2434b8dfc8f9df2099a2071c7	pubmed	Cutaneous melanoma	Cutaneous melanoma Cutaneous melanoma is a highly malignant tumour. The incidence has increased dramatically over the last few decades and is now estimated at between 4-5000 new cases per year in France.The term 'naevus', unless otherwise specified, refers to an acquired or congenital benign melanocytic tumour (commonly known as a naevus, naevi or mole). A melanoma can develop de novo, or within a pre-existing benign naevus. A melanoma can arise in any area containing melanocytes, but approximately 90% are cutaneous tumours.These recommendations refer to localized primary tumours, those presenting with regional nodes and those with distant metastases. The management of mucosal, visceral and ophthalmic melanomas is not covered.These recommendations are based on literature published until the end of 1998. Data published since does not change these recommendations. An update is planned for early 2001.RISK FACTORS AND PREVENTIONThe identification of risk factors is useful for the prevention of melanoma. Two types of risk factors have been identified: individual (constitutional) factors (photosensitivity, numerous naevi, atypical naevi, giant congenital naevi, personal or family history of melanoma) and behavioural factors (excess exposure to sun or artificial ultraviolet rays) (level of evidence A).The primary prevention of melanoma depends on a reduction in exposure to ultraviolet rays, either solar or artificial. Secondary prevention is based on the early diagnosis of a melanoma at a curable stage and the surveillance of high-risk patients.DIAGNOSIS AND HISTOPATHOLOGICAL ASSESSMENTDiagnosis is the first step in the management of a melanoma (standard). Certain clinical criteria in a pigmented cutaneous lesion are suggestive of malignancy (standard). The criteria are classified as follows: q criteria A : asymmetry q criteria B : irregular borders q criteria C : heterogeneous colour q criteria D : large diameter q criteria E : evolution (recent change) -this criteria must coexist with at least one of the preceding criteria. Some authors use the three change criteria: change in size, colour and shape. Other authors have proposed a list of seven criteria: three major criteria (change in size, change in colour, change in shape) and four minor criteria (diameter greater than 7 mm, hypersensitivity, bleeding and inflammation). Epiluminescence microscopy (ELM), or dermatoscopy, can improve the clinical diagnosis of pigmented lesions. It can differentiate a melanocytic from a non-melanocytic pigmented lesion such as a seborrheic keratosis, pigmented basal-cell carcinoma or haemangioma. Dermatoscopy for the early diagnosis of a melanoma should only be used by those familiar with the technique. Its accuracy depends on the experience of the dermatologist. Currently, it cannot be recommended as a routine technique. The standard practice for the management of cutaneous melanocytic lesions thought to be malignant is a limited but complete excision under local anaesthetic of the lesion with a narrow rim (2 mm) of normal skin. The incision will usually be elliptical with the long axis parallel to the skin lines to allow for re-excision with minimal skin loss. If the initial excision is incorrect (for example a transverse incision across a forearm rather than a longitudinal incision down the arm) a skin graft may be necessary at the time of re-excision. Cutaneous lesions should be excised rather than biopsied for the following reasons: q if the lesion is benign, there is no need for further treatment q there is a risk of misdiagnosis if a melanocytic lesion is only partially examined q an examination of the entire lesion is necessary to assess all histological parameters, maximum thickness in particular. The thickness of the lesion and the clearance of the margins can only be determined by histological examination. Tissue destruction can compromise the final diagnosis and the assessment of histological prognostic factors. A scalpel rather than a laser or electro-coagulation should therefore be used for the excision. All excisional or incisional biopsies must be sent to the pathologist (standard). Frozen sections must be discouraged. Excision margins should be documented in the operation note. Standard histological examination is generally sufficient. The amount of information that can be obtained from the excised sample depends on the quality of the specimen. The age, the sex of the patient and the site of the lesion are mandatory for the histopathological interpretation. Immunohistochemistry alone cannot provide a diagnosis of malignancy and should not be used routinely. It can, however, confirm the melanocytic nature of a cutaneous lesion with an unusual presentation, whether it is primary or secondary (particularly for non-pigmented lesions) and can improve the detection of occult metastases in lymph nodes. The histopathological report must include at least (NIH consensus conference of 1992 and the French Consensus Conference of 1995) the: q diagnosis of the melanocytic nature of the lesion and confirmation of its malignancy q maximum tumour thickness in millimetres (according to Breslow's method). q assessment of completeness of excision of invasive and in situ components; microscopic measurement of the shortest extent of clearance q level of invasion (Clark) q presence and extent of regression q presence and extent of ulceration. Optional parameters are: q histological type and special variants q pre-existing lesion q mitotic rate q vascular invasion q neurotropism q cell type q tumour lymphocyte infiltration q growth phase; vertical or radial. A complete clinical examination is standard for an isolated primary melanoma to detect a second primary melanoma and/or metastases, including nodal metastases. The clinical examination must include an examination of the entire skin surface (including scalp) and of all regional nodes (standard). In the case of an isolated primary melanoma with no clinically detectable nodes, there is no need for further investigations. Studies have shown that the risk of nodal involvement is correlated with the maximum thickness and level of invasion of the primary tumour. There is no indication for routine nodal dissection for diagnosis or staging; this has no impact on survival and the surgery carries significant morbidity. There is no effective adjuvant treatment. An ultrasound of superficial regional nodes is indicated for cases of clinical uncertainty (option). Sentinel nodes can be identified by blue dye or a radio-labelled colloid marker. This is not a routine procedure, since no gain in survival has been demonstrated after nodal dissection and/or with adjuvant treatment in the case of tumour involvement of a sentinel node. Nodes can be identified electively with a morbidity of almost zero. These techniques facilitate planned lymph-node dissection to detect microscopic metastases. Technetium lymphoscintigraphy can localize nodal drainage pathways for melanomas situated in medial regions . This is only of interest if prophylactic nodal dissection is planned within a prospective study (e.g. the sentinel node study according to Morton's technique). In cases of regional or metastatic nodal involvement, a search for other metastatic lesions is justified to guide subsequent therapy. In about 10% of cases distant asymptomatic metastases are discovered at the time of diagnosis of involved nodes. There is no consensus regarding the efficacy of imaging techniques to detect distant metastases; abdominal, thoracic and cerebral CT scans seem the most useful. Other investigations can be made according to physical signs. Immunoscintigraphy is still in the process of development and is not recommended in routine practice to demonstrate clinically undetectable metastases. For patients with metastatic disease at any site at presentation, a search for the primary tumour must include a careful history of any previous treatment to a cutaneous lesion and an examination of the whole body (standard). In the case of an isolated node, cytological analysis of a sample obtained by fine-needle aspiratation can be considered as a diagnostic, aid but a definitive diagnosis can only be made following histopathological examination of tissue (standard). If a pigmented lesion is found to contain melanin by histochemistry, there is no need for immunohistochemistry. If the lesion is achromic, immunohistochemistry is necessary to confirm melanocytic origin. Histopathological examination of lymph nodes requires at least one section through the centre of each node (standard). The number of nodes examined, the number of involved nodes and any capsular rupture must be reported (standard). If there is nodal involvement, the number of nodes greater than 3 cm should be defined by TNM classification criteria. If there is no evidence of nodal invasion on microscopy, immunohistochemistry should be used for the detection of occult metastases. Polymerase chain reaction (PCR) is not a validated technique in melanoma and should not be used routinely. ## Classification and prognostic factors Five different international classifications are accepted to define the clinical stages of melanoma. The AJCC/UICC classification (option) is used most often in English-speaking countries and in the literature. For single excisable melanomas, the Breslow index is the most powerful and most commonly used prognostic factor (level of evidence A). There is a close correlation between survival and the Breslow index. For thin melanomas (Breslow index less than 1 mm), the level of invasion (Clark's level) has prognostic value. Other clinical criteria (sex, age, site of the lesion) have prognostic value (level of evidence C), but these parameters have complex inter-relations and their value is low when compared to that of the Breslow index. When a melanoma presents with locoregional node involvement, the number of involved nodes is the most important prognostic factor (level of evidence B). For patients with metastatic melanoma, the number of metastatic sites and the time interval between the primary tumour and the metastases appear/to be the most important prognostic factors. ## Treatment modalities ## Surgery The standard treatment of a localized primary melanoma is surgery [fig_ref] Figure 1: surgery [/fig_ref]. After initial surgery, a wider second excision may be necessary with margins depending on the results of the initial histological examination (standard). These margins will vary according to the depth of the tumour, specifically the Breslow index (standard). In France there are two guidelines which are used to base the extent of excision margins; those established by ANDEM in 1994 and those of the French consensus conference in 1995. The ANDEM system is recommended on the basis of simplicity and compatability with published data (level of evidence B). The required margin of excision is dependent on the thickness of the lesion: q melanoma in situ (non invasive): margin of 0.5 cm from edge to edge q Breslow melanoma ≤ 1 mm: margin of 1 cm q melanoma with Breslow ≥ 1 mm, ≤ 2 mm: margins of 1-2 cm q melanoma with Breslow ≥ 2 mm, ≤ 4 mm: margins of 2 cm q melanoma with Breslow > 4 mm: margins of 3 cm. For melanomas of Breslow thickness less than 1 mm, the same recommendations were made at the time of the NIH consensus conference in 1992. There is no consensus dealing with the excision margins in cases where tumour regression is noted on histological examination. The excision margins should be those for lesions in the category immediately above the actual thickness. The value of regional nodal dissection is controversial and the data in the literature are contradictory. The theoretical aims of prophylactic nodal dissection are to improve overal survival (by diminishing the risk of metastases by spread from involved nodes) and to provide prognostic information (although this will not be useful until there is effective adjuvant treatment). Nodal dissection should only be considered for lesions on the limbs where there is a single route of lymph drainage. Surgery is always associated with some morbidity, especially in the lower limbs. The early complication rate is between 10-15% in the best series of inguinal dissection. The rate of late lymphoedema is between 6-15% in the lower limbs and 6% in the upper limbs. At the present time, routine nodal dissection after excision of an isolated cutaneous melanoma is not recommended (level of evidence C). ## Radiotherapy There is no indication for radiotherapy in operable melanoma excised with adequate margins (standard) [fig_ref] Figure 1: surgery [/fig_ref]. ## Adjuvant therapy There is no survival advantage when adjuvant chemotherapy is given after excision of an isolated tumour or after excision of nodal metastases (level of evidence B). Adjuvant chemotherapy should not be given outside a trial. No survival advantage has been shown from the use of hormone therapy (progestogens) in the adjuvant setting (level of evidence B). Adjuvant hormone therapy should not be used outside a study. The results of controlled studies of immunotherapy in the adjuvant setting have not been consistent, but suggest that a benefit may be possible for certain sub-groups of patients (level of evidence C). Adjuvant intra-arterial infusions have not been shown to be of definite benefit (level of evidence B). Intra-arterial perfusion therapy with hyperthermia and/or chemotherapy and/or immunotherapy should not be considered as primary therapy and must only be undertaken by experienced teams within controlled studies. ## Therapeutic strategy ## Treatment of localized primary melanoma The standard treatment of a localized primary melanoma is surgery [fig_ref] Figure 1: surgery [/fig_ref]. After initial surgery, a wider second excision may be necessary with margins depending on the results of the initial histological examination (standard). These margins will vary according to the depth of the tumour, specifically the Breslow index (standard). There is no indication for radiotherapy (standard) or adjuvant chemotherapy (level of incidence B, standard). ## Treatment of regional node involvement The standard treatment of patients presenting with regional node involvement, whether it be the presenting feature, a synchronous presentation with the primary tumour, or the first indication of recurrence, is surgical dissection of involved nodes . No other treatment has been shown to be superior (level of evidence B). The appropriate surgery is nodal dissection, although there is no consensus regarding its extent. After complete nodal dissection, there is no indication for any further treatment (level of evidence B). Adjuvant radiotherapy has not been shown to be of benefit after complete nodal clearance (level of evidence C). Radiotherapy is an option in the case of incomplete nodal clearance, for example in the case of fixed nodes, extensive invasion or capsular disruption. Controlled studies of adjuvant immunotherapy have given inconsistent results but suggest that there may be a benefit in subgroups of patients, in particular those patients with metastatic regional nodes (level of evidence C). Adjuvant therapy with interferon has shown a significant advantage in terms of overall survival in one study (level of evidence C), which was not confirmed by a subsequent study. This therapy has considerable toxicity and patients must be strictly selected and closely followed during treatment. Adjuvant immunotherapy is an option for operable patients with regional nodal metastases, but cannot be recommended ## Figure 2 Treatment of cutaneous melanoma with regional node involvement as primary/first-line treatment in operable melanoma with or without involved nodes. Further randomized controlled studies are required to confirm the potential role of adjuvant immunotherapy. ## Treatment of an isolated local recurrence Surgical excision is the standard treatment. ## Treatment of metastatic melanoma There is no standard therapy for metastatic melanoma . With the possible exception of the resection of in-transit metastases or slowly developing single metastases, there is no curative treatment. Therapy should be adapted according to the number of lesions, the rate of progression of the disease and the performance status of the patient. Some palliative chemotherapy and immunotherapy protocols have resulted in significant tumour regression with a median duration of remission of 4 to 5 months. Conventional palliative chemotherapy is dacarbazine. Polychemotherapy has not been shown to be superior to dacarbazine alone with respect to survival (level of evidence B). The exact role of immunotherapy in the treatment of metastatic disease remains to be determined. ## Treatment of a hutchinson's melanotic freckle or lentigo maligna (melanoma in situ) The standard treatment is surgical excision with a margin of 0.5 cm (see . ## Treatment of in-transit metastases The standard treatment for in-transit metastases (more than 3-5 cm from the primary lesion) is surgical excision . In the case of very numerous metastases, treatment by perfusion of an isolated limb can be considered (level of evidence C). This should only be done by a specialized team trained in this technique. ## Follow-up Follow-up is based on clinical examination (standard). Selfsurveillance should be encouraged by the provision of relevant patient information (standard). Surveillance is indicated in all cases throughout life (standard), especially in the case of an isolated operable melanoma. There is no case for routine blood tests or imaging in the absence of clinical signs or symptoms. There is no international consensus as to the pattern of follow-up. In France, the recommendations for follow-up are as follows. ## Melanoma in situ After complete excision with adequate excision margins, the risk of local recurrence is negligible. Patients should be followed annually throughout life in order to detect a second melanoma. ## Melanoma with a breslow index of less than 1.5 mm Follow-up every 6 months for 10 years, then annually throughout life. Melanoma with a Breslow index of greater than 1.5 mm or with histological regression whatever the depth, or with a level of Clark equal to IV or V Follow-up every 3 months for 4 years, every 6 months for years 5-10, then annually throughout life. The rate of recurrence beyond the fifth year is the same whatever the Breslow index of the initial tumour. ## Advanced disease There is no consensus regarding the approach to follow-up. [fig] Figure 1: surgery: repeat surgery with margins according to the tumour • no nodal clearance • no adjuvant treatment Follow-up Treatment of primary localized cutaneous melanoma [/fig] [fig] Figure 3, Figure 4, Figure 5: Treatment of metastatic melonoma HUTCHINSON'S MELANOTIC FRECKLE OR LENTIGO MALIGNA Standard surgery with a margin of 0.5 cm Option if complete exicision is impossible or contra-indicated: Treatment of Hutchinsons melanotic freckle MELANOMA WITH IN-TRANSIT METASTASES Standard surgery with complete excision of all lesions Option intra-arterial chemotherapy to isolated limb ± hyperthermia Follow-up Treatment of melanoma with in-transit metastases [/fig]	None	https://www.nature.com/articles/6691771.pdf	Cutaneous melanoma is a highly malignant tumour. The incid has increased dramatically over the last few decades and is estimated at between 4–5000 new cases per year in France. The term ‘naevus’, unless otherwise specified, refers to acquired or congenital benign melanocytic tumour (commo known as a naevus, naevi or mole). A melanoma can develo novo, or within a pre-existing benign naevus. A melanoma arise in any area containing melanocytes, but approximately are cutaneous tumours. These recommendations refer to localized primary tumo those presenting with regional nodes and those with di metastases. The management of mucosal, visceral and ophth melanomas is not covered. These recommendations are based on literature published the end of 1998. Data published since does not change recommendations. An update is planned for early 2001.
849944605ac1e4f23d7c7010589884fd9c46b873	pubmed	I Cardiovascular Prevention Guideline of the Brazilian Society of Cardiology - Executive Summary	I Cardiovascular Prevention Guideline of the Brazilian Society of Cardiology - Executive Summary Atherosclerotic coronary artery, cerebrovascular or obstructive peripheral diseases with clinical manifestations (cardiovascular events) and still in the subclinical form, documented by use of diagnostic methodology; Arterial revascularization procedures;Type 1 and type 2 diabetes mellitus;Chronic kidney disease. # Introduction Brazil currently faces a major health challenge: the pandemic scenario of cardiovascular morbidity and mortality. According to Brazilian Health Ministry data, 326,000 deaths due to cardiovascular diseases (CVD) occurred in 2010, corresponding to approximately 1,000 deaths/day, 200,000 deaths due exclusively to ischemic heart and cerebrovascular diseases, reflecting a gloomy scenario far from the minimally acceptable control. This current scenario can be attributed to many reasons, such as the insufficiency and inadequacy of public health policies for CVD prevention, leading to the well-known lack of infrastructure in primary health care, hindering the fight against preventable affections, mainly in the neediest areas. In addition, it is worth mentioning the well-known sociocultural factors, such as the excessive consumption of high-caloric foods in association with physical inactivity, and, consequently, the development of obesity and diabetes, and excessive salt intake. Those factors contribute to the development of arterial hypertension, being decisive to the high prevalence of CVD and no opportunity to provide instructions on lifestyle changes. The medical societies, in partnership with governments and universities, have endeavored to elaborate valuable documents containing strategic plans of CVD prevention and fight. However, simple and objective guidelines, which can be easily accessed and managed by health care personnel, are required to implement that which has been long discussed by specialists and scientists, although with modest results. For the first time, guidelines and consensus documents, most of which already published in several other guidelines of specialties, have been gathered in a single document to provide the clinician with easy access to the recommendations for primary and secondary CVD prevention. For that, the Brazilian Society of Cardiology (SBC) has gathered specialized physicians with large experience in preventive actions to elaborate the present document. Chapter 1 presents the cardiovascular risk stratification for atherosclerosis prevention and treatment. In this chapter, the authors discuss questions such as acute coronary event as the first manifestation of atherosclerotic disease in at least half of the individuals with that complication. Thus, the identification of predisposed asymptomatic individuals is crucial to the effective prevention with correct definition of therapeutic goals, especially the criteria to identify high-risk patients . The authors discuss the so-called risk scores, through which the overall risk is calculated, enabling the clinician to quantify and qualify the patients' individual risk, for both women [fig_ref] Table 2 -: Scoring according to overall risk for women HDL-C [/fig_ref] and men [fig_ref] Table 4 -: Scoring according to overall risk for men [/fig_ref]. The combination of those different scores allow the clinician to better estimate the risk, stratifying it gradually: presence of significant atherosclerotic disease or its equivalents; calculation of risk score; aggravating factors (Chart 1) and risk stratification based on lifespan. The authors propose a simplified algorithm for cardiovascular risk stratification, which is exemplified in . The recommendations listed as class I and level of evidence A are few, because the other recommendations still require more comprehensive studies with long-term follow-up [fig_ref] Table 6 -: Classification of recommendation and level of evidence for risk stratification in cardiovascular... [/fig_ref]. Chapter 2 approaches tobacco smoking, the major avoidable risk factor. It is known that 50% of the deaths of smokers, most of which caused by CVD, could be prevented with smoking cessation. In this chapter, the authors discuss preventive measures for tobacco use. Data from the Surveillance of Risk Factors and Protection Against Chronic Diseases via Telephone Inquiry (VIGITEL, in Portuguese), disclosed on April 2012, revealed advances in tobacco use control in Brazil, with 14.8% of smokers older than 18 years. They also approached the primordial prevention of tobacco use, enumerating factors that contribute to smoking initiation and proposing practical strategies for its combat. In addition, the authors discuss techniques to treat the psychological dependence of smokers with general and specific behavioral approaches. Furthermore, this chapter presents instruments to help to assess and understand the patient's profile by using universally accepted scales, such as Prochaska and Di Clemente's and Fagerström's. Finally, the authors approach, in a practical way, pharmacological treatment strategies of tobacco use, such as nicotine replacement with bupropion and varenicline, in addition to second-line drugs (nortriptyline), with their possible associations. [fig_ref] Table 7 -: Classification of recommendation and level of evidence for the treatment of smoking... [/fig_ref] summarizes the classification of recommendation and level of evidence of those strategies. Chapter 3 discusses the real benefits of primary and secondary CVD prevention, with evident confirmation of diet, supplements and vitamins, aiming at helping the clinician to guide the community in choosing and consuming those products. In addition to supplements, omega-3 fatty acids, vitamins B, C, D and E, folates, alpha-linolenic acids and carotenoids were assessed [fig_ref] Table 8 -: Summary of the recommendations for not using vitamin supplements to prevent cardiovascular... [/fig_ref] Chapter 4 approaches obesity, overweight and nutrition transition, as well as the consequences for cardiovascular morbidity and mortality of their association with arterial hypertension, dyslipidemias, type 2 diabetes, osteoarthritides and cancer. Tables 9 and 10 list the classification of recommendation and levels of evidence for primary and secondary prevention. Chapter 5 summarizes the recommendations for systemic arterial hypertension (SAH), emphasizing its importance for the development of several pathologies, such as coronary artery disease, heart failure, cerebrovascular disease and chronic kidney disease. [fig_ref] Table 11 -: Routine initial assessment of the hypertensive patient [/fig_ref] shows the routine initial assessment of hypertensive patients, and [fig_ref] Table 2 -: Scoring according to overall risk for women HDL-C [/fig_ref] , its complementary assessment. Therapeutic decision should consider the patient's additional risk. [fig_ref] Table 3 -: Overall cardiovascular risk in 10 years for women [/fig_ref] shows nonpharmacological measures, which are listed according to their recommendation class and level of evidence. shows the algorithm of pharmacological treatment based on the patients' hypertension stages. Monotherapy can be initiated with any drug class, but SAH control is only achieved in one-third of the cases with that strategy. Chart 2 shows the goals to be met according to patients' characteristics. Chapter 6 was aimed at discussing dyslipidemias, in an attempt to, after stratifying the individual risk, establish the therapeutic goals according to the overall risk level (low, intermediate or high). Specific goals are listed for high-and intermediate-risk patients. Patients at low cardiovascular risk should have their goals individualized at their clinician's discretion and according to lipid reference values. [fig_ref] Table 4 -: Scoring according to overall risk for men [/fig_ref] presents strategies for lifestyle changes. [fig_ref] Table 5 -: Overall cardiovascular risk in 10 years for men [/fig_ref] lists the pharmacological alternatives based on their recommendation class and level of evidence. Chapter 7 discusses diabetes, emphasizing its high prevalence in the adult population, up to 13.5% in some municipalities, which could represent a current population of 17 million individuals with diabetes. Those numbers are increasing due to factors such as population growth and aging, and increasing urbanization, sedentary lifestyle and obesity. This important chapter discusses essential measures for prevention, such as lifestyle changes [fig_ref] Table 6 -: Classification of recommendation and level of evidence for risk stratification in cardiovascular... [/fig_ref]. ## Special article ## Simão et al. cardiovascular prevention guideline Arq Bras Cardiol. 2014; 102(5):420-431 ## Chart 1 -aggravating risk factors - Family history of early coronary artery disease (male first-degree relative < 55 years-old or female first-degree relative < 65 years-old); - Criteria of metabolic syndrome according to the International Diabetes Federation; - Microalbuminuria (30-300 mg/min) or macroalbuminuria (>300 mg/min); - Left ventricular hypertrophy; - High-sensitivity C-reactive protein > 3 mg/L; - Evidence of subclinical atherosclerotic disease: carotid stenosis/thickening > 1mm coronary calcium score > 100 or > 75 th percentile for age or sex ankle-brachial test < 0.9 Chapter 8 provides a review on metabolic syndrome. There are several versions of the metabolic syndrome definition, and this guideline adopted the joint position paper of several international organizations on the topic. The authors discuss the epidemiological aspects of its prevalence, approaching different population groups, and aspects related to cardiovascular and metabolic risks, in addition to metabolic syndrome risk factors. [fig_ref] Table 7 -: Classification of recommendation and level of evidence for the treatment of smoking... [/fig_ref] shows the recommendation class and level of evidence of interventions in metabolic syndrome. ## Special article ## Simão et al. cardiovascular prevention guideline Arq Bras Cardiol. 2014; 102(5):420-431 Chapter 9 discusses the role played by physical activity, physical exercise and sports in CVD prevention. Physically active individuals tend to be healthier and have better quality of life and longer life expectancy. [fig_ref] Table 8 -: Summary of the recommendations for not using vitamin supplements to prevent cardiovascular... [/fig_ref] lists the recommended physical exercise levels. In addition, the risks of physical activity are approached, as well as the basic principles for exercise prescription and strategies to encourage referral, implementation and adherence. Chapter 10 discusses psychosocial factors in CVD prevention. Beginning with the definition of the concept, the chapter discusses the psychosocial conditions frequently associated with cardiovascular risk, such as low socioeconomic status, lack of social support, stress at work place and family life, depression, anxiety, hostility and type D personality. In addition, it assesses the recommendation class and level of evidence of approaching the psychosocial factors in [fig_ref] Table 9 -: Summary of the recommendations for obesity and overweight in cardiovascular disease primary... [/fig_ref] and for adherence [fig_ref] Table 2 -: Scoring according to overall risk for women HDL-C [/fig_ref] by using cognitive-behavioral methods and indicating the 'ten strategic steps' to improve counseling for behavioral changes. Interventions on depression, anxiety and distress are also proposed as potential tools for adherence to preventive strategies (Chart 3), which can also be improved with the simple measures. Chapter 11 approaches dyslipidemia, obesity and SAH in childhood and adolescence. Brazilian population studies have shown a 10%-35% prevalence of dyslipidemia in children and adolescents. [fig_ref] Table 2 -: Scoring according to overall risk for women HDL-C [/fig_ref] shows the reference values for lipids and lipoproteins in those age groups. recommendation for primary SAH in children and adolescents. Pharmacological treatment is indicated for individuals with symptomatic hypertension, secondary hypertension, SAH target-organ lesion, types 1 and 2 diabetes mellitus, and persistent SAH despite the adoption of nonpharmacological measures, a situation in which such measures are an adjunct to the pharmacological treatment. The diagnosis of obesity or overweight in children is clinical, and should be established via history and physical exam, followed by comparison of anthropometric data with population parameters, by using curves of body mass index (BMI) for age. Prevention comprises adequate nutrition during pregnancy, breastfeeding encouragement, identification of familial risk factors, careful child's growth and development follow-up, habit ## Special article ## Simão et al. cardiovascular prevention guideline Arq Bras Cardiol. 2014; 102(5):420-431 changes, especially the adoption of a healthy diet and global increase in physical activity. It is important to involve the child's entire family, parents, teachers and health care professionals, in addition to count on a multidisciplinary team. The systematic analysis of studies on the effectiveness of interventions to promote physical activity in the pediatric age group (more particularly adolescents) has shown better results when the actions associate school, family and community, and when the educational actions involve environmental and health policies. [fig_ref] Table 2 -: Scoring according to overall risk for women HDL-C [/fig_ref] shows the recommendations and their levels of evidence to prevent CVD in children and adolescents. Chapter 12 discusses topics related to legislation and prevention of CVD risk factors. The authors approach specific sanitary laws, discussing their effective role in health promotion and prevention, by creating healthy environments, in addition to emphasizing the importance of surveillance, prevention, health care, rehabilitation and health promotion Chapter 13 discusses specific aspects of prevention of CVD associated with autoimmune diseases, influenza, chronic kidney disease, obstructive arterial disease, socioeconomic factors, obstructive sleep apnea, erectile dysfunction and periodontitis [fig_ref] Table 2 -: Scoring according to overall risk for women HDL-C [/fig_ref]. We provide the medical class with a guideline that gathers, in one single publication, compiled and updated essential prevention topics to be used as a reference in CVD prevention. # Author contributions ## Potential conflict of interest The author Harry Correa Filho declares have conflict with the companies: Pfizer, Astra Zeneca. # Sources of funding There were no external funding sources for this study. ## Study association This study is not associated with any thesis or dissertation work. ## Dietary fat Fat ingestion by infants should not be restricted without medical indication I C From the 12th to the 24th month, transition to family meals with fat corresponding to 30% of the total caloric ingestion, 8%-10% of which of saturated fat I B From 2 to 21 years of age, fat should correspond to 25%-30% of the total caloric ingestion, 8%-10% of which of saturated fat I A Avoid trans fat I B Cholesterol < 300 mg/dL I A ## Others From 2 to 21 years of age, encourage fiber ingestion, limit sodium ingestion and encourage healthy life habits: family meals, breakfast, limit fast snacks I B ## Physical activity Parents should create an environment that promotes physical activity and limit sedentary activities, and be role models I C [table] Table 2 -: Scoring according to overall risk for women HDL-C: high-density lipoprotein cholesterol; TC: total cholesterol; SBP: systolic blood pressure [/table] [table] Table 3 -: Overall cardiovascular risk in 10 years for women [/table] [table] Table 4 -: Scoring according to overall risk for men [/table] [table] Table 5 -: Overall cardiovascular risk in 10 years for men [/table] [table] Table 6 -: Classification of recommendation and level of evidence for risk stratification in cardiovascular prevention [/table] [table] Table 7 -: Classification of recommendation and level of evidence for the treatment of smoking in cardiovascular prevention [/table] [table] Table 8 -: Summary of the recommendations for not using vitamin supplements to prevent cardiovascular disease (CVD) and recommendations for the consumption of products rich in omega-3 fatty acids•There is no evidence that supplementation of vitamin A or beta-carotene is beneficial to the primary or secondary prevention of CVD III A• Supplementations of vitamin B and folic acid are not effective to the primary or secondary prevention of CVD III A • There is no evidence that supplementation of vitamin C is beneficial to CVD prevention, progression or mortality II A • Supplementation of vitamin D is not recommended to CVD prevention in individuals with normal serum levels of that vitamin. Likewise, there is no evidence that supplementation in individuals with deficiency of that vitamin will prevent CVD. III C • Marine omega-3 supplementation (2-4g/day) or even at higher doses should be recommended for severe hypertriglyceridemia (>500mg/dL), at risk for pancreatitis, refractory to nonpharmacological measures and drug treatment I A • At least two fish-based meals per week, as part of a healthy diet, are recommended to reduce the cardiovascular risk. That is particularly recommended for high-risk individuals, such as those with previous myocardial infarction. I B • Supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is not recommendedfor individuals at risk for cardiovascular disease undergoing evidence-based preventive treatment. III A •The consumption of polyunsaturated omega-3 fatty acids of vegetable origin, as part of a healthy diet, should be recommended to reduce the cardiovascular risk, although the real benefit of that recommendation is arguable and the evidence is inconclusive. IIb B• Alpha-linolenic acid (ALA) supplementation is not recommended for cardiovascular disease prevention. III B [/table] [table] Table 9 -: Summary of the recommendations for obesity and overweight in cardiovascular disease primary prevention [/table] [table] Table 10 -: Summary of the recommendations for obesity and overweight in cardiovascular disease secondary prevention [/table] [table] Table 11 -: Routine initial assessment of the hypertensive patient [/table] [table] Table 12 -: Complementary assessment of hypertensive patients [/table] [table] Table 22: shows the classification of SAH for children and adolescents. Changes in lifestyle are the initial therapeutic [/table] [table] Table 13 -: Nonpharmacological treatment of hypertensive patients CombinationsTwo antihypertensive drugs of different classes and at low dosesInadequate response or intolerable adverse events [/table] [table] Table 14 -: Recommendations for the nonpharmacological treatment of dyslipidemia in cardiovascular prevention [/table] [table] Table 15 -: Recommendations for the pharmacological treatment of dyslipidemia [/table] [table] Table 16 -: Dietary and physical activity interventions in diabetes mellitus (DM) to prevent cardiovascular disease [/table] [table] Table 18 -: Recommended exercise levels for health promotion and maintenance [/table] [table] Table 19 -: Classification of recommendation and level of evidence in approaching psychosocial factors in primary prevention [/table] [table] Table 20 -: Classification of recommendation and level of evidence of adherence to strategy in cardiovascular prevention, lifestyle and medication [/table] [table] Table 21 -: Reference values for lipids and lipoproteins in children and adolescents [/table] [table] Table 23 -: Classification of recommendation and level of evidence for the presence of cardiovascular diseases (CVD) in children and adolescents• Obesity screening by use of BMI in children ≥ 6 years, providing or indicating intensive behavioral interventions directed to achieving a healthy weight • Ask about early CAD family history to identify children at risk • In the presence of positive family history, assess all family members, especially the parents I B • In children aged > 2 years with BMI ≥ 85 th percentile: Reinforce preventive instructions (see below) Identify complications and RF: SBP, gallbladder disease symptoms, diabetes, sleep apnea, hypothyroidism, orthopedic disorders, lipid profile I C • In children aged > 2 years with BMI ≥ 85 th -94 th percentile,all measures above plus: control of weight gain and fat ingestion, focusing on nutrition and development treatment of RF and complications multidisciplinary approach of moderate to high intensity measure aspartate aminotransferase (AST), alanine aminotransferase (ALT) and blood sugar in children ≥ 10 years of age From the 12th to the 24th month, transition to non-aromatic low-fat milk (2% or skim) I B From 2 to 21 years of age, non-aromatic skim milk should be the major beverage I A Avoid sugar beverages, encourage water ingestion I B [/table] [table] Table 24 -: Recommendation for approaching special conditions in cardiovascular disease prevention• In the context of preventing cardiovascular events, the benefit of using more strict therapeutic targets, especially due to the presence of autoimmune diseases, is uncertain.IIb C • Annual influenza vaccination for patients with established coronary artery or cerebrovascular disease, regardless of age I B • Annual influenza vaccination for patients at high risk for coronary events, but with no cardiovascular disease, regardless of age. IIa C • Patients with chronic kidney disease should be considered at very high risk for cardiovascular risk factors, requiring the assessment of glomerular filtration rate reduction and presence of co-morbidities. I C • Patients with obstructive arterial disease should be considered at very high risk, similarly to that of manifest coronary artery disease, for approaching cardiovascular risk factors. I C • Socioeconomic indicators should be investigated in clinical assessment and considered when approaching a patient, to improve quality of life and the prognosis of cardiovascular diseases. IIa B • All patients with obstructive sleep apnea should be considered as potential candidates to primary prevention, undergo cardiovascular risk stratification and be treated according to estimated risk. IIa A • All men with erectile dysfunction should be considered as potential candidates to primary prevention, undergo cardiovascular risk stratification and be treated according to estimated risk. IIa B • Patients with periodontitis should be considered for cardiovascular risk stratification and intensive local treatment. IIa B [/table]	None	None	Brazil currently faces a major health challenge: the pandemic scenario of cardiovascular morbidity and mortality. According to Brazilian Health Ministry data, 326,000 deaths due to cardiovascular diseases (CVD) occurred in 2010, corresponding to approximately 1,000 deaths/day, 200,000 deaths due exclusively to ischemic heart and cerebrovascular diseases, reflecting a gloomy scenario far from the minimally acceptable control.
9e7765925da8282258bf5350e073aef552b1ddfd	pubmed	Bariatric surgery: an IDF statement for obese Type 2 diabetes	Bariatric surgery: an IDF statement for obese Type 2 diabetes The International Diabetes Federation Taskforce on Epidemiology and Prevention of Diabetes convened a consensus working group of diabetologists, endocrinologists, surgeons and public health experts to review the appropriate role of surgery and other gastrointestinal interventions in the treatment and prevention of Type 2 diabetes. The specific goals were: to develop practical recommendations for clinicians on patient selection; to identify barriers to surgical access and suggest interventions for health policy changes that ensure equitable access to surgery when indicated; and to identify priorities for research. Bariatric surgery can significantly improve glycaemic control in severely obese patients with Type 2 diabetes. It is an effective, safe and cost-effective therapy for obese Type 2 diabetes. Surgery can be considered an appropriate treatment for people with Type 2 diabetes and obesity not achieving recommended treatment targets with medical therapies, especially in the presence of other major co-morbidities. The procedures must be performed within accepted guidelines and require appropriate multidisciplinary assessment for the procedure, comprehensive patient education and ongoing care, as well as safe and standardized surgical procedures. National guidelines for bariatric surgery need to be developed for people with Type 2 diabetes and a BMI of 35 kg ⁄ m 2 or more. ## Review criteria The working group reviewed literature focusing on bariatric surgery published between 1991 and 2010, in the areas of national and international guidelines, systematic reviews of the literature and high-quality clinical trials for the treatment of obesity and diabetes in adults and adolescents. The group synthesized the available evidence for efficacy, safety and costeffectiveness of the established bariatric procedures in relation to current standard therapy for people with obesity and Type 2 diabetes. The group also explored weight loss and non-weight loss effects of the surgery on glycaemic control and novel gastrointestinal procedures and devices being developed to treat Type 2 diabetes. All papers identified were English-language, full-text papers. ## Executive summary Text Box 1: Background - Obesity and Type 2 diabetes are serious chronic diseases associated with complex metabolic dysfunctions that increase the risk for morbidity and mortality. - The dramatic rise in the prevalence of obesity and diabetes has become a major global public health issue and demands urgent attention from governments, healthcare systems and the medical community. - Continuing population-based efforts are essential to prevent the onset of obesity and Type 2 diabetes. At the same time, effective treatment must also be available for people who have developed Type 2 diabetes. - Faced with the escalating global diabetes crisis, healthcare providers require as potent an armamentarium of therapeutic interventions as possible. - In addition to behavioural and medical approaches, various types of surgery on the gastrointestinal tract, originally developed to treat morbid obesity ('bariatric surgery'), constitute powerful options to ameliorate diabetes in severely obese patients, often normalizing blood glucose levels, reducing or avoiding the need for medications and providing a potentially cost-effective approach to treating the disease. ## Text box 2: bariatric surgery - Bariatric surgery is an appropriate treatment for people with Type 2 diabetes and obesity not achieving recommended treatment targets with medical therapies, especially when there are other major co-morbidities. - Surgery should be an accepted option in people who have Type 2 diabetes and a BMI of 35 kg ⁄ m 2 or more. - Surgery should be considered as an alternative treatment option in patients with a BMI between 30 and 35 kg ⁄ m 2 when diabetes cannot be adequately controlled by optimal medical regimen, especially in the presence of other major cardiovascular disease risk factors. - In Asian, and some other ethnicities of increased risk, BMI action points may be reduced by 2.5 kg ⁄ m 2 . - Clinically severe obesity is a complex and chronic medical condition. Societal prejudices about severe obesity, which also exist within the healthcare system, should not act as a barrier to the provision of clinically effective and cost-effective treatment options. - Strategies to prioritize access to surgery may be required to ensure that the procedures are available to those most likely to benefit. - Available evidence indicates that bariatric surgery for obese patients with Type 2 diabetes is cost-effective. - Bariatric surgery for Type 2 diabetes must be performed within accepted international and national guidelines. This requires appropriate assessment for the procedure and comprehensive and ongoing multidisciplinary care, patient education, followup and clinical audit, as well as safe and effective surgical procedures. National guidelines for bariatric surgery in people with Type 2 diabetes and a BMI of 35 kg ⁄ m 2 or more need to be developed and promulgated. - The morbidity and mortality associated with bariatric surgery is generally low and similar to that of well-accepted procedures such as elective gall bladder or gallstone surgery. - Bariatric surgery in severely obese patients with Type 2 diabetes has a range of health benefits, including a reduction in all-cause mortality. # Introduction Why is this position statement needed? The global prevalence of Type 2 diabetes is rising dramatically, driven by an 'obesogenic' environment that favours increasing sedentary behaviour and easier access to attractive calorie-dense foods acting on susceptible genotypes [bib_ref] The IDF Diabetes Atlas: providing evidence, raising awareness and promoting action, Unwin [/bib_ref]. The most recent global predictions by the International Diabetes Federation (IDF) suggest that there are 285 million people with diabetes currently worldwide. This is set to escalate to 438 million by 2030 [bib_ref] Global estimates of the prevalence of diabetes for 2010 and 2030, Shaw [/bib_ref] , with a further half billion at high risk. Diabetes is looming as one of the greatest public health threats of the 21st century. Type 2 diabetes is a risk factor for vascular damage: both microvascular (retinopathy; nephropathy and neuropathy) and macrovascular (premature and more extensive cardio-, cerebroand peripheral vascular disease). Premature mortality and morbidity in diabetes result from such complications. The disease results from inadequate insulin production and action and results in hyperglycaemia, but is also associated with multiple other dysfunctions involving lipid metabolism, oxidative stress, inflammation and haemato-rheology. In addition, obesity, by itself, generates similar cardio-metabolic dysfunction [bib_ref] Mechanisms linking obesity with cardiovascular disease, Van Gaal [/bib_ref]. The dramatic rise in the prevalence of obesity and diabetes has become a major global public health issue [bib_ref] Global estimates of the prevalence of diabetes for 2010 and 2030, Shaw [/bib_ref]. The problem is complex [bib_ref] Population-based prevention of obesity: the need for comprehensive promotion of healthful eating,..., Kumanyika [/bib_ref] and will require strategies at many levels to prevent, control and manage. There is increasing evidence that the health of obese people with Type 2 diabetes, including the metabolic control of diabetes and its associated risk factors, can benefit substantially from bariatric surgery-that is, surgical procedures to produce substantial weight loss [bib_ref] Effects of bariatric surgery on mortality in Swedish obese subjects, Sjostrom [/bib_ref] [bib_ref] Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis, Buchwald [/bib_ref]. Several gastrointestinal (GI) operations that were originally designed to treat morbid obesity also cause dramatic improvement of Type 2 diabetes and can effectively prevent progression from impaired glucose tolerance to diabetes in severely obese individuals [bib_ref] Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery, Sjostrom [/bib_ref]. In addition, bariatric surgery has been shown to substantially improve hypertension, dyslipidaemia and sleep apnoea [bib_ref] Bariatric surgery: a systematic review and metaanalysis, Buchwald [/bib_ref] and several reports have documented an improvement of overall survival [bib_ref] Effects of bariatric surgery on mortality in Swedish obese subjects, Sjostrom [/bib_ref] and specific reduction in diabetes-related mortality [bib_ref] Long-term mortality after gastric bypass surgery, Adams [/bib_ref]. Despite a number of evidence-based reviews and consensus statements having been published regarding the utilization of bariatric surgery in patients with obesity and diabetes [bib_ref] Inter-disciplinary European guidelines on surgery of severe obesity, Fried [/bib_ref] [bib_ref] American Association of Clinical Endocrinologists, The Obesity Society, and American Society for..., Mechanick [/bib_ref] [bib_ref] The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use..., Rubino [/bib_ref] [bib_ref] Bariatric surgery to treat severely obese patientswith type 2 diabetes: a consensus..., Zimmet [/bib_ref] , the IDF has not previously considered this rapidly developing area of care for worldwide use. Therefore, a need exists for worldwide expert guidance in the preoperative evaluation, choice of interventional procedure, perioperative management and long-term care of patients who seek surgery to improve diabetes control. The IDF Taskforce on Epidemiology and Prevention convened a consensus working group of diabetologists, endocrinologists, surgeons and public health experts in December 2010 to discuss the appropriate role of bariatric surgery and other gastrointestinal interventions in the treatment and prevention of obesity and Type 2 diabetes. The specific goals of the panel were: to develop practical recommendations for clinicians; to identify barriers that currently prevent access to surgery and suggest interventions for health policy changes that ensure equitable access to surgery when indicated; and to identify priorities for clinical research. This consensus statement considers primarily established bariatric surgical procedures. It is acknowledged that this is an emerging field and there is a large range of novel extraluminal and endoluminal gastrointestinal surgical procedures and devices that are in the development phase. Some focus primarily on weight loss and others additional non-weight loss metabolic benefits. The use of these requires further validation before they can be recommended. ## How is obesity defined? Obesity is usually classified by body mass index (BMI), calculated as body weight in kilograms divided by the height in metres squared (kg ⁄ m 2 ). Classifications of BMI, as defined by the World Health Organization (WHO), based on associations with adverse health consequences, are listed in [fig_ref] Table 1: The classification of weight category by BMI [/fig_ref]. Other methods, including waist circumference and central and peripheral fat mass, have also been used, but currently the clearest evidence suggests continued use of BMI as an index of obesity, particularly when BMI exceeds 30 kg ⁄ m 2 . BMI categories have been developed primarily in populations of mainly European ethnicity, and often underestimate health risks in other populations. In addition, BMI does not necessarily reflect the proportion of body weight that consists of fat or the distribution of fat: both these aspects of body composition can affect the health risks of excess weight. Nevertheless, at present, in the absence of a better alternative, BMI is the internationally accepted standard used by researchers and policymakers to allocate individuals to different size categories. Clinically severe or 'morbid' obesity is considered to be class III obesity or class II obesity with significant obesity-related co-morbidity, including Type 2 diabetes [fig_ref] Table 1: The classification of weight category by BMI [/fig_ref]. Additional cut-points for public health action have been suggested to address the increased risk of diabetes and cardiovascular disease in Asian populations and further investigation should examine other at-risk ethnicities. ## The link between obesity and type 2 diabetes Type 2 diabetes is a heterogeneous disorder and, while its causes have yet to be fully explained, obesity is considered the primary risk factor [bib_ref] Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm..., Nathan [/bib_ref]. It has been estimated that the risk of developing Type 2 diabetes is increased 93-fold in women and 42-fold in men who are severely obese rather than of healthy weight [bib_ref] Weight gain as a risk factor for clinical diabetes mellitus in women, Colditz [/bib_ref] [bib_ref] Obesity, fat distribution, and weight gain as risk factors for clinical diabetes..., Chan [/bib_ref]. A small proportion of people with Type 2 diabetes, approximately 15% in populations of European origin, are not overweight [bib_ref] The relative contributions of different levels of overweight and obesity to the..., Gregg [/bib_ref]. In the short term, even modest weight loss in people with Type 2 diabetes who are overweight or obese is associated with improvements in glycaemic control and associated conditions such as hypertension and dyslipidaemia [bib_ref] Reduction in weight and cardiovascular disease risk factors in individuals with type..., Pi-Sunyer [/bib_ref]. However, there is strong evidence that significant weight loss achieved by using lifestyle and medical methods by obese, particularly severely obese, people is modest and rarely sustained, particularly in the severely obese [bib_ref] Effects of bariatric surgery on mortality in Swedish obese subjects, Sjostrom [/bib_ref] [bib_ref] Long-term non-pharmacologic weight loss interventions for adults with type 2 diabetes, Norris [/bib_ref] [bib_ref] Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus, Norris [/bib_ref]. There are now few medications approved for weight loss with recent withdrawals associated with adverse events. ## Negative attitudes toward obesity There are widely held community attitudes that the majority of obese individuals are responsible for their current weight. Severe obesity is too often misconstrued as a 'cosmetic' problem and a result of personal failure or lack of motivation. However, this perspective ignores the very strong genetic and developmental bases to severe obesity [bib_ref] Genetic factors in human obesity, Farooqi [/bib_ref] compounded by physical, emotional and societal issues. It also fails to consider the pervasive obesity-promoting effects of modern societies (the 'obesogenic environment') [bib_ref] Prevention of type 2 diabetes. Prevention needs to reduce obesogenic environments, Swinburn [/bib_ref] , where an abundant food supply, changes in food preparation, increasing sedentary behaviour and other lifestyle factors mitigate against weight control for individuals. Additionally, it ignores the emerging evidence that body weight is defended by powerful physiological mechanisms [bib_ref] Diabetes, obesity, and the brain, Schwartz [/bib_ref] [bib_ref] Changes in energy expenditure resulting from altered body weight, Leibel [/bib_ref] , making long-term maintenance of weight loss difficult. In the context of treatment, negative societal attitudes have been a barrier to the provision of clinically effective, and costeffective, health care for people with severe obesity and Type 2 diabetes [bib_ref] Bariatric surgery: a dilemma for the health system?, Foo [/bib_ref] [bib_ref] Referral for a bariatric surgical consultation: it is time to set a..., Dixon [/bib_ref]. As noted earlier, obesity is a complex, multifactorial and chronic disorder with serious adverse consequences for health, which requires a comprehensive approach to both prevention and treatment. People affected by severe obesity often struggle not only with the health and physical consequences of their chronic condition, but discrimination at work, socially and within the healthcare system. ## Why consider bariatric surgery? Both insulin resistance and insulin secretory reserve are important in the pathogenesis of Type 2 diabetes [bib_ref] Defects in insulin secretion and action in the pathogenesis of type 2..., Tripathy [/bib_ref] , but to different extents in different people. It is very important to recognize that not all Type 2 diabetes is the same and it is. We address eligibility and prioritization for bariatric surgery within the coloured zones above. Source: Adapted from the World Health Organization (WHO) 2004. currently difficult to match the different therapies available to different phenotypes often resulting to suboptimal responses to therapy. Type 2 diabetes is a progressive disease and the usual natural history is of progressive loss of insulin secretory capacity over time and the need for intensification of therapy and polypharmacy. Arresting this progression is a formidable therapeutic challenge. Treatment for Type 2 diabetes must also include active management of all cardiovascular risk factors (hypertension, dyslipidaemia, smoking and inactivity) but glycaemic control is very important-and not just for prevention of microvascular disease. Years of improved glycaemic control continue to deliver reduced risk of macrovascular disease and mortality over subsequent years [bib_ref] Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up..., Riddle [/bib_ref] [bib_ref] Longterm follow-up after tight control of blood pressure in type 2 diabetes, Holman [/bib_ref]. Given the role of obesity in the aetiology of Type 2 diabetes, guidelines on its treatment provide that weight loss, with its many benefits, should be the most logical and cost-effective means of controlling Type 2 diabetes [bib_ref] Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm..., Nathan [/bib_ref]. Lifestyle interventions to promote weight loss and increase physical activity should be included as an essential component of diabetes treatment regimens. Medical therapeutic options targeting primarily glucose control are all ideally added to, and not exchanged for, lifestyle change. Unfortunately, such strategies have very limited success in controlling blood glucose levels amongst the severely obese, with many of these patients not achieving targets. A number of these medications used for treating Type 2 diabetes, including insulin, themselves can result in weight gain. A major problem for managing Type 2 diabetes is the need for continuous monitoring and intensification of therapies by adding new agents in increasing doses over time. The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus statement recommends that an HbA 1c of 7% (53 mmol ⁄ mol) is a call to action [bib_ref] Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for..., Nathan [/bib_ref]. Some national guidelines, such as those from the UK's National Institute for Health and Clinical Excellence (NICE), support more vigorous intensification of glycaemic therapies in the early stages of diabetes. NICE used HbA 1c ‡ 6.5% (48 mmol ⁄ mol) to increase from monotherapy, but ‡ 7% (53 mmol ⁄ mol) for increasing to triple therapies and beyond. This is very important. In one trial that randomized people with Type 2 diabetes and existing cardiovascular disease to very intensive management targeting HbA 1c < 6.5% (48 mmol ⁄ mol), mortality was higher in the intensive group, driven by deaths in those people who failed to show HbA 1c improvement as treatment was intensified [bib_ref] Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up..., Riddle [/bib_ref]. This should not be taken to mean people with early Type 2 diabetes should be treated less vigorously as the legacy effect of early intervention is considerable [bib_ref] High innate production capacity of proinflammatory cytokines increases risk for death from..., Trompet [/bib_ref]. A critical issue has been the rate at which healthcare professionals escalate therapies. Current approaches that rely on loss of glycaemic control and on intensifying lifestyle or other time-consuming measures set clinicians up for failure to achieve targets [bib_ref] Evaluation of risk factors for development of complications in Type II diabetes..., Liebl [/bib_ref]. It may be possible to achieve much more in terms of complication prevention-or even possibly slowed rate of progression-if treatments are started and intensified early. There have even been suggestions of starting polypharmacy at diagnosis [bib_ref] Early insulin treatment to prevent cardiovascular disease in prediabetes and overt diabetes, Roman [/bib_ref] [bib_ref] Earlier intervention in type 2 diabetes: the case for achieving early and..., Bailey [/bib_ref] , but there is limited current evidence to demonstrate the efficacy of this [bib_ref] Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up..., Riddle [/bib_ref]. Apart from the side-effect profiles and suboptimal deployment of existing medical diabetes therapies, there remain issues around patient engagement in many aspects of their lives. Very few clinical services routinely provide psychological support to encourage lifelong engagement in self-care. The continuing morbidity and mortality in persons with diabetes is a sign that the answer as to the best management for Type 2 diabetes in terms of maximizing metabolic control is still elusive. Given this scenario, the option of bariatric intervention needs to be considered in appropriately selected individuals. ## Evolving concept: bariatric-metabolic surgery The term 'bariatric' surgery, derived from the Greek word baros for weight, defines surgical procedures designed to produce substantial weight loss. Accordingly, goals of bariatric surgery originally evolved around achieving substantial sustained weight loss. In reality, weight loss is only one of the outcomes of such surgery. Bariatric surgery can be associated with substantial other health benefits, including improvement or normalization of hyperglycaemia. hyperlipidaemia, blood pressure, obstructive sleep apnoea and improved quality of life [bib_ref] Surgery for obesity, Colquitt [/bib_ref]. In view of the broad benefits of weight loss and the growing evidence that some bariatric procedures provide metabolic changes that cannot be explained completely by their effects on body weight alone [bib_ref] Etiology of type II diabetes mellitus: role of the foregut, Pories [/bib_ref] , the name 'bariatric-metabolic surgery' is emerging as a more appropriate name. ## Bariatric surgery and type 2 diabetes Bariatric procedures aim to reduce weight and maintain weight loss through altering energy balance, primarily by reducing food intake and modifying the physiological changes that drive weight regain. There also appear to be independent metabolic benefits, associated with effects of incretins and possibly other hormonal or neural changes after some surgical procedures [bib_ref] Metabolic surgery: the role of the gastrointestinal tract in diabetes mellitus, Rubino [/bib_ref] , in addition to weight loss. For example, rapid and sustained improvements in glycaemic control can be achieved within days of gastric bypass surgery, before any significant weight loss is evident [bib_ref] Effect of weight loss by gastric bypass surgery versus hypocaloric diet on..., Laferrere [/bib_ref] [bib_ref] Who would have thought it? An operation proves to be the most..., Pories [/bib_ref]. A 2009 Cochrane review including patients with and without diabetes concluded that bariatric surgery resulted in greater weight loss than conventional treatment in obese class I (BMI > 30 kg ⁄ m 2 ) as well as severe obesity, accompanied by improvements in co-morbidities such as Type 2 diabetes, hypertension and improvements in health-related quality of life [bib_ref] Surgery for obesity, Colquitt [/bib_ref]. A less rigorous systematic review and meta-analysis of 621 studies which included approximately 135 000 patients identified 103 studies reporting on the remission of the clinical and ⁄ or laboratory manifestations of diabetes [bib_ref] Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis, Buchwald [/bib_ref]. Overall, 78.1% of patients had 'remission' of diabetes following surgery. Among patients with diabetes at baseline, 62% remained in remission more than 2 years after surgery. There were significant limitations to this review as remission was largely based on clinical reporting, not HbA 1c or other biochemical outcomes, and follow-up of most cohorts poorly described. The Swedish Obese Subjects study clearly demonstrated the prevention and sustained remission of Type 2 diabetes in a group of 2037 [bib_ref] Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery, Sjostrom [/bib_ref] severely obese patients electing to have bariatric surgery when compared with well-matched controls at 2 and 10 years follow-up [fig_ref] Table 2: Two-and 10-year diabetes incidence and remission* rates from the Swedish Obese Subjects... [/fig_ref]. The extent of remission of Type 2 diabetes is influenced by the extent of weight loss, weight regain, duration of diabetes, the pre-surgery hypoglycaemic therapy requirements, and the choice of bariatric procedure. In addition, each patient's commitment to modifying their diet and levels of exercise within a framework of ongoing multidisciplinary care will influence outcomes. Remarkably, there is only a sole acceptably designed prospective randomized control trial (RCT) which has investigated bariatric surgery specifically as a treatment for Type 2 diabetes [bib_ref] Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized..., Dixon [/bib_ref]. It compared laparoscopic adjustable gastric banding as part of a comprehensive management programme to conventional diabetes therapy with a focus on weight loss by diet and exercise. After 2 years, remission of diabetes was significantly more common in those who had received surgery (73 vs. 13%). ## Bariatric surgery benefits beyond diabetes? Severe obesity is associated with a large number of health problems in addition to Type 2 diabetes. A review of more than 1.4 million participants in prospective studies largely from North America, Europe and Australia show a consistent progressive rise in the mortality hazard ratios with increasing BMI [bib_ref] Body mass index and mortality among 1.46 million white adults, Berrington De Gonzalez [/bib_ref] [fig_ref] Table 3: Mortality hazard ratios for white non-smokers[44] DIABETICMedicine IDF position statement-bariatric surgery •... [/fig_ref]. A similar analysis by the Prospective Studies Collaboration found the risk of diabetes-related death was quadrupled for morbidly obese individuals [bib_ref] Body mass index and cause-specific mortality in 900 000 adults: collaborative analyses..., Whitlock [/bib_ref]. Follow-up of participants in the Swedish Obese Subjects Study after an average of 11 years found that bariatric surgery was associated with a 29% reduction in all-cause mortality after accounting for sex, age and risk factors in this severely obese group [bib_ref] Effects of bariatric surgery on mortality in Swedish obese subjects, Sjostrom [/bib_ref]. Bariatric surgery also led to a specific reduction in cancer incidence in women [bib_ref] Effects of bariatric surgery on cancer incidence in obese patients in Sweden..., Sjostrom [/bib_ref]. Other studies have confirmed this mortality advantage when compared with community matched control subjects [bib_ref] Long-term mortality after gastric bypass surgery, Adams [/bib_ref] [bib_ref] Substantial intentional weight loss and mortality in the severely obese, Peeters [/bib_ref]. A large retrospective cohort study of almost 8000 patients who had undergone gastric bypass surgery were compared for long-term mortality with age-, sexand BMI-matched control subjects who had applied for driver's licences (Utah, USA) [bib_ref] Long-term mortality after gastric bypass surgery, Adams [/bib_ref]. The analysis reported an adjusted longterm all-cause mortality reduction of 40% in the surgical group. Specific mortality reductions in the operated group were 56% for coronary artery disease, 92% for diabetes and 60% for cancer when compared with matched controls. It would be expected that morbidly obese patients who have bariatric surgery as a treatment primarily for Type 2 diabetes would also experience the benefits of weight loss on other aspects of their health; for example, debilitating osteoarthritis or obstructive sleep apnoea. Many studies have demonstrated major improvements in health-related quality of life following bariatric surgery using both generic and obesity-specific qualityof-life instruments [bib_ref] Two-year changes in health-related quality of life in gastric bypass patients compared..., Kolotkin [/bib_ref] [bib_ref] Quality of life after lap-band placement: influence of time, weight loss, and..., Dixon [/bib_ref]. ## Is bariatric surgery cost-effective? The costs of Type 2 diabetes are substantial. In the USA, the lifetime cost has been estimated at $US172 000 for a person diagnosed at the age of 50 years and $US305 000 if diagnosed at the age of 30 years. The estimate included both the direct medical costs of diabetes and its complications and indirect costs caused by work absence, reduced productivity at work, disability and premature death. Over 60% of the medical cost was incurred within 10 years of diagnosis. Bariatric surgery for severe obesity, regardless of diabetes status, has been assessed as cost-effective [bib_ref] The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity:..., Picot [/bib_ref] and, in some analyses, cost saving or dominant [bib_ref] A study on the economic impact of bariatric surgery, Cremieux [/bib_ref]. A literature review identified three cost-effective analyses of bariatric surgery for patients specifically with diabetes [fig_ref] Table 4: Cost-effectiveness of bariatric procedures in people with diabetes [/fig_ref]. All three studies found bariatric surgery to be either very cost-effective or dominant as a therapy for Type 2 diabetes relative to standard therapy. Study analyses have been conservative. The finding of 'cost-effectiveness' indicates that health benefits are achieved at an acceptable price relative to country-specific cost-effectiveness thresholds. The 'dominant' result indicates that an intervention generates both cost savings and health benefits over the lifetime of the cohort. This is a rare Remission based on fasting plasma glucose < 7.0 mmol ⁄ l and not on hypoglycaemic therapy [bib_ref] Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery, Sjostrom [/bib_ref]. outcome and provides the most compelling evidence for funding based on economic criteria. It is recognized that cost-effectiveness studies have not been conducted in low-and middle-income countries where highcost interventions for macro-and microvascular complications may not be available. However, life expectancy might indeed be improved by bariatric surgery in these settings and morbidity decreased. It is up to each health system to determine whether bariatric surgery with its support services is economically appropriate when weighed against the provision of essential medicines and other secondary prevention initiatives, such as foot care, education and retinal screening, which can be cost saving in low-income countries. ## What eligibility guidelines exist? A number of guidelines exist on the use of bariatric surgery for the treatment of severe obesity in general, and for the treatment of Type 2 diabetes in particular. They are summarized in [fig_ref] Table 5: National and international guidelines for eligibility for bariatric surgery [/fig_ref]. Most of the existing guidelines reflect the expert recommendations of the National Institutes of Health (NIH) Consensus Development Conference Statement March 1991. The current NIH website warns that their information is dated and provided solely for historic purposes. A recent Diabetes Surgery Summit of 50 international experts examined gastrointestinal surgery for the management of Type 2 diabetes. Delegates strongly endorsed that conventional gastrointestinal surgery-Roux-en-Y gastric bypass (RYGB), laparoscopic adjustable gastric band (LAGB) or bilio-pancreatic diversion (BPD)-should be considered for the treatment of Type 2 diabetes in acceptable surgical candidates with BMI > 35 kg ⁄ m 2 who are inadequately controlled by lifestyle and medical therapy. Further trial evidence was deemed necessary for inadequately controlled Type 2 diabetes in candidates suitable for surgery with mild-to-moderate obesity (BMI 30-35 kg ⁄ m 2 ) [bib_ref] The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use..., Rubino [/bib_ref]. ## Recommendations for adolescents Long-term whole-of-family lifestyle change, with high-quality medical management, is the mainstay of paediatric obesity treatment. However, the growing prevalence of severe obesity in children and adolescents demonstrates a need for additional therapy. Bariatric surgery is only considered suitable for adolescents of developmental and physical maturity. There are a range of guidelines and consensus reports that have similar recommendations. A recent position statement was developed by the Australian and New Zealand Colleges for paediatric physicians and surgeons and the Obesity Surgery Society of Australia and New Zealand [bib_ref] Recommendations for bariatric surgery in adolescents in Australia and New Zealand, Baur [/bib_ref]. The statement recommended surgery be considered if adolescents had BMI > 40 kg ⁄ m 2 , or > 35 kg ⁄ m 2 with severe co-morbidities (including Type 2 diabetes), were aged 15 years or more, with Tanner pubertal stage 4 or 5 and skeletal maturity, and could provide informed consent. Potential candidates should have failed a multidisciplinary programme of lifestyle AE pharmacotherapy for 6 months, and they and their family must be motivated and understand the need to participate in post-surgical therapy and follow-up. Surgery should be provided in units affiliated with teams experienced in the assessment and long-term follow-up of the metabolic and psychosocial needs of adolescent patients. Very similar eligibility criteria, with some variation in youngest age and BMI, have been listed in European and US publications [bib_ref] Inter-disciplinary European guidelines on surgery of severe obesity, Fried [/bib_ref] [bib_ref] Bariatric surgery for severely overweight adolescents: concerns and recommendations, Inge [/bib_ref]. This IDF position statement advises that only two procedures, namely Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB), are currently conventional bariatric surgical procedures for adolescents. ## Do procedures vary in effectiveness? A number of bariatric surgical procedures are effective in achieving weight loss. Those that involve more extensive surgery, such as Roux-en-Y gastric bypass, generally lead to greater weight loss and more profound metabolic changes, at least initially, than less invasive, non-diversionary procedures such as laparoscopic adjustable gastric banding. Roux-en-Y gastric bypass procedures influence the gut hormonal milieu and provide an early non-weight related improvement in glycaemic control of Type 2 diabetes. It is not clear if these changes are durable or have a fundamental effect on the underlying mechanisms driving Type 2 diabetes. In the longer term, weight loss may be the key benefit. There is absolutely no evidence to support subcutaneous lipectomy (liposuction) as a treatment for Type 2 diabetes in obese patients [bib_ref] Absence of an effect of liposuction on insulin action and risk factors..., Klein [/bib_ref]. A systematic review of the literature by Buchwald et al. [bib_ref] Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis, Buchwald [/bib_ref] reported that diabetes remits or improves in the majority of patients after bariatric surgery. The procedures producing greater excess weight loss lead to higher remission rates [fig_ref] Table 6: Estimated weight loss and percentage of those with diabetes who remit at... [/fig_ref]. This review, however, was limited by the quality of the available literature where follow-up varied, there was no consistent definition of remission, and biochemical measures of remission were usually not reported. The choice of bariatric procedure is complex, requiring a careful risk-benefit analysis and acceptance of variation in regional practice and expertise. The decision must be made by severely obese patients in consultation with their bariatric surgical multidisciplinary team. ## Text box 3 factors to consider when choosing a procedure in patients with type 2 diabetes include: - Expertise and experience in the bariatric surgical procedures - The patient's preference when the range of risks and benefits, the importance of compliance, and the effects on eating choices and behaviours have been fully described - The patient's general health and risk factors associated with high perioperative morbidity and mortality - The simplicity and reversibility of a procedure - The duration of Type 2 diabetes and the degree of apparent residual B-cell function - The follow-up regimen for the procedure and the commitment of the patient to adhere to it It is important to recognize that all conventional surgical procedures vary in their risks and benefits and, to date, there are few hard data that can be used to match patients to procedures. Recommendations made by this consensus apply to currently accepted bariatric surgical procedures and do not apply to new experimental procedures or devices. The consensus group consider that Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, bilio-pancreatic diversion (BPD) and the duodenal switch variant (BPD-SD), and sleeve gastrectomy (SG) as currently accepted procedures [bib_ref] Metabolic ⁄ bariatric surgery worldwide, Buchwald [/bib_ref]. However, it was acknowledged that there was limited medium-or long-term data regarding sleeve gastrectomy, and there are safety, nutritional and metabolic concerns with bilio-pancreatic diversion and the duodenal switch variant. Two procedures were considered accepted procedures in adolescents-Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding (see Recommendations for adolescents above). What are the risks of bariatric surgery? The 30-day mortality associated with bariatric surgery is estimated at 0.1-0.3%, a rate similar to that for laparoscopic cholecystectomy [bib_ref] Trends in mortality in bariatric surgery: a systematic review and meta-analysis, Buchwald [/bib_ref] and described as 'low'. Programme and patient factors found to be associated with increased risk are shown in [fig_ref] Table 7: Patient and programme factors associated with risk of surgery [/fig_ref]. The presence of Type 2 diabetes has not been found to be associated with increased risk for bariatric surgery. The most common complications of bariatric surgery include anastomotic and staple-line leaks (3.1%), wound infections (2.3%), pulmonary events (2.2%) and haemorrhage (1.7%). Morbidity rates are lower after laparoscopic procedures, which constitute a steadily increasing proportion of bariatric operations [bib_ref] Use and outcomes of laparoscopic versus open gastric bypass at academic medical..., Nguyen [/bib_ref]. Other complications remained unchanged (ulcers, dumping, haemorrhage, wound re-opening, deep-venous thrombosis and pulmonary embolism, heart attacks and strokes) and none increased. Early post-operative morbidity and mortality are related to the complexity of the surgery. The US Bariatric Outcomes Longitudinal Database (BOLD) reviewed over 57 000 consecutive procedures and reported one or more complication at 1-year rates of 4.6, 10.8, 14.9 and 25.7% following laparoscopic adjustable gastric band, sleeve gastrectomy, Roux-en-Y gastric bypass and bilio-pancreatic diversion, respectively [bib_ref] Baseline data from American Society for Metabolic and Bariatric Surgery-designated Bariatric Surgery..., Demaria [/bib_ref]. Thirty-day post-surgical mortality follows a similar trend, with 0.1% for laparoscopic adjustable gastric band, 0.5% for Roux-en-Y gastric bypass and 1.1 for biliopancreatic diversion [bib_ref] Trends in mortality in bariatric surgery: a systematic review and meta-analysis, Buchwald [/bib_ref]. The US Agency for Healthcare Research and Quality reported a ninefold increase in bariatric surgery for the period 1998-2004, with a reduction in overall early mortality from 0.89 to 0.19%. Improvements have been attributed to higher hospital volumes, a move to laparoscopic surgery and an increase in banding procedures [bib_ref] Recent improvements in bariatric surgery outcomes, Encinosa [/bib_ref]. Longer-term surgical complications and need for surgical revisions are not uncommon and expected problems are usually specific to the surgical intervention. Early detection and appropriate management of complications is very important. All those managing post-bariatric surgical patients should have a low threshold for surgical referral should a complication be suspected. Longer-term concerns, especially with Roux-en-Y gastric bypass and bilio-pancreatic diversion, include vitamin and mineral deficiencies, osteoporosis and, rarely, Wernicke's encephalopathy and severe hypoglycaemia from insulin hypersecretion [bib_ref] American Association of Clinical Endocrinologists, The Obesity Society, and American Society for..., Mechanick [/bib_ref] [bib_ref] Standards of medical care in diabetes-2010, Ada [/bib_ref]. Clinical guidelines developed by the American Association of Clinical Endocri nologists, The Obesity Society and the American Society for Metabolic and Bariatric Surgery address these important issues [bib_ref] American Association of Clinical Endocrinologists, The Obesity Society, and American Society for..., Mechanick [/bib_ref]. A summary of nutritional risk with each procedure is shown in [fig_ref] Table 8 A: summary of more common nutritional concerns for each procedure LAGB SG RYGB... [/fig_ref]. This does not reflect all nutritional risks. Long-term dietary advice, evaluation and supplementation are required for all procedures. The risks of each procedure need to be considered in the light of potential reductions in mortality, morbidity or co-morbidity, quality of life and productivity. Realistic expectations are important and the risk-benefit ratio assessed individually for each patient, accounting for both peri-operative risk and possible long-term complications. Continuing efforts are required to monitor the safety, efficacy and long-term effects of bariatric surgery. There is a range of national bariatric surgery registries and continuing long-term longitudinal studies. We encourage the expansion of national registries and acknowledge that these must be well resourced to function appropriately. Severe obesity and Type 2 diabetes are chronic conditions needing a chronic-disease approach to care. ## Components of successful bariatric surgery There is a range of comprehensive guidelines for the use of bariatric procedures for obesity, including the UK National Institute for Health and Clinical Excellence (2006), the combined American Association of Clinical Endocrinologists, The Obesity Society and the American Society for Metabolic and Bariatric Surgery guidelines (2008) [bib_ref] American Association of Clinical Endocrinologists, The Obesity Society, and American Society for..., Mechanick [/bib_ref] and European clinical guidelines (2007) [bib_ref] Inter-disciplinary European guidelines on surgery of severe obesity, Fried [/bib_ref]. Text box 4 Considerations with respect to Type 2 diabetes and components of successful programmes include: - Bariatric surgery is a component of the ongoing process of chronic disease management of Type 2 diabetes and obesity - Bariatric surgery should be performed in high-volume centres with multidisciplinary teams that are experienced in the management of obesity and diabetes. Members of the team should have understanding across disciplines and work together with common expectations and goals. The team needs to integrate with primary care, diabetes management, nutritional and lifestyle support, and surgeon's teams with consistent messages and agreed policies - The surgical team must have undertaken relevant supervized training and have specialist experience in types of bariatric surgery performed within the programme - Pre-surgical assessment needs to be comprehensive, including assessment of metabolic, physical, psychological and nutritional health. Patients should have realistic expectations of the risks and benefits of surgery along with their lifelong role in lifestyle intervention, nutritional support and follow-up - Management of diabetes and other co-morbidities should be optimized and short-term pre-operative weight loss considered to improve health and visibility at the time of surgery - The multidisciplinary team need to understand and recognize early and long-term complications in a timely manner and know when to refer back to the surgeon or others for specific care - Lifelong follow-up on at least an annual basis is needed for ongoing lifestyle support, and post-surgical and diabetes monitoring - Teams should collect prospective data and measure diabetes outcomes in methods consistent with IDF recommendations - Regular, post-operative nutritional monitoring is required, with attention to appropriate diet, monitoring of micronutrient status and individualized nutritional supplementation, support and guidance to achieve long-term weight loss and weight maintenance - Follow-up should include a psychological evaluation, support and therapy if appropriate. Mental illness, especially depression, is common in diabetes and severe obesity - In order to help sustain weight loss from bariatric surgery, patients must be committed to increased levels of ongoing daily physical activity - All practices are encouraged to engage and promote national programmes of 'centres of excellence' or equivalent and collect prospective data through registries Diabetes-who to consider for surgery? There is clear evidence that bariatric surgery is a very effective therapy for obese patients with Type 2 diabetes. The place of surgery in diabetes treatment algorithms needs to be established (see below). Currently, surgery is considered optional and, as such, in the countries with the highest bariatric surgery uptake, less than 2% of eligible patients are treated annually. Indications for bariatric surgery typically classify those who are eligible for surgery, but a recommendation of surgical referral as best practice or prioritization has not been widely considered. Diabetes management algorithms should now include points at which bariatric surgery should be considered and points at which referral is recommended or prioritized [fig_ref] Table 9: Eligibility and prioritization for bariatric surgery based on failed non-surgical weight-loss therapy,... [/fig_ref]. [formula] + + + +++ +++ [/formula] +, recommended daily intake (allowance) or standard multivitamin preparation likely to be sufficient. ++, significant risk of deficiency or increased requirements. Specific supplementation is appropriate especially in higher-risk groups. +++, high risk of deficiency. Additional specific supplementation is necessary to prevent deficiency. Careful monitoring is recommended. Supplementation well in excess of daily requirements may be necessary. BPD, bilio-pancreatic diversion; BPD-DS, bilio-pancreatic diversion with duodenal switch; LAGB, laparoscopic adjustable gastric band; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy. DIABETICMedicine IDF position statement-bariatric surgery - J. B. Dixon et al. In patients with Type 2 diabetes, eligibility or prioritization for surgery should consider BMI, ethnicity, associated weightrelated co-morbidity, weight trajectory and the response of diabetes and co-morbidity to optimal medical therapy. Conditional eligibility or prioritization should be assessed by a team specializing in diabetes. Surgical referral implies a thorough bariatric surgical multidisciplinary team assessment of risk and benefit. Contraindications for bariatric surgery include: current drug or alcohol abuse; uncontrolled psychiatric illness; and lack of comprehension of the risks-benefits, expected outcomes, alternatives and lifestyle changes required with bariatric surgery [bib_ref] American Association of Clinical Endocrinologists, The Obesity Society, and American Society for..., Mechanick [/bib_ref]. In addition, there are general conditions that would contraindicate elective surgery and specific conditions that substantially increase the risk of surgery, later complications or poor outcomes. These should be assessed by the surgical team. ## Integration into diabetes treatment algorithms Existing international treatment guidelines for Type 2 diabetes provide little information or direction on the role of bariatric interventions in treatment. By contrast, the American Diabetes Association recommends that bariatric surgery be considered as a treatment option for Type 2 diabetes when the patient's BMI exceeds 35 kg ⁄ m 2 [bib_ref] Standards of medical care in diabetes-2010, Ada [/bib_ref]. Algorithms developed for treating Type 2 diabetes should include recommendations as to where bariatric surgery is an option and the circumstances where it should be prioritized. Almost all severely obese patients are unsuccessful in their efforts to achieve sustained and significant weight loss and there is evidence that weight loss induced by bariatric surgery can lead to remission of hyperglycaemia in the majority of patients with diabetes [bib_ref] Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis, Buchwald [/bib_ref] [bib_ref] Narrative review: effect of bariatric surgery on type 2 diabetes mellitus, Vetter [/bib_ref]. Earlier intervention increases the likelihood of remission [bib_ref] Health outcomes of severely obese Type 2 diabetic subjects 1 year after..., Dixon [/bib_ref] [bib_ref] Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus, Schauer [/bib_ref]. In the remaining patients, residual hyperglycaemia is easier to manage following bariatric surgery. It can therefore be argued that bariatric surgery for the severely obese with Type 2 diabetes should be considered early as an option for eligible patients, rather than being held back as a last resort. ## Equity of access to bariatric surgery Obesity is more common in socio-economically disadvantaged people in the developed world, but the vast majority of bariatric surgery procedures in the developed world are performed in the private sector. Current access to surgical treatment for people with severe obesity and Type 2 diabetes is not equitable and discriminates against individuals who are most likely to benefit. There are particular problems in those emerging countries where rates of severe obesity are increasing rapidly and healthcare resources are extremely limited. There will be resource implications in the short term from increasing access to bariatric surgery, but it is essential to consider not just the financial costs of the procedures and necessary follow-up, but also the potential savings from achieving improved control of Type 2 diabetes, its related metabolic and other complications and co-morbidities. # Measuring diabetes-related outcomes There needs to be an agreed definition of success and, on the basis of present data, the achievable goal of bariatric surgery is not cure, but remission, of the diabetes state. Improved patient health would be recognized by individualized optimization of the metabolic state, which involves normalization or improvement of the metabolic state (Text box 5). Text box 5 Criteria for remission or optimal metabolic state and substantial improvement Optimization of the metabolic state may be defined as: - HbA 1c £ 42 mmol ⁄ mol (6%) - no hypoglycaemia - total cholesterol < 4 mmol ⁄ l; LDL cholesterol < 2 mmol ⁄ l - triglycerides < 2.2 mmol ⁄ l - blood pressure < 135 ⁄ 85 mmHg - > 15% weight loss - with reduced medication from the pre-operated state or without other medications (where medications are continued, reduced doses from pre-surgery with minimal side effects would be expected) A substantial improvement in the metabolic state may be defined as: - lowering of HbA 1c by > 20% - LDL < 2.3 mmol ⁄ l - blood pressure < 135 ⁄ 85 mmHg with reduced medication from the pre-operated state The above definitions, with a focus on diabetes, complement broader success measures, including substantial sustained weight loss, improved quality of life and improvement or remission of obesity-associated co-morbidity.. àHbA 1c > 58 mmol ⁄ mol (7.5%) despite fully optimized conventional therapy, especially if weight is increasing, or other weight responsive co-morbidities not achieving targets on conventional therapies. For example, blood pressure, dyslipidaemia and obstructive sleep apnoea. Several novel procedures have developed from elegant experiments using rodent models to examine the mechanism of action of bariatric surgery. The aim has been to enhance the nonweight-loss glycaemic control benefits of the gastrointestinal interventions. These procedures may evolve as therapy for Type 2 diabetes in those without significant weight issues. These novel procedures include duodenal-jejunal bypass (DJB) [bib_ref] Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2..., Rubino [/bib_ref] and ileal interposition (IT) [bib_ref] Weight loss through ileal transposition is accompanied by increased ileal hormone secretion..., Strader [/bib_ref]. First described by Rubino [bib_ref] The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role..., Rubino [/bib_ref] , duodenal-jejunal bypass is a stomach-sparing bypass of a short portion of proximal intestine, comparable with the segment excluded in a standard Roux-en-Y gastric bypass. A number of early human clinical trials have been performed and improvements in glycaemic control have been reported, but these may be less impressive in subjects with a lower BMI [bib_ref] Surgery for non-obese type 2 diabetic patients: an interventional study with duodenal-jejunal..., Geloneze [/bib_ref] [bib_ref] Early changes in incretin secretion after laparoscopic duodenal-jejunal bypass surgery in type..., Lee [/bib_ref]. Ileal interposition involves the surgical transposition of a small segment of ileum into the proximal intestine. Generally, shortterm studies in humans have reported improved glycaemia [bib_ref] Thirty-day morbidity and mortality of the laparoscopic ileal interposition associated with sleeve..., Depaula [/bib_ref] [bib_ref] Ileal interposition with sleeve gastrectomy for control of type 2 diabetes, Kumar [/bib_ref]. These procedures remain experimental and are likely to require technical refinements before larger-scale longer-term safety and efficacy studies. ## Novel bariatric-metabolic devices Multiple, mostly novel, devices and techniques are being explored to utilize the gatrointestinal tract's putative mechanism for altering energy balance and for non-weight-loss effects on glucose tolerance. In general, the techniques can be divided by mode of placement into those that are upper gastrointestinal endoscopic or laparoscopic, with some combining approaches. Endoscopically placed upper gastrointestinal devices include the simple positioning of a device in the upper gastrointestinal tract. Examples include intra-gastric balloons, which are currently available for temporary placement (usually 6 months, but repeat treatment for extending the duration of treatment beyond 2 years have been reported) and which provide 10-15% weight loss during the period of placement, plus a range of novel devices under development, which are placed in the stomach to mimic restriction, or placed in the trans-pyloric area to delay or regulate gastric emptying. Some endoscopically placed devices are physically fixed to the upper gastrointestinal tract to mimic proximal gastric restriction of the laparoscopic adjustable gastric band, while some use endoluminal impervious sleeves to bypass the gastro-duodenal upper jejunal area to mimic the Roux-en-Y gastric bypass, or bypass the duodenum and proximal jejunum to mimic the duodenal-jejunal bypass. A range of laparoscopic procedures to place novel electronic gastric or gastro-duodenal motility stimulators, and vagal nerveblocking devices are also under investigation. Results in humans to date have been mixed, with some devices providing inadequate weight loss and others promising results. These are considered less invasive than most conventional bariatric surgical procedures. Whilst there is excitement in the novel medical device area, the efficacy, safety, durability and clinical utility of many of these procedures in the management of obese people with Type 2 diabetes is still to be established. 8. Procedure selection requires appropriate assessment of risk vs. benefit of each operation as part of the process for selecting the surgical treatment options for an individual patient 9. New bariatric procedures require robust assessment for their efficacy, safety and durability, using similar principles to those for assessing new drug therapies and having regards to the benefits and risks of established therapy 10. Regional surgical expertise, multidisciplinary team experience and documented quality outcomes are important factors in the regional choice of bariatric procedures 11. There should be a minimal accepted data set for pre-surgery and follow-up to allow audit of clinical programmes, for example: - HbA 1c - fasting glucose and insulin - BMI - waist circumference - retinopathy status (recent eye examination) - nephropathy (e.g. test for microalbuminuria within previous year) - liver functions tests - lipid profile ## Recommendations ## Diabeticmedicine IDF position statement-bariatric surgery - J. B. Dixon et al. - blood pressure measurement - foot exam (recent) - documentation of medications-(glycaemia, lipids and hypertension) - these should be used preoperatively - fasting C-peptide where available - auto-antibody status, e.g. anti-GAD where available 12. All longitudinal studies should include quality of life as one of the outcomes 13. It should be recognized that a prolonged period of normalization of glycaemic control has benefit even if there is eventual relapse ## Research recommendations 1. Studies are needed to establish more robust criteria than BMI for predicting benefit from surgery and define which patients benefit most from which procedures 2. Studies are needed to establish the benefit of surgery for persons with diabetes and BMI < 35 kg ⁄ m 2 3. Studies are needed to establish whether bariatric procedures prevent or slow the progressive loss of B-cell function characteristic of Type 2 diabetes 4. Studies are required to document the course of complications after surgery to obtain evidence that surgery stabilizes and ideally improves microvascular complications 5. Studies are needed to establish the duration of the benefit of surgery 6. Studies are needed to establish the mechanisms of the success of surgery and the mechanisms associated with recurrence 7. Studies are needed to establish the long-term complications of surgery 8. New techniques should be assessed rigorously for efficacy and safety and, ideally, mechanisms, and demonstrate their equivalence or superiority to classical surgical techniques, moving to human studies after appropriate preclinical studies 9. Studies are needed to define the best regimens of diabetes management post-bariatric surgery 10. It will be important to phenotype candidates for surgery to define what will be the most appropriate bariatric procedure for persons with diabetes in different age groups, different duration of diabetes, etc. 11. Randomized controlled trials are needed to evaluate and compare different bariatric procedures for the treatment of diabetes between themselves, as well as emerging nonsurgical therapies # Conclusion Clinically severe obesity is a complex and chronic medical condition. Bariatric surgery is an effective and cost-effective therapy for Type 2 diabetes and obesity with an acceptable safety profile. Surgery provides an appropriate treatment for people with Type 2 diabetes and obesity not achieving recommended treatment targets with medical therapies, especially when there are other major co-morbidities. National guidelines for bariatric surgery need to be developed and implemented for people with Type 2 diabetes. Bariatric surgery should be incorporated into Type 2 diabetes treatment algorithms and the establishment of national bariatric surgical registries recommended. ## Conflict of interest [table] Table 1: The classification of weight category by BMI [/table] [table] Table 2: Two-and 10-year diabetes incidence and remission rates from the Swedish Obese Subjects Study[7] [/table] [table] Table 3: Mortality hazard ratios for white non-smokers[44] DIABETICMedicine IDF position statement-bariatric surgery • J. B. Dixon et al. [/table] [table] Table 4: Cost-effectiveness of bariatric procedures in people with diabetes [/table] [table] Table 5: National and international guidelines* for eligibility for bariatric surgery (adults) The guidelines above are qualified by the following common elements: appropriate non-surgical weight-loss measures have been tried and failed; there is the provision for, and a commitment to, long-term follow-up; and individual risk-benefit ratio needs to be evaluated.ADA, American Diabetes Association; NCD, non-communicable disease; A, eligible BMI; B, eligible conditional BMI; NHMRC, National Health and Medical Research Council; NICE, National Institute for Health and Clinical Excellence; NIH, National Institutes of Health; SIGN, Scottish Intercollegiate Guidelines Network. [/table] [table] Table 6: Estimated weight loss and percentage of those with diabetes who remit at 2 years after conventional bariatric procedures* [/table] [table] Table 7: Patient and programme factors associated with risk of surgery [/table] [table] Table 8 A: summary of more common nutritional concerns for each procedure LAGB SG RYGB BPD BPD-DS [/table] [table] Table 9: Eligibility and prioritization for bariatric surgery based on failed non-surgical weight-loss therapy*, BMI, ethnicity and disease control [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1464-5491.2011.03306.x	Diabet. Med. 28, 628–642 (2011)
1d6aa697268b436daa95b0f53fc0a669f966d301	pubmed	Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal	Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal # Introduction In 1961, Sarles et al. [bib_ref] Chronic inflammatory sclerosis of the pancreas-an autoimmune pancreatic disease?, Sarles [/bib_ref] asked the following question regarding the particular cases of pancreatitis with hypergammaglobulinemia: "Chronic inflammatory sclerosis of the pancreas-an autoimmune pancreatic disease?" As similar cases were rarely observed, a relationship between such pancreatitis and autoimmunity was viewed skeptically during the following several decades. In 1992, Toki et al. [bib_ref] An unusual type of chronic pancreatitis showing diffuse irregular narrowing of the..., Toki [/bib_ref] have reported 4 cases with unusual diffuse irregular narrowing of the main pancre-concept of AIP has changed slightly to include extrapancreatic lesions and associated disorders, which suggests that the current diagnostic criteria are becoming inadequate. In 2003, the Research Committee of Intractable Diseases of the Pancreas, supported by the Japanese Ministry of Health, Labour and Welfare (Chairman, M. Otsuki), began to review the current diagnostic criteria in light of recently acquired information and knowledge. The team organized a working group (WG), consisting of the team members and researchers specializing in autoimmune pancreatitis, to develop a proposal for the revision of the current diagnostic criteria. This report describes the background of the proposed amendments and the final proposal for the revised version of the clinical diagnostic criteria of AIP. shows the diagnostic criteria 2002 of AIP proposed by the Japan Pancreas Society.The members of the WG accumulated 147 cases of AIP and identified the cases that did not fulfill the current diagnostic criteria but were strongly suspected to be AIP. It then evaluated those cases in detail using imaging, laboratory, and pathological findings, and unanimously rediagnosed some of them as AIP. Using the analyzed data, the members then summarized the current status and problems of AIP in Japan, as outlined below. After reviewing the material in an expanded open discussion in October 2004 in Fukuoka City, the Research Committee of Intractable Diseases of the Pancreas amended the current diagnostic criteria for AIP. Major discussions in this open meeting are summarized below. . Diagnostic criteria 2002 of autoimmune pancreatitis by the Japan Pancreas Society 1. Diffuse or segmental narrowing of the main pancreatic duct with irregular wall (more than 1/3 length of the entire pancreas) and diffuse or localized enlargement of the pancreas by imaging studies 2. High serum γ-globulin and/or IgG, or the presence of autoantibodies, such as antinuclear antibodies and rheumatoid factor 3. Marked interlobular fibrosis and prominent infiltration of lymphocytes and plasma cells in the periductal area, occasionally with lymphoid follicles, in the pancreas For diagnosis, criterion 1 must be present together with criterion 2 and/or 3 Concept and definition of AIP 1. The following extrapancreatic lesions may be associated with AIP: biliary lesions, sialadenitis, retroperitoneal fibrosis, enlarged celiac and hilar lymph nodes, chronic thyroiditis, and interstitial nephritis [bib_ref] Clinicopathological features of autoimmune pancreatitis in relation to elevation of serum IgG4, Kamisawa [/bib_ref] [bib_ref] Extrapancreatic lesions in autoimmune pancreatitis, Kamisawa [/bib_ref] [bib_ref] Systemic extrapancreatic lesions associated with autoimmune pancreatitis, Ohara [/bib_ref] [bib_ref] Clinical differences between primary sclerosing cholangitis and sclerosing cholangitis with autoimmune pancreatitis, Nakazawa [/bib_ref] [bib_ref] Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of..., Hamano [/bib_ref] [bib_ref] Autoimmune pancreatitis, Okazaki [/bib_ref] [fig_ref] Table 2: Clinicopathological features of autoimmune pancreatitis [/fig_ref]. AIP may be a systemic disorder. 2. Sclerosing cholangitis associated with AIP is different from primary sclerosing cholangitis (PSC), because of its effective response to steroid therapy and of the presence of IgG4-positive plasma cell infiltration. 9-14 3. Sialadenitis coexisting with AIP is negative for both anti-SSA and anti-SSB antibodies and shows IgG4positive plasma cell infiltration, suggesting that it is different from typical Sjögren's syndrome but is similar to the sclerosing sialadenitis observed in Mikulicz's disease and Küttner's tumor. 9,10,14 4. In Western countries, ulcerative colitis and the formation of tumors associated with pancreatic lesions are more frequently observed than in Japan. [bib_ref] Controversies in clinical pancreatology: autoimmune pancreatitis: does it exist?, Pearson [/bib_ref] Moreover, pancreatic duct lesions with infiltration of leukocytes as well as LPSP are sometimes observed in Western countries [bib_ref] Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases, Notohara [/bib_ref] [bib_ref] Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study..., Zamboni [/bib_ref] but not in Japan. These findings may thus be somewhat contrary to the definition and concept of the disease adopted in Japan. 5. The biggest problem in diagnosing AIP is how to distinguish it from pancreatic or biliary cancer. With the current diagnostic criteria for AIP, many cases that seem to be AIP are excluded, as the criteria were established to rule out false positive cases but to confidently diagnose definite cases of AIP. [bib_ref] Controversies in clinical pancreatology: autoimmune pancreatitis: does it exist?, Pearson [/bib_ref] [bib_ref] Autoimmune pancreatitis, Okazaki [/bib_ref] Image findings 1. Some cases are consistent with the hematological and histopathological findings of AIP, even though the pancreatic image data show that the lesions are localized to less than one-third of the pancreas. . The receiver operating characteristic (ROC) curves. The ROC curves for the 147 cases of AIP and 180 cases of control diseases, the cutoff value for the serum IgG4 was determined to be 128 mg/dl cells, and obliterative phlebitis. In lymphocyte infiltration, T cells are often predominant, and plasma cells are IgG4-positive. [bib_ref] Autoimmune pancreatitis, Okazaki [/bib_ref] 2. European and U.S. reports of the destruction of the pancreatic duct epithelium in the presence of predominant neutrophils (idiopathic ductcentric chronic pancreatitis 17 or granulocyte epithelial lesion [bib_ref] Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study..., Zamboni [/bib_ref] have not been confirmed in Japan owing to insufficient study and will be a topic of further study. 3. Pathologically, extrapancreatic lesions are similar to the fibrosis and the lymphoplasmacytic infiltration seen in the pancreatic lesions. ## Background of the amendment of the diagnostic criteria proposed by the working group of the research committee of intractable diseases of the pancreas ## Prognosis 1. Some patients with AIP form pancreatic stones, and the long-term prognosis of AIP is still unclear. 14 ## Final revision based on the discussion in the open forums In two recently held open forums, the committee members vigorously exchanged opinions about the amendments proposed by the Research Committee of Intractable Diseases of the Pancreas, and unanimously agreed to the finalized amendments [fig_ref] Table 3: Clinical Diagnostic Criteria of Autoimmune Pancreatitis [/fig_ref]. The medical treatment guidelines in the current diagnostic criteria have been deleted from the proposed amendments. Those issues that were discussed in the open forums but not included in the proposed amendments are noted below as topics for future consideration. 1. Cases of AIP reported from Western countries are more often associated with ulcerative colitis and the formation of tumors compared with Japanese cases; these associations are somewhat contrary to the definition and concept of the disease adopted in It is suspected that the pathogenesis of autoimmune pancreatitis (AIP) involves autoimmune mechanisms. Currently, the main characteristic findings of observed cases of AIP are the diffuse enlargement of the pancreas and the narrowing of the pancreatic duct, associated with findings suggestive of the involvement of autoimmune mechanisms such as increased levels of γ-globulin and IgG, the presence of autoantibodies, and an effective response to steroid therapy. In some cases, AIP shows extrapancreatic manifestations such as sclerosing cholangitis, sclerosing sialadenitis, and retroperitoneal fibrosis, suggesting that AIP is a systemic disease. In Western countries, AIP is more frequently observed in association with ulcerative colitis and tumor formation, which observations are somewhat contrary to the definition and concept of the disease adopted in Japan. Patients with AIP often experience discomfort in the epigastrium, obstructive jaundice due to bile duct stricture, and diabetes mellitus. AIP is more common in middle-aged and elderly men. Although long-term prognosis of the disease is not clear, pancreatic stone formation has been found in some cases. When diagnosing AIP, it is important to differentiate it from neoplastic lesions such as pancreatic or biliary cancers, and to avoid facile therapeutic diagnosis by steroid administration. The present criteria, therefore, are based on the minimum consensus features of AIP in order to avoid the misdiagnosis of pancreatic or biliary cancer as far as possible but not to pick up suspicious cases of AIP. I. Clinical diagnostic criteria 1. Diffuse or segmental narrowing of the main pancreatic duct with irregular wall and diffuse or localized enlargement of the pancreas by imaging studies, such as abdominal ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). 2. High serum γ-globulin, IgG, or IgG4, or the presence of autoantibodies, such as antinuclear antibodies and rheumatoid factor. ## Marked interlobular fibrosis and prominent infiltration of lymphocytes and plasma cells in the periductal area, occasionally with lymphoid follicles in the pancreas. Diagnosis of autoimmune pancreatitis is established when criterion 1, together with criterion 2 and/or 3, are fulfilled. However, it is necessary to exclude malignant diseases such as pancreatic or biliary cancers. ## Description notes A. Imaging studies 1. Diffuse or localized swelling of the pancreas Abdominal US, CT, and/or MRI show diffuse or localized swelling of the pancreas. a. On US, pancreatic swelling is usually hypoechoic, sometimes with scattered echogenic spots. b. Contrast-enhanced CT generally shows delayed enhancement similar to a normal pancreas with sausage-like enlargement, and/or a capsular-like low-density rim. c. MRI shows diffuse or localized enlargement of the pancreas with lower density in the T1-weighed image and higher density in the T2-weighed image compared with the corresponding liver image. ## Narrowing of the pancreatic duct The main pancreatic duct shows diffuse or localized narrowing. a. Unlike obstruction or stricture, narrowing of the pancreatic duct extends over a larger range, where the duct is narrowed with irregular walls. In typical cases, more than one-third of the entire length of the pancreatic duct is narrowed. Even in cases where the narrowing is segmental and extends to less than one-third of the total length, the upper part of the main pancreatic duct rarely shows notable dilatation. b. When the pancreatic images show typical findings but laboratory data do not, AIP is possible. However, without histopathological examination, it is difficult to distinguish AIP from pancreatic cancer. c. To obtain images of the pancreatic duct, it is necessary to use endoscopic retrograde cholangiopancreatography in addition to direct images taken during an operation or of specimens. Currently, it is difficult to depend for the diagnosis on magnetic resonance cholangiopancreatography. 3. The pancreatic image findings described above may be observed retrospectively from the time of diagnosis. B. Laboratory data 1. In many cases, patients with AIP show increased levels of serum γ-globulin, IgG, or IgG4. High serum IgG4, however, is not specific to AIP, since it is also observed in other disorders such as atopic dermatitis, pemphigus, or asthma. Currently, the significance of high serum IgG4 in the pathogenesis and the pathophysiology of AIP is unclear. 2. Although increased levels of serum γ-globulin (≥2.0 g/dl), IgG (≥1800 mg/dl), and IgG4 (≥135 mg/dl) may be used as a criterion for the diagnosis of AIP, further studies are necessary. 3. Autoantibodies such as antinuclear, anti-lactoferrin, anti-carbonic anhydrase antibody and rheumatoid factor are often detected in patients with AIP. C. Pathohistological findings of the pancreas 1. Fibrotic changes associated with prominent infiltration of lymphocytes and plasma cells, occasionally with lymphoid follicles, are observed. In many cases, infiltration of IgG4-positive plasma cells is observed. 2. Lymphocytic infiltration is prominent in the periductal area, together with interlobular fibrosis, occasionally including intralobular fibrosis. 3. Inflammatory cell infiltration involves the ducts and results in diffuse narrowing of the pancreatic duct with atrophy of acini. 4. Obliterative phlebitis is often observed. 5. Although fine-needle biopsy under ultrasonic endoscopy is useful for differentiating AIP from malignant tumors, diagnosis may be difficult if the specimen is too small. D. Endocrine and exocrine function of the pancreas Some patients with AIP show a decline of exocrine pancreatic function and develop diabetes mellitus. In some cases, steroid therapy improves endocrine and exocrine pancreatic dysfunction. II. Relationship to extrapancreatic lesions and other associated disorders AIP may be associated with sclerosing cholangitis, sclerosing sialadenitis, or retroperitoneal fibrosis. Most AIP patients with sclerosing sialadenitis show negativity for both anti-SSA and anti-SSB antibodies, which may suggest that AIP differs from Sjögren's syndrome. Sclerosing cholangitis-like lesions accompanying AIP and primary sclerosing cholangitis respond differently to steroid therapy and have different prognoses, suggesting that they are not the same disorder. Further studies are necessary to clarify the role of autoimmune mechanisms in AIP. Japan. [bib_ref] Controversies in clinical pancreatology: autoimmune pancreatitis: does it exist?, Pearson [/bib_ref] [bib_ref] Clinicopathological features of autoimmune pancreatitis in relation to elevation of serum IgG4, Kamisawa [/bib_ref] [bib_ref] Idiopathic chronic pancreatitis with periductal lymphoplasmacytic infiltration: clinicopathologic features of 35 cases, Notohara [/bib_ref] [bib_ref] Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study..., Zamboni [/bib_ref] These points were excluded from the Japanese notes, because in Japan, the basic concepts of AIP are generally accepted as pancreatitis featuring abnormal immunity, an enlarged pancreas, and a narrowing of the pancreatic duct. However, these controversial points were considered for inclusion in the introduction to the English notes because they were deemed necessary to clarify the inconsistencies between the findings of foreign and domestic researchers. 2. It was argued that AIP can be diagnosed by imaging data and the effective response to steroid therapy alone. This argument, however, was excluded because of two problems. First, no other autoimmune disorders use steroidal effect for diagnosis except for the scoring system for autoimmune hepatitis, in which the steroidal effect is not used for the differential diagnosis of malignancy. Second, above all, there was a concern that its adoption might encourage the use of facile therapeutic diagnostic techniques just to distinguish AIP from malignant tumors such as pancreatic cancer. 3. There was an argument as to whether the proposal should specify methods for ruling out other pancreatic disorders and pancreatic/biliary cancers. It was decided that each institute may decide the methods at their discretion, because standardization is rather difficult. # Conclusion The current concept of AIP including extrapancreatic lesions and associated disorders suggests that AIP may be a systemic disorder. As the concept of the disease has undergone changes, a revised version of the clinical diagnostic criteria of AIP in Japan has been proposed. Although it is not possible to establish diagnostic criteria that satisfy everyone, the Japanese criteria are based on the minimum consensus features of AIP in order to avoid the misdiagnosis of malignancy as far as possible, but not to pick up suspicious cases of AIP. [fig] On 7: October 2005 and 22 April 2006, the Research Committee of Intractable Diseases of the Pancreas and the Japan Pancreas Society jointly held open forums to discuss the proposed amendments. [/fig] [table] Table 2: Clinicopathological features of autoimmune pancreatitis [/table] [table] Table 3: Clinical Diagnostic Criteria of Autoimmune Pancreatitis (revised proposal) (Proposed by the Research Committee of Intractable Diseases of the Pancreas, supported by the Japanese Ministry of Health, Labour and Welfare, and the Japan Pancreas Society) [/table]	None	https://link.springer.com/content/pdf/10.1007/s00535-006-1868-0.pdf	None
28ff37c5788a0f33e0dac32be5e0cc453f90fc64	pubmed	International Diabetes Federation guideline for management of postmeal glucose: a review of recommendations	International Diabetes Federation guideline for management of postmeal glucose: a review of recommendations Diabetes is a significant and growing concern, with over 246 million people around the world living with the disease and another 308 million with impaired glucose tolerance. Depending on the resources of different nations, intervention has generally focused on optimizing overall glycaemic control as assessed by glycated haemoglobin (HbA 1c ) and fasting plasma glucose (FPG) values. Nevertheless, increasing evidence supports the importance of controlling all three members of the glucose triad, namely HbA 1c , FPG and postmeal glucose (PMG) in order to improve outcome in diabetes. As part of its global mission to promote diabetes care and prevention and to find a cure, the International Diabetes Federation (IDF) recently developed a guideline that reviews evidence to date on PMG and the development of diabetic complications. Based on an extensive database search of the literature, and guided by a Steering and Development Committee including experts from around the world, the IDF Guideline for Management of Postmeal Glucose offers recommendations for appropriate clinical management of PMG. These recommendations are intended to help clinicians and organizations in developing strategies for effective management of PMG in individuals with Type 1 and Type 2 diabetes. The following review highlights the recommendations of the guideline, the supporting evidence provided and the major conclusions drawn. The full guideline is available for download at www.idf.org. # Introduction Diabetes has no geographical boundaries and the disease, once ascribed to more affluent countries, is now known to profoundly affect developing nations. More than 246 million people around the world are now living with diabetes and 308 million people are estimated to have impaired glucose tolerance (IGT). These alarming figures translate to an estimated 3.8 million people succumbing to the disease in the past year. As a global issue, diabetes outcome is closely tied to the management strategies and resources available in the various regions of the world. However, even within the limitations of healthcare resources in certain nations, there is a need to optimize diabetes management to minimize related morbidity and mortality. Among the many methods recognized for improving outcome in diabetes, such as lifestyle modification and control of related risk factors, the importance of tailoring therapies to achieve specific glycaemic targets is increasingly apparent. Traditionally, intervention has largely focused on optimizing overall glycaemic control as assessed by glycated haemoglobin (HbA 1c ) and fasting plasma glucose (FPG) values [bib_ref] Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the..., Nathan [/bib_ref]. However, studies have highlighted the importance of targeting postmeal hyperglycaemia and demonstrate a strong relationship between elevated postmeal glucose (PMG) and the risk of complications . As part of its global mission to promote diabetes care and prevention and to find a cure, the International Diabetes Federation (IDF) has developed a guideline that reviews the relationship between PMG and the development of diabetes complications, as well as recommendations for the appropriate management of PMG. Below is an overview of the guideline's major conclusions and recommendations for management of postmeal glycaemia. ## Origin of guideline The postmeal guideline was developed under the direction of the IDF, through consultation of a Steering Committee (four members) and Development Committee (14 members). These committees were composed of individuals from around the world experienced at guideline development and healthcare delivery and living with diabetes. A series of four key questions served as the basis for an extensive, systematic search of the literature published over the past 20 years. Question 1: Is postprandial hyperglycaemia harmful? Question 2: Is treatment of postmeal hyperglycaemia beneficial? Question 3: Which therapies are effective in controlling postmeal plasma glucose? Question 4: What are the targets for postmeal glycaemic control and how should they be assessed? Relevant reports were obtained through a computerized search of the literature using PubMed and other search engines; scanning of incoming journals in the medical library and review of references in pertinent review articles, major textbooks and syllabi from national and international meetings on the subjects of diabetes, using relevant title and text words (e.g. postprandial, postmeal, hyperglycaemia, mealtime, self-monitoring, oxidative stress, inflammation) as search criteria. The committee reviewed over 1600 studies and numerous key reports before making recommendations based on the strength of the evidence. The draft guideline, which extended to management of both Type 1 and Type 2 diabetes, was distributed for wider review by IDF member associations, global and regional IDF elected representatives, interested professionals, industry and others on IDF contact lists. ## Rationale for postmeal glucose control In people with normal glucose tolerance, plasma glucose generally rises no higher than 7.8 mmol/l (140 mg/dl) (which reflects the World Health Organization definition). For this guideline, postmeal hyperglycemia is defined as a plasma glucose level > 7.8 mmol/l (140 mg/dl) 2 h after the ingestion of food. Development of postmeal hyperglycaemia coincides with a loss of first-phase insulin secretion, a decrease in insulin sensitivity and an inability to adequately suppress hepatic glucose production . As frank diabetes develops [bib_ref] The role of impaired early insulin secretion in the pathogenesis of Type..., Pratley [/bib_ref] , PMG excursions continue to worsen [bib_ref] The loss of postprandial glycemic control precedes stepwise deterioration of fasting with..., Monnier [/bib_ref]. The contribution of postmeal plasma glucose to HbA 1c is proportionally greatest with HbA 1c values of 6.5%, while nocturnal FPG is at a near-normal level. As HbA 1c rises above 8%, the relative contribution of postmeal hyperglycaemia to overall glycaemic control diminishes, while the contribution of FPG predominates [bib_ref] The loss of postprandial glycemic control precedes stepwise deterioration of fasting with..., Monnier [/bib_ref]. These results explain previous findings that, while the contribution of postmeal plasma glucose to overall glycaemia is ~70% at HbA 1c values < 7.3%, the postmeal contribution is 40% with HbA 1c values above 9.3% [bib_ref] Contributions of fasting and postprandial plasma glucose increments to the overall diurnal..., Monnier [/bib_ref]. Such findings form the basis for a glucose triad model of diabetes management, in which all three glycaemic parameters of HbA 1c , PMG and FPG interrelate, and are essential targets for intervention in attempts to optimize overall glycaemic control [fig_ref] FIGURE 1: Glycated haemoglobin [/fig_ref]. Postmeal or post-challenge hyperglycaemia is common in the diabetes population and is commonly found even in individuals considered to have adequate overall metabolic or glycaemic control. A cross-sectional study in the USA involving 218 individuals with Type 2 diabetes identified post-challenge glucose values ≥ 11.1 mmol/l (200 mg/dl) in nearly 74% of individuals overall and in 39% of those with HbA 1c values < 7.0% [bib_ref] Postchallenge hyperglycemia in a national sample of US adults with Type 2..., Erlinger [/bib_ref]. Individuals with Type 1 diabetes on 'intensive' insulin therapy are also typically subject to these glycaemic excursions, with 72-h continuous monitoring recording postmeal elevations above 7.8 mmol/l (140 mg/dl) in 77% of this patient population [bib_ref] Efficacy of continuous glucose monitoring system (CGMS) to detect postprandial hyperglycemia and..., Maia [/bib_ref]. The closer the achieved HbA 1c is to the normal range, the lower the risk of complications [bib_ref] Association of glycaemia with macrovascular and microvascular complications of Type 2 diabetes..., Stratton [/bib_ref]. Given that PMG is a major contribution to overall glycaemia across a range of HbA 1c values [bib_ref] Contributions of fasting and postprandial plasma glucose increments to the overall diurnal..., Monnier [/bib_ref] , targeting postmeal hyperglycaemia may help reduce risk of complications. The evidence and recommendations for the management of PMG are reviewed. ## Question 1: is postprandial hyperglycaemia harmful? Epidemiological studies have identified postmeal and postchallenge hyperglycaemia as independent risk factors for macrovascular disease in individuals with IGT and Type 2 diabetes . Findings from two large-scale studies, the European 'DECODE' and the Asian 'DECODA' study, demonstrated 2-h plasma glucose to be a strong predictor of cardiovascular disease and all-cause mortality [bib_ref] Screen-detected diabetes, hypertension and hypercholesterolemia as predictors of cardiovascular mortality in five..., Nakagami [/bib_ref] [bib_ref] Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-h diagnostic criteria, Decode Study Group [/bib_ref] and a better indicator than fasting glucose [bib_ref] Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-h diagnostic criteria, Decode Study Group [/bib_ref]. In addition, a meta-analysis of 38 prospective studies confirmed that, while cardiovascular risk increases linearly within a wide range of 2-h plasma glucose values, a threshold effect is detected for FPG values up to ~5.6 mmol/l (100 mg/dl) [bib_ref] Is non-diabetic hyperglycemia a risk factor for cardiovascular disease? A meta-analysis of..., Levitan [/bib_ref]. Postmeal hyperglycaemia more reliably predicted incidence of cardiovascular events in individuals with Type 2 diabetes than elevations in FPG, with cardiovascular risk greater in women than men when comparing the top vs. bottom tertiles of post-lunch plasma glucose values [bib_ref] Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting..., Cavalot [/bib_ref]. Along with population studies demonstrating an association between postmeal hyperglycaemia and macrovascular risk, surrogate markers of cardiovascular disease also appear to depend on PMG elevations. Even mild-to-moderate postmeal hyperglycaemia in individuals without diabetes was demonstrated to be an independent risk factor for development of carotid intima-media thickness (CIMT), a marker of atherosclerosis [bib_ref] Postprandial plasma glucose is an independent risk factor for increased carotid intima-media..., Hanefeld [/bib_ref]. In addition, a causal association was found between postmeal hyperglycaemia and oxidative stress, inflammation and endothelial dysfunction [bib_ref] Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery, Kawano [/bib_ref] [bib_ref] Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic..., Monnier [/bib_ref] and adhesion molecules [bib_ref] Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative..., Ceriello [/bib_ref]. Significant reductions in myocardial blood flow and blood volume are observed following ingestion of a mixed meal in individuals with Type 2 diabetes, while such myocardial perfusion deficits are not found during the postmeal state in individuals without diabetes [bib_ref] Postprandial myocardial perfusion in healthy subjects and in Type 2 diabetic patients, Scognamiglio [/bib_ref]. A number of other diabetes-related conditions are also associated with postmeal and post-challenge hyperglycemia, including independent correlation with diabetic retinopathy and neuropathy, as well as an association with diabetic nephropathy [bib_ref] Postprandial hyperglycemia is an important predictor of the incidence of diabetic microangiopathy..., Shiraiwa [/bib_ref] , increased cancer risk [bib_ref] Prospective study of hyperglycemia and cancer risk, Stattin [/bib_ref] and cognitive dysfunction in elderly individuals with Type 2 diabetes [bib_ref] Postprandial plasma glucose excursions and cognitive functioning in aged Type 2 diabetics, Abbatecola [/bib_ref]. ## Recommendation - Postmeal hyperglycaemia is harmful and should be addressed. ## Question 2: is treatment of postmeal hyperglycaemia beneficial? Although randomized controlled trials have not yet established whether controlling postmeal glycaemia will in itself reduce macrovascular or microvascular risk, evidence suggests that therapies 'preferentially' targeting postmeal hyperglycaemia appear to be beneficial [bib_ref] Acarbose reduces the risk for myocardial infarction in Type 2 diabetic patients:..., Hanefeld [/bib_ref] [bib_ref] Regression of carotid atherosclerosis by control of postprandial hyperglycemia in Type 2..., Esposito [/bib_ref] [bib_ref] Acarbose treatment and the risk of cardiovascular disease and hypertension in patients..., Chiasson [/bib_ref]. Treatment with acarbose, an α -glucosidase inhibitor that delays carbohydrate absorption following meals, significantly reduced postmeal hyperglycaemia, along with risk of myocardial infarction and other cardiovascular events in individuals with Type 2 diabetes [bib_ref] Acarbose reduces the risk for myocardial infarction in Type 2 diabetic patients:..., Hanefeld [/bib_ref] and IGT [bib_ref] Acarbose treatment and the risk of cardiovascular disease and hypertension in patients..., Chiasson [/bib_ref]. A positive effect is also observed on CIMT in individuals with Type 2 diabetes with the use of repaglinide, a rapid-acting insulin secretagogue that preferentially targets PMG; after a 1-year study period, regression of CIMT (i.e. decrease in CIMT of > 0.02 mm) was observed in 52% of individuals receiving repaglinide, compared with only 18% of those treated with glibenclamide (glyburide) [bib_ref] Regression of carotid atherosclerosis by control of postprandial hyperglycemia in Type 2..., Esposito [/bib_ref]. Similar findings are observed in individuals with IGT, demonstrating that acarbose therapy reduces CIMT progression compared with placebo control [bib_ref] Acarbose slows progression of intima-media thickness of the carotid arteries in subjects..., Hanefeld [/bib_ref]. Rapid-acting insulin analogues also appear to have a positive effect on surrogate markers of cardiovascular disease, including nitrotyrosine, endothelial function and methylglyoxal (MG) and 3-deoxyglucosone (3-DG) , with acarbose treatment also showing some similar effects on these markers [bib_ref] Effects of a single administration of acarbose on postprandial glucose excursion and..., Shimabukuro [/bib_ref]. Along with evidence for a reduction in macrovascular risk with treatments that preferentially target PMG in individuals with Type 2 diabetes [bib_ref] Acarbose reduces the risk for myocardial infarction in Type 2 diabetic patients:..., Hanefeld [/bib_ref] [bib_ref] Regression of carotid atherosclerosis by control of postprandial hyperglycemia in Type 2..., Esposito [/bib_ref] [bib_ref] Acarbose treatment and the risk of cardiovascular disease and hypertension in patients..., Chiasson [/bib_ref] , findings from recent interventional studies demonstrate that targeting postmeal hyperglycaemia helps optimize HbA 1c [bib_ref] Impact of fasting and postprandial glycemia on overall glycemic control in Type..., Woerle [/bib_ref] [bib_ref] 4T Study Group. Addition of biphasic, prandial, or basal insulin to oral..., Holman [/bib_ref]. Individuals with Type 2 diabetes achieving a target HbA 1c ≤ 7.0% had significantly lower PMG values after the end of a 3-month intensified diabetes management programme compared with those who did not [bib_ref] Impact of fasting and postprandial glycemia on overall glycemic control in Type..., Woerle [/bib_ref]. Fasting levels were not significantly different between the two groups, suggesting that, although control of FPG alone was necessary, it was not sufficient for achieving the HbA 1c target. In addition, severe hypoglycaemia was not associated with targeting postmeal hyperglycaemia. ## Recommendation - Implement treatment strategies to lower postmeal plasma glucose in people with postmeal hyperglycaemia. Guidelines from various professional diabetes organizations continue to encourage physical activity, nutritional intervention and weight control as essential components of a comprehensive programme for diabetes management . Nevertheless, the precise composition of the 'optimal' diet is still debated, although reducing glycaemic load (GL) has emerged as a favourable option [bib_ref] Food glycemic index, as given in glycemic index tables, is a significant..., Wolever [/bib_ref] [bib_ref] Comparison of 4 diets of varying glycemic load on weight loss and..., Mcmillan-Price [/bib_ref]. Glycaemic load is an estimate of the glycaemic effects of a diet, accounting for both the type of carbohydrate consumed [i.e. according to the glycaemic index (GI)] and the amount [bib_ref] Food glycemic index, as given in glycemic index tables, is a significant..., Wolever [/bib_ref]. With glycaemic load and glycaemic index reliably predicting the glycaemic response following a mixed meal [bib_ref] Food glycemic index, as given in glycemic index tables, is a significant..., Wolever [/bib_ref] [bib_ref] Comparison of 4 diets of varying glycemic load on weight loss and..., Mcmillan-Price [/bib_ref] , nutritional planning that incorporates these measures may not only reduce PMG excursions but is also found to modestly lower HbA 1c [bib_ref] Meta-analysis of lowglycemic index diets in the management of diabetes: response to..., Brand-Miller [/bib_ref] and possibly reduce cardiovascular risk [bib_ref] Meta-analysis of the health effects of using the glycaemic index in meal-planning, Opperman [/bib_ref]. A number of therapeutic agents that preferentially lower postmeal plasma glucose are currently available. These therapies include α -glucosidase inhibitors, glinides (rapidacting insulin secretagogues), rapid-acting insulin, biphasic (premixed) insulins and human regular insulin. In addition, newer classes of therapies have emerged that are also associated with a reduction in PMG excursions and improvement in Journal compilation © 2008 Diabetes UK. [fig_ref] FIGURE 1: Glycated haemoglobin [/fig_ref] HbA 1c . These agents include amylin analogues, glucagon-like peptide-1 (GLP-1) derivatives and dipeptidyl peptidase-4 (DPP-4) inhibitors [bib_ref] Effects of pramlintide on postprandial glucose excursions and measures of oxidative stress..., Ceriello [/bib_ref] [bib_ref] GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of Type 2..., Ahren [/bib_ref]. ## Recommendation - A variety of both non-pharmacologic and pharmacologic therapies should be considered to target postmeal plasma glucose. ## Question 4: what are the targets for postmeal glycaemic control and how should they be assessed? A 2-h postmeal goal of < 7.8 mmol/l (< 140 mg/dl) is recommended, in line with targets published in guidelines from other associations. Such guidelines define normal glucose tolerance (NGT) as post-challenge values of < 7.8 mmol/l 2 h after ingestion of a 75-g glucose load, corresponding to postmeal values of healthy individuals after meals [bib_ref] Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese..., Polonsky [/bib_ref]. The 2-h time frame for testing is also in agreement with published guidelines and in addition reflects the 2-to 3-h return of postmeal hyperglycaemia to basal levels in individuals with normal glucose tolerance. The guideline encourages performing glucose monitoring as frequently as needed in order to guide therapy to achieve PMG targets. In particular, the guideline suggests considering self-monitoring of blood glucose (SMBG), as it is the only way to directly assess PMG. However, some degree of controversy surrounds SMBG use, particularly with respect to the frequency of monitoring in non-insulin requiring diabetes [bib_ref] Impact of self monitoring of blood glucose in the management of patients..., Farmer [/bib_ref]. Nevertheless, most professional diabetes organizations continue to advocate its use, generally recommending that self-monitoring is performed at least three times daily in individuals treated with insulin and according to treatment regimen and level of glycaemic control in non-insulin dependent diabetes. What is more, the use of structured SMBG appears to result in a significant reduction in HbA 1c , even in individuals with non-insulin requiring diabetes [bib_ref] Self-monitoring of glucose in Type 2 diabetes mellitus: a Bayesian meta-analysis of..., Jansen [/bib_ref]. These findings support the implementation of SMBG as part of a structured programme that may involve the training of clinicians and patients to accurately interpret results and adjust therapy accordingly in a timely manner. ## Glycaemic goals for clinical management of diabetes - HbA 1c < 6.5% - Premeal (fasting) < 5.5 mmol/l (< 100 mg/dl) - Two hours postmeal < 7.8 mmol/l (< 140 mg/dl) Note: Lower glucose parameters to as near normal as safely possible. Glycaemic targets should be individualized. These goals are not appropriate for children and pregnant women. ## Recommendations - Two-hour postmeal plasma glucose should not exceed 7.8 mmol/l (140 mg/dl) as long as hypoglycaemia is avoided. - Self-monitoring of blood glucose should be considered because it is currently the most practical method for monitoring postmeal glycaemia. - Efficacy of treatment regimens should be monitored as frequently as needed to guide therapy towards achieving postmeal plasma glucose target. ## Relevance of guideline and implications The importance of managing PMG to improve overall glycaemic control in diabetes is now fairly widely recognized in guidelines from professional associations . As the research base continues to expand, the answers to other relevant questions are eagerly anticipated, such as whether there is a causal association between PMG and macrovascular complications and the role of SMBG in individuals who are not on insulin therapy. Until that time, logic and clinical judgment preside when interpreting the evidence presented in the guideline and deciding on an optimal management plan. Management strategies should depend on a practical evaluation of how best to integrate the recommendations into modern practice, with consideration to locally available therapies and resources. # Conclusions Postmeal hyperglycaemia occurs early in the development of diabetes, progressively worsens with deteriorating HbA 1c and is often inadequately controlled. In addition, elevations in Acts as a replacement for naturally occurring amylin, a hormone secreted by pancreatic B-cells along with insulin, that decreases glucagon release, slows gastric emptying and decreases food intake DPP-4 inhibitors Inhibits DPP-4 enzyme that degrades GLP-1 Glinides Stimulates a rapid but short-lived release of insulin GLP-1 derivatives Acts as a replacement for GLP-1, an incretin hormone secreted by the gut that stimulates insulin secretion, reduces glucagon secretion and delays gastric emptying rate Rapid-acting insulins Developed to mimic physiological insulin response to meals with rapid onset and peak activity and short duration of action DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1. PMG are strongly associated with a number of serious complications of diabetes, both through a direct contribution to HbA 1c as well as an independent association with various diabetes-related complications. Based on evidence to date, the guideline recommends implementing a comprehensive management programme that targets both postmeal and fasting glucose, which should be initiated simultaneously at any HbA 1c level to improve outcome in diabetes. A variety of both non-pharmacological and pharmacological therapies should be considered to target postmeal plasma glucose. Monitoring should occur as frequently as needed to guide therapy and SMBG should be considered. Subject to available therapies and resources, a 2-h postmeal plasma glucose target of < 7.8 mmol/l (140 mg/dl) is considered both reasonable and achievable. ## Comment Since publication of the guideline, results from an interventional study of 644 outpatients with Type 2 diabetes demonstrated that the glucose spike (i.e. the difference between premeal glucose value and peak value of glycaemia during three different meals) was the most important predictor of CIMT progression compared with all examined glycaemic parameters, with peak value of glycaemia occurring 1.5 h after the start of the meal [bib_ref] Post-meal glucose peaks at home associate with carotid intima-media thickness in Type..., Esposito [/bib_ref]. ## Competing interests [fig] FIGURE 1: Glycated haemoglobin (HbA 1c ), postmeal glucose (PMG) and fasting plasma glucose (FPG) interrelate and are essential targets for intervention in attempts to optimize overall glycaemic control. [/fig] [fig] Question 3: Which therapies are effective in controlling postmeal plasma glucose? [/fig]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1464-5491.2008.02565.x	Diabetes is a significant and growing concern, with over 246 million people around the world living with the disease and another 308 million with impaired glucose tolerance. Depending on the resources of different nations, intervention has generally focused on optimizing overall glycaemic control as assessed by glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) values. Nevertheless, increasing evidence supports the importance of controlling all three members of the glucose triad, namely HbA1c, FPG and postmeal glucose (PMG) in order to improve outcome in diabetes. As part of its global mission to promote diabetes care and prevention and to find a cure, the International Diabetes Federation (IDF) recently developed a guideline that reviews evidence to date on PMG and the development of diabetic complications. Based on an extensive database search of the literature, and guided by a Steering and Development Committee including experts from around the world, the IDF Guideline for Management of Postmeal Glucose offers recommendations for appropriate clinical management of PMG. These recommendations are intended to help clinicians and organizations in developing strategies for effective management of PMG in individuals with Type 1 and Type 2 diabetes. The following review highlights the recommendations of the guideline, the supporting evidence provided and the major conclusions drawn. The full guideline is available for download at http://www.idf.org.
6f1fb9984706c09fb131d5117b3874415eff6235	pubmed	British Society of Gastroenterology/Association of Coloproctologists of Great Britain and Ireland guidelines for the management of large non-pedunculated colorectal polyps	British Society of Gastroenterology/Association of Coloproctologists of Great Britain and Ireland guidelines for the management of large non-pedunculated colorectal polyps These guidelines provide an evidence-based framework for the management of patients with large nonpedunculated colorectal polyps (LNPCPs), in addition to identifying key performance indicators (KPIs) that permit the audit of quality outcomes. These are areas not previously covered by British ABSTRACT These guidelines provide an evidence-based framework for the management of patients with large nonpedunculated colorectal polyps (LNPCPs), in addition to identifying key performance indicators (KPIs) that permit the audit of quality outcomes. These are areas not previously covered by British Society of Gastroenterology (BSG) Guidelines. A National Institute of Health and Care Excellence (NICE) compliant BSG guideline development process was used throughout and the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to structure the guideline development process. A systematic review of literature was conducted for English language articles up to May 2014 concerning the assessment and management of LNPCPs. Quality of evaluated studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist System. Proposed recommendation statements were evaluated by each member of the Guideline Development Group (GDG) on a scale from 1 (strongly agree) to 5 (strongly disagree) with >80% agreement required for consensus to be reached. Where consensus was not reached a modified Delphi process was used to re-evaluate and modify proposed statements until consensus was reached or the statement discarded. A round table meeting was subsequently held to finalise recommendations and to evaluate the strength of evidence discussed. The GRADE tool was used to assess the strength of evidence and strength of recommendation for finalised statements. KPIs, a training framework and potential research questions for the management of LNPCPs were also developed. It is hoped that these guidelines will improve the assessment and management of LNPCPs. ## Objective To provide a structured framework for the management of large non-pedunculated colorectal polyps (LNPCPs). # Aims and methods The purpose of the guideline is to provide an evidence-based framework for the optimal management of LNPCPs for clinicians involved in their management, including gastroenterologists, nurse practitioners, physicians, colorectal surgeons, radiologists and pathologists. These guidelines refer specifically to lesions considered benign at the time of assessment and/or lesions without biopsy-proven malignancy. The management of malignant lesions is detailed in a recent position statement by the Association of Coloproctologists of Great Britain and Ireland (ACPGBI) and updated National Institute of Health and Care Excellence (NICE) guidelines for colorectal carcinoma. LNPCPs carry an increased risk of colorectal cancer, can be challenging lesions to resect endoscopically and are associated with an increased risk of incomplete excision and complications. The UK incidence of LNPCPs is unknown and no previous framework exists for the management of these lesions. Key questions we sought to cover included: 1. What are the key definitions and terms associated with LNPCPs? 2. What are the available management options? 3. What are the key principles for optimal management, including both assessment and therapy? 4. Which are the most complex lesions and how should they be managed? 5. What histopathological considerations are important in the management of LNPCPs? 6. When is surgical or conservative management more appropriate than endoscopic therapy? 7. Can multidisciplinary input into assessment and therapy improve management? 8. What information should patients be given about their management? 9. How should anticoagulant and antiplatelet drugs be managed before and after procedure? 10. How should patients be followed up after endoscopic removal of LNPCPs? 11. What are the most appropriate key performance indicators for monitoring the quality of management of LNPCPs? 12. What can be done to improve formal training in the management of LNPCPs? 13. What aspects of LNPCP management have the weakest evidence base and what are the key research questions which will help address these? The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a Open Access Scan to access more free content methodological framework for the development of the guidelines. In accordance with the British Society of Gastroenterology (BSG) NICE-compliant guideline process, a Guideline Development Group (GDG) including gastroenterologists, endoscopists, colorectal surgeons, gastrointestinal pathologists and a patient representative was selected to ensure wide-ranging expertise across all relevant disciplines. The surgical and histopathological representatives were nominated by the ACPGBI and the Royal College of Pathologists, respectively. A writing subcommittee was formed to identify key search terms for a comprehensive literature review of the management of LNPCPs and to develop draft recommendation statements. A literature search for English language articles published up to the present was performed using PubMed. The term 'colonic polypectomy' was entered into the PubMed MeSH database. A total of 5989 articles were returned. The terms 'therapy' and 'surgery' were used to filter the results based on relevance, after which, 2230 articles were returned and scrutinised for relevant articles. Additional PubMed searches were performed using additional search terms agreed by the writing subcommittee. The search terms used were 'colorectal laterally spreading type polyps', 'endoscopic mucosal resection', 'complex colonic polyps', 'difficult colonic polyps', 'surgical management of colorectal laterally spreading type polyps', 'endoscopic polypectomy', 'anticoagulation in endoscopic polypectomy', 'obtaining informed consent for endoscopic procedures', 'diathermy in polypectomy', 'argon plasma coagulation for polypectomy', 'submucosal injection for endoscopic mucosal resection', 'malignant colonic polyps', 'piecemeal endoscopic mucosal resection', 'colorectal endoscopic submucosal dissection', 'surgical management of colonic polyps', 'laparoscopic surgery of colonic polyps', 'training in endoscopic polypectomy' and 'transanal endoscopic microsurgery Returned abstracts were reviewed for relevance. Additional references were obtained by cross-referencing and by recommendation from the GDG. Relevant published national and international guidelines were also scrutinised. The 'Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist System' was used to evaluate the quality of studies and studies considered of suboptimal quality were excluded. Initial draft statements formulated by the writing committee were reviewed by the GDG to allow for modification and to identify additional references. After a preliminary discussion, formal anonymous voting rounds were undertaken. Each statement was scored by each member of the GDG using a five-point scale. Consensus required at least 80% agreement. Where consensus was not reached, feedback from the GDG members was disseminated after each round to allow members to reconsider their original position. Where appropriate, revisions to statements were made and a further voting round was undertaken. A final round of voting for statements where consensus had not been reached took place at a round table meeting at the BSG offices on 26 March 2014 (figure 1). Voting was anonymous throughout, with the final round of voting made using an electronic keypad system. The GRADE tool was used to evaluate the strength of evidence and the strength of recommendations made (see below). The GRADE system specifically separates the strength of evidence from the strength of a recommendation. While the strength of a recommendation may often reflect the evidence base, the GRADE system allows for occasions where this is not the case-for example, where it seems good sense to make a recommendation despite the absence of high-quality scientific evidence such as a large randomised controlled trial (RCT) (table 1). Diagram of statements used/discarded at each round. An overview of the GRADE system 5 ## Grade-strength of evidence grade-strength of recommendation High quality: Further research is very unlikely to change our confidence in the estimate of effect The trade-offs: Taking into account the estimated size of the effect for main outcomes, the confidence limits around those estimates and the relative value placed on each outcome Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate The quality of the evidence Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate Translation of the evidence into practice in a particular setting: Taking into consideration important factors that could be expected to modify the size of expected effects Very low quality: Any estimate of effect is very uncertain Uncertainty about the baseline risk for the population of interest EXECUTIVE SUMMARY OF KEY RECOMMENDATIONS Guideline recommendations: ▸ Definitions -We suggest that the term 'non-pedunculated colorectal polyp' (NPCP) is the most appropriate term to define sessile and flat colonic lesions, whereas the Paris classification and the term 'laterally spreading type polyp' (LST) may be used to subclassify lesions further. -We suggest that the term 'large NPCP' (LNPCP) may be used to describe NPCPs >2 cm in size. -We recommend that lesions displaying the following characteristics are identified as those with an increased risk of malignancy: lesions exhibiting: pit pattern type V, Paris 0-IIc or 0-IIa+IIc morphology, non-granular LST (laterally spreading type polyp, LST-NG), granular LSTs (LST-G) with a dominant nodule, distorted surface pattern, colour and vessels (NICE NBI type III), thick and irregular microvessels (Sano capillary pattern type III) (GRADE of evidence: moderate; Strength of recommendation: strong). -We recommend that the following lesions with the following characteristics are identified as having an increased risk of incomplete excision/recurrence: size >40 mm, location involving ileocaecal valve, appendix, diverticulum or dentate line; within an inflamed segment of colitis; prior failed attempt at resection or recurrence at site of previous resection (excluding unifocal, diminutive and easily resected/ablated residual adenoma on first site check); non-lifting sign after submucosal injection; endoscopist concern about difficult location (eg, behind flexure or fold, in stenotic diverticular disease) (GRADE of evidence: low; Strength of recommendation: strong). -We recommend that endoscopic factors associated with an increased risk of adverse events include: caecal location, size >40 mm and endoscopist inexperience (GRADE of evidence: low; Strength of recommendation: strong). -Complex NPCP: we suggest this term to describe NPCPs with any of the following features: (a) increased risk of malignancy; (b) increased risk of incomplete resection/ recurrence; (c) increased risk of adverse event; (d) size, morphology, size, access (SMSA) level 4 (GRADE of evidence: low; Strength of recommendation: weak). ▸ Service provision and management principles -We recommend that hospitals that detect or manage LNPCPs should develop a referral pathway to facilitate their management and processes to monitor the quality of the service. ## Definitions and terminology The term 'non-pedunculated colorectal polyp' (NPCP) was considered the clearest and most appropriate term to define sessile and flat colonic lesions. In accordance with other international series, it was agreed that the Paris classification and the term 'laterally spreading type polyp' (LST) may be used to subclassify lesions further. It was also agreed that these guidelines should focus primarily on polyps at least 2 cm in size, given the increased complexity associated with their removal and the increased risk of malignancy in this group. These lesions are referred to as LNPCPs unless specified otherwise. However, much of the guidance in this document may be applicable to smaller polyps. 1. We recommend that lesions with the following characteristics should be identified as those with as increased risk of malignancy: lesions exhibiting; pit pattern type V, Paris 0-IIc or 0-IIa+IIc morphology, non-granular LST (LST-NG), granular LSTs (LST-G) with a dominant nodule, distorted surface pattern, colour and vessels (NICE NBI type III), thick and irregular microvessels (Sano capillary pattern type III) (GRADE of evidence: moderate; Strength of recommendation: strong). ## Consensus reached: 100% agreement NPCPs with morphological features of depression (Paris 0-IIc/IIa+c) appear to correlate strongly with malignancy. A 2002 Paris workshop quoted an unpublished study of 3680 lesions where 61% of 0-IIc lesions displayed submucosal invasion, markedly higher than the morphological group with the next highest incidence of submucosal invasion (Paris Is: 34%).Lesions displaying surface characteristics of pit pattern type V are strongly associated with deep submucosal invasion. Specific analysis of lesions with type V pit pattern found a vastly higher incidence of malignancy than with other pit pattern types (56% vs 4.4% ( pit pattern III) vs 5% ( pit pattern IV) vs 0% ( pit patterns I+II), n=479, p<0.001). LSTs may be divided into granular (LST-G) and non-granular (LST-NG) types.In a study of 511 LSTs, the frequency of submucosal invasion with LST-NG type lesions was twice that of LST-G type lesions (14% vs 7%, p<0.01).Closer scrutiny of LST-NG type lesions suggests that pseudo-depressed LST-NG lesions are associated with the highest risk of submucosal invasion: a Japanese study of 1363 LSTs of at least 10 mm in size demonstrated submucosal invasion in 42.1% of pseudodepressed LST-NG lesions compared with 6.1% flat elevated LST-NGs (p<0.01).LST-G lesions with a nodule >10 mm were also strongly associated with submucosal invasion (>10 mm nodule: (29.8%) vs <10 mm nodule: (2%), OR=71.01, p<0.001).In view of these results, it appears that both LST-G type lesions with a large dominant nodule and LST-NGs warrant greatest concern.The identification of irregular and thickened microvessels using narrow-band imaging (NBI) (Sano capillary pattern classification) has been identified as an accurate method of determining depth of submucosal invasion. 14 A study of 130 NPCPs reported that the Sano CP type III pattern was associated with 84.8% sensitivity, 88.7% specificity and 87.7% diagnostic accuracy for differentiating deep submucosal invasion (sm2/3) from more superficial involvement (sm1).Another recently validated method of identifying deep submucosal invasion, the NICE NBI classification, allows examination of the surface characteristic of a polyp based on surface appearance, colour and vessel pattern without the aid of magnifying colonoscopy. A 2013 Japanese study demonstrated an overall sensitivity and negative predictive value for high confidence prediction of deep malignant submucosal invasion of 92% in a tertiary centre setting.2. We recommend that lesions with the following characteristics are identified as having an increased risk of incomplete excision/recurrence: size >40 mm, location involving ileocaecal valve, appendix, diverticulum or dentate line; within an inflamed segment of colitis; prior failed attempt at resection or recurrence at site of previous resection (excluding unifocal, diminutive and easily resected/ablated residual adenoma on first site check); non-lifting sign after submucosal injection; endoscopist concern about difficult location (eg, behind flexure or fold, in stenotic diverticular disease); (GRADE of evidence: low; Strength of recommendation: strong). Consensus reached: 92.3% agreement Various features of NPCPs have been identified that may predict the difficulty of achieving complete resection. Very large lesions are more technically challenging and timeconsuming to remove as they are associated with a higher likelihood of needing eventual surgical management. A study of LNPCPs managed within the UK Bowel Cancer Screening Programme (BCSP) identified lesions >40 mm as more likely to require surgery (20-29 mm (7.8%) vs 30-39 mm (23.9%) vs >40 mm (27.5%), p<0.001) and requiring an increased number of endoscopic procedures to achieve clearance (20-29 mm (1.84) vs 30-39 mm (2.31) vs >40 mm (2.33), p<0.001).Polyps that cross two haustral folds and polyps behind a fold or that have a 'clamshell' distribution around a fold are recognised as challenging to remove endoscopically.NPCPs that fail to lift in response to an accurately placed submucosal fluid injection (non-lifting sign) without prior intervention have an increased risk of deep submucosal invasion indicating a reduced likelihood of successful removal with snare polypectomy (see later). NPCPs subject to a previously failed endoscopic attempt, that have occurred in the context of IBD or are located in a site of previous endoscopic resection site are likely to be subject to scarring and submucosal fibrosis and may not lift adequately after submucosal fluid injection. An analysis of cases of failed endotherapy highlighted non-lifting lesions as a major risk factor (relative risk (RR)=4.96, 95% CI 3.51 to 7.01, p<0.001).Peri-diverticular polyps may also pose a problem with endoscopic access as this portion of the colon may be narrower and less amenable to a stable endoscopic position. Moreover, polyp tissue may encroach into a diverticulum. Lesions involving the ileocaecal valve have also been associated with a higher failure rate (RR=2.61, 95% CI 1.28 to 5.32, p=0.020).These lesions may be difficult to access and visualise (especially in distinguishing ileal mucosa from adenomatous tissue), while ileal involvement adds further complexity. 3. We recommend that endoscopic factors associated with an increased risk of adverse events include: caecal location, size >40 mm and endoscopist inexperience (GRADE of evidence: low; Strength of recommendation: strong). Consensus reached: 84.6% agreement NPCPs located in the right colon, especially in the caecal pole, and lesions >40 mm appear to be linked to an increased risk of adverse events following advanced polypectomy. Right-sided lesions are associated with an increased risk of perforation due to thermal tissue injury with polypectomy in the thinner right-sided colon.Lesions involving the caecal pole, including those that affect the appendiceal orifice, are considered to carry the highest risk as this is where the colonic wall is at its thinnest, while the front-on access angle increases the potential for the entire colonic wall to be ensnared during polypectomy.An Australian study identified right-sided location as an important risk factor for post-procedure bleeding (PPB) (adjusted OR=4.4, 95% CI 1.3 to 14.1, p=0.014), with the highest incidence found in the caecum.These findings were similar to that of a retrospective analysis of 146 lesions where an almost fivefold increased risk of delayed haemorrhage was seen with right-sided polyps (OR=4.67, 95% CI 1.88 to 11.61, p=0.001), while univariate analysis suggested that caecal polyps conferred the highest risk (OR=13.82, 95% CI 2.66 to 71.73). Multivariate analysis also reported an increase in bleeding risk by 13% for every 1 mm increase in polyp diameter (OR=1.13, 95% CI 1.05 to 1.20, p<0.001).A polyp size of >40 mm was identified as a major risk factor for PPB in a study of 493 LNPCPs compared with resection of lesions <40 mm (OR=43.043, 95% CI 4.306 to 430.314, p=0.001).Further evidence of caecal location and lesion size >40 mm as risk factors for adverse events was reported in a study of adverse events from 167 208 polypectomies performed within the English Bowel Cancer Screening Programme. Caecal location (OR=2.13, 95% CI 1.36 to 3.34, p<0.01) and polyp size of >40 mm (OR=3.90, 95% CI 3.35 to 4.94, p<0.001) were both identified as strong risk factors for adverse events in endoscopic polypectomy. The risk of adverse events increased further with combination of both these factors with a predicted risk of bleeding of one in eight.Endoscopist inexperience also appears to be a clear risk factor for adverse outcomes. An almost threefold increase in the risk of heavy bleeding and perforation with inexperienced endoscopists was seen in a 2008 study (OR=2.96, 95% CI 1.57 to 5.61, p=0.0008).A trend of increased adverse events after therapeutic colonoscopy by less experienced endoscopists has also been shown in large-volume studies by Singh et alThe GDG considered it important to use the term 'complex NPCP' to describe lesions with a greater than average risk of malignancy, incomplete resection/recurrence or complications that may be best suited to management by clinicians with the relevant skills and experience within a multidisciplinary environment. An additional method of stratifying lesion complexity has also been devised. The SMSA scoring system predicts the difficulty of achieving successful endoscopic polypectomy based on the size, morphology, site and access of a polyp (see below). A study stratifying lesions (n=220) using the SMSA scoring system reported a lower level of endoscopic clearance with lesions felt to be the most complex (SMSA level 4) than with less complex lesions (SMSA level 2 and 3) (87.5% vs 97.5%, p=0.009). This system may aid in service planning and stratifying lesions that require referral to an expert centre (tables 4 and 5). Service provision and management principles 1. We recommend that hospitals that detect or manage LNPCPs should develop a referral pathway to facilitate their management and processes to monitor the quality of the service. The pathway should ensure that patients have access to, and information about, a full range of therapeutic options, including laparoscopic surgery, a provision for the management of complex rectal lesions and endoscopists capable of performing endotherapy on complex NPCPs (GRADE of evidence: very low; Strength of recommendation: strong). ## Consensus reached: 100% agreement A structured referral pathway may ensure better interspecialty communication and timely and efficient management of LNPCPs.A pathway enables the creation of an audit trail and subsequent monitoring of performance. Patients, irrespective of their location, should have access to a full range of management options that minimise the risk of morbidity and mortality. This includes access to endoscopists capable of performing advanced therapy on LNPCPs. In expert hands, over 90% of selected lesions may be successfully removed, and surgery avoided, including lesions previously felt to be endoscopically unresectable. The management of rectal lesions also requires special consideration given the complexity and morbidity associated with resectional surgery in this area and possible need for a permanent stoma.In this context it is important to differentiate between complex benign polyps (the main subject of this document) and early rectal cancer. The management of rectal NPCPs is discussed in greater detail in 'Surgical management of LNPCPs'. The provision of advanced endoscopy services is also likely to be more cost-effective for hospital trusts and so a referral network to another centre is appropriate if the necessary expertise is not available locally. A 2013 UK analysis estimated a cost saving of £726 288 in a study of 220 patients (£3301.31 per patient) managed with endoscopy as opposed to surgery.For lesions where surgery is required, laparoscopic surgery should be available as a minimally invasive option with an equivalent lesion resection rate and accelerated post-operative recovery(see 'Surgical management of LNPCPs'). ## We suggest that clinicians involved in the management of LNPCPs should have access to a multidisciplinary network such as a MDM to discuss complex cases (complex as defined in these guidelines). Membership should include at least one complex NPCP endoscopist, at least one colorectal laparoscopic surgeon and a gastrointestinal histopathologist (GRADE of evidence: very low; Strength of recommendation: weak). Consensus reached: 92% agreement 3. We recommend that all endoscopists performing endotherapy on LNPCPs should be highly experienced in standard polypectomy, should have endoscopy service approval for this work and should be subject to regular audit to ensure their key performance indicators are above minimum quality standards (GRADE of evidence: low; Strength of recommendation: strong). ## Consensus reached: 92.3% agreement Although advanced polypectomy is an effective modality, the technical demands mean that the potential for serious complications such as haemorrhage and perforation are higher than for standard snare polypectomy. Patient safety is paramount and the ability to accurately identify underperformance will allow prompt remedial action. In addition, failure to achieve complete resection complicates further management and means the risk of subsequent malignancy is suboptimally managed.Increased endoscopist experience is associated with superior outcomes. A 2002 study reported significantly increased successful LNPCP clearance by the expert group compared with a nonexpert group (76% vs 40%, p=0.01).Endoscopist inexperience conclusively appears to directly affect patient safety. An almost threefold increase in the risk of heavy bleeding and perforation with the least experienced endoscopists and significantly increased adverse events for therapeutic colonoscopy with less experienced endoscopists in large-volume trials strongly highlights the importance of endoscopists who manage LNPCPs independently gaining sufficient experience beforehand.Technical endotherapy skill appears to vary widely even amongst experienced endoscopists. The CARE Study (n=418) found outcomes of incomplete resection varied widely between experienced endoscopists. The incomplete resection rate (IRR) for polyps thought to have been completely resected was higher than expected (IRR: 10.1% (95% CI 6.9% to 13.3%)), and increased significantly with larger polyp size (IRR 10-20 mm vs <10 mm: 17.3% vs 6.8%, p=0.003). 39 These findings suggest that advanced endoscopic polypectomy capabilities are not universal. Auditing outcomes using identified key performance indicators (KPIs) may enable endoscopists managing LNPCPs independently to demonstrate competency with consistent high-quality outcomes, resulting in improved outcomes and safety. 4. We suggest that patients with benign NPCPs should not undergo surgery without prior complex polyp MDM discussion (GRADE of evidence: very low; Strength of recommendation: weak). ## Consensus reached: 84.6% agreement There is increasing support for the view that multidisciplinary management can improve the management of LNPCPs, ideally via a dedicated complex polyp MDM or within an existing colorectal multidisciplinary team meeting where endoscopists capable of performing endotherapy on complex NPCPs are available. Key multidisciplinary team stakeholders should include a complex NPCP endoscopist, a laparoscopic colorectal surgeon and a gastrointestinal histopathologist. It is recognised that radiological input may be warranted in certain cases-for example, where there is difficulty in determining whether a lesion is benign or malignant. However, the GDG felt that the proportion of cases where radiological investigation changes the management of NPCPs was low. Radiological input was therefore not considered mandatory for a complex polyp MDM but suggested for consideration in selected cases. Reports from specialised MDMs within the fields of gastroenterology and endoscopy have commented that increased, more rounded, clinician input contributes to a more robust decisionmaking process and closer analysis of the full range of management options. A prospective study (n=1909) reported that a benign hepatopancreatobiliary MDM before endoscopic retrograde cholangiopancreatography was associated with improved safety and decreased overall complications compared with control cases (6.9% vs 12.0%, p<0.001) and lower severe complication rates (0.4% vs 2.5%, p=0.035).Increased interaction between endoscopists and colorectal surgeons should encourage consideration of all possible management options. The availability of a multidisciplinary network with access to an expert centre may result in enhanced treatment options and avoidance of surgery. The therapeutic capabilities of different endoscopists are not uniform, and increasing evidence suggests that many LNPCPs initially felt to be endoscopically unresectable and therefore referred for surgery can be removed endoscopically in an expert setting. This is preferable given the increased cost, mortality and morbidity associated with surgery. A 2014 study of 38 LNPCPs initially referred for surgery without biopsy-proven cancerreported successful endotherapy in 71% of cases including 26% of lesions for which previous endotherapy was unsuccessful, whereas a 2011 Australian study and a 2013 UK study were able to achieve complete endoscopic resection in 74.5% of previously attempted lesions and 87.5% of the most complex LNPCPS, respectively. Close interaction with histopathology is also important to establish comprehensive information about the adequacy of histopathology specimens, the possibility of malignant features, and establishing whether complete resection after endotherapy can be determined.. We suggest that primary therapeutic management of LNPCPs should be undertaken within 8 weeks of receipt of referral (GRADE of evidence: very low; Strength of recommendation: weak). ## Consensus reached: 100% agreement Previous reports suggest that 7-15% of LNPCPs may already harbour malignancy.The risk of malignancy in this patient group indicates a need for timely treatment. However, this needs to be balanced with ensuring that patients are managed by clinicians with the appropriate expertise. There is also a need to ensure that a lesion has been adequately assessed either at the referring or receiving centre before treatment, which may necessitate additional diagnostic endoscopy and assessment time to ensure optimal management. An 8-week target was suggested as feasible and aligned with the National Health Service (NHS) 62-day target from referral to treatment for suspected cancers. Although there is no evidence for 8 weeks specifically, a drive towards ensuring that management is timely is desirable. The exact time sequence for adenoma to carcinoma transformation with NPCPs is unclear, but growth model studies have sought to estimate progression times. A 2001 polyp growth model study reported a transformation rate of 3% a year for lesions >1 cm and 20% a year for lesions with carcinoma in situ.A precolonoscopy barium enema study of polyps >1 cm left untreated between 12 and 229 months estimated a cumulative risk of cancer at the polyp site at 5, 10 and 20 years as 2.5%, 8% and 24%, respectively.It appears unlikely that a projected time frame of 8 weeks will compromise patient safety, while more time is available to ensure that an appropriate endoscopist is available.. We recommend that endoscopic resection is first-line therapy for the removal of LNPCPs where there is no suspicion of malignancy (suspicion of malignancy as defined in these guidelines) (GRADE of evidence: moderate; Strength of recommendation: strong). ## Consensus reached: 92.3% agreement While surgical therapy has historically been used to remove some colorectal LSTs, endoscopic removal is now recognised as first-line therapy internationally. While endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are both management options, the limited availability of ESD in Western countries, together with technical considerations such as procedure time and a higher level of perforation (up to 10%), means that EMR appears the most viable option for lesions with no features indicative of malignancy. The availability of EMR is high and international studies, including those of complex lesions, have shown that EMR is effective, with reported curative rates of approximately 90%. The ACE study demonstrated treatment success in 91% of treatment-naive lesions and 74.5% of previously attempted lesions, with 89.2% of LNPCPS successfully removed in a single session.A 2012 study of 315 'defiant' polyps referred to an expert centre reported successful endoscopic removal in 91% of cases, all in a single session.A 2013 UK study of the endoscopic management of 220 colorectal lesions using EMR in an expert centre, demonstrated successful endoscopic treatment in 96% of cases with 87.5% of LNPCPs felt to be the most complex (SMSA level 4) successfully removed.The economic argument for endoscopic management as first-line treatment is strong with a cost saving of $5108.45 per patient compared with surgery in a UK setting, and a $6990 saving per patient estimated in an Australian study .Surgical resection appears less safe, with reported rates of morbidity and mortality of 20% and 1%, respectively.7. We recommend that piecemeal resection (either endoscopic or surgical) should be avoided if malignancy is suspected (GRADE of evidence: low; Strength of recommendation: strong). Consensus reached: 84.6% agreement An important oncological principle is that suspected malignant lesions are removed en bloc. En bloc lesion removal is associated with a lower level of lesion recurrence and a higher early cure rate than piecemeal resection.In addition, en bloc resection allows precise histological analysis such as definitive evaluation of lateral and vertical resection margins and depth of invasion and thus is essential to ascertain the presence of favourable or unfavourable histological criteria.Although, en bloc resection of LNPCPs using EMR is often not possible, the likelihood of achieving this is higher with ESD, with various studies demonstrating en bloc resection with this technique at a rate of approximately 90%.A Japanese retrospective analysis comparing lesions managed by ESD (n=145, 66% containing malignancy) with piecemeal EMR ( pEMR) (n=228, 69% containing malignancy) demonstrated only 2% recurrence with ESD compared with 14% recurrence with EMR ( p<0.0001), reporting a markedly higher cure rate with no significant difference in complications between the two groups.Another comparison study between en bloc endoscopic removal (ESD/EMR) and pEMR of benign lesions reported a similar trend for recurrence (n=269, ESD: 0%, EMR: 1.4%, pEMR: 12.1%, p<0.001) with similar complication rates.Unlike piecemeal resection, en bloc removal may be effective as both a diagnostic and therapeutic tool where a suspicion of malignancy exists. A 2012 Japanese retrospective series (n=589) assessing ESD outcomes for lesions with suspected but not proven malignancy at endoscopic assessment demonstrated en bloc and curative resection in 87% and 80% of cases, respectively.A 2013 multicentre Japanese study reported outcomes from a series of lesions removed by ESD that were retrospectively found to contain submucosal malignancy. Five-year recurrence-free survival was reported in 98% of 'low-risk' cases managed with ESD (negative vertical margins, were reported as well as moderately differentiated adenocarcinoma, absence of lymphovascular invasion, and invasion depth <1000 mm), whereas figures of 87% and 97% were reported in 'high-risk' lesions ( presence of any of the earlier described features) for lesions managed with ESD and ESD + surgery, respectively.However, while the potential efficacy of ESD is clear, there are significant challenges with achieving appropriate training, access and standardisation in a non-Japanese setting. The use of multidisciplinary networks appears important in ensuring increased access to ESD for UK patients. Aside from surgical resectional therapy, the use of minimally invasive surgical therapy such as transanal endoscopic microsurgery (TEMS) resection in the management of rectal polyps can be used to achieve en bloc resection of rectal lesions where malignancy requires exclusion. TEMS for the management of rectal LNPCPs has been associated with lower rates of early recurrence than with pEMR, in addition to allowing more robust histological examination. It should be noted, however, that late recurrence rates appear equivalent when allowing for repeat EMR and that TEMS has been associated with longer hospitalisation. In a few specialist centres, TEMS can involve an overnight stay only or be performed as a day-case procedure.TEMS is discussed in greater detail in 'Surgical management of LNPCPs'. pEMR is already established as resulting in a higher level of recurrence, but the risk appears even larger with malignancy. One study found a 10-fold increase in recurrence compared with benign lesions (n=50, 33.3% vs 3.1%, p<0.05) while a 2009 Japanese study (n=572) also reported higher recurrence (25% vs 17.1%, p<0.01).Piecemeal removal of malignancy has also been identified as an independent risk factor for incomplete resection by a 2011 Korean study (n=236, OR=3.365, 95% CI 1.295 to 8.744, p=0.013).Unlike en bloc retrieval, piecemeal removal results in the retrieval of poorer quality histological samples and it is often not possible to evaluate the completeness of resection, depth of invasion, lateral resection margins and other prognostic features. Surgery is often required in this situation owing to inadequate staging.The ability to evaluate resection margins is vital as it helps to ascertain the completeness of resection and can predict the likelihood of residual disease. A meta-analysis of 31 studies (n=1900) identified positive resection margins (<1 mm) as a strong risk factor for residual disease (OR=22, p<0.0001).A finding of indeterminate resection margin status, a common problem with piecemeal removal, may also predict an increased risk of residual/recurrent disease as demonstrated by Butte et al 63 (n=143, resection margins <1 mm: 16%, indeterminate margins: 21%, negative resection margins (>1 mm): 0%, p=0.009) (figure 2). Evaluation of the depth of submucosal invasion is also important as its depth has been shown to correspond to the risk of lymph node metastases. A large analysis of T1 colorectal carcinomas in 2002 (n=7543) found that lesions with deep submucosal invasion (sm3) were associated with a highly significant risk of lymph node metastases ( p<0.001).This histological information is therefore vital in establishing whether a patient has been cured, the risk of recurrence and planning of subsequent treatment. Although piecemeal endotherapy is effective for the management of benign lesions, for probable malignancy (eg, non-lifting sign in treatment-naïve lesions, pit pattern V, Paris 0-IIc, LST-NG, NICE NBI type III, Sano capillary pattern type 3), a higher level of recurrence and incomplete resection, an inability to sample or remove the lymph node basin and an inability to confirm eradication owing to the retrieval of suboptimal histological specimens highlight its inadequacy.Another note of caution is that several reports indicate a high level of residual malignancy on surgical resection specimens where complete polypectomy had been considered to have taken place. A study of 143 malignant lesions managed endoscopically reported residual malignancy in 19% of cases, while another analysis of 63 lesions resected endoscopically with a retrospective finding of early malignancy found residual malignancy in the colon wall and/or lymph nodes in almost 50% of cases managed surgically. However, this situation may be minimised through detailed assessment for complexity, advanced morphology and risk of complications as mentioned above.. We suggest that in the context of significant comorbidity, conservative management may sometimes be appropriate after detailed patient discussion and documentation (GRADE of evidence: very low; Strength of recommendation: weak). Consensus reached: 85.7% agreement While LNPCPs are associated with a risk of malignant transformation and may sometimes already harbour malignancy, the risk of symptomatic malignancy and cancer-related mortality Poor prognostic histological features.from these lesions may be outweighed by patient factors that may more imminently reduce life expectancy. In this context, subjecting a patient to the additional immediate risks of endoscopic or surgical resection may not be in their best interests. As previously discussed, adenoma to carcinoma transformation to a point where a lesion becomes symptomatic may take years.Patient factors requiring consideration include advanced age, frailty, comorbidities such as chronic cardiorespiratory conditions and other established malignancy. The use of mortality index models such as the Schonberg Index may help to stratify individual patient risk before attempting invasive treatment.For patients with increased age or severe comorbidity, both endoscopic and surgical therapy may prove hazardous, with the use of sedation and general anaesthetic posing significant cardiopulmonary safety concern. An Australian study reported an increased risk in 30-day mortality in non-cardiac surgery in patients over 70 (OR=1.09 per year over 70 years, 95% CI 1.04 to 1.13, p<0.001).The risks of increased surgical mortality and morbidity are important factors, as is consideration of whether a patient might survive a serious endoscopic complication and subsequent treatment. Conservative management may therefore prove appropriate where life expectancy is already greatly reduced. ## Lesion assessment 1. We recommend that all LNPCPs should be photographed or videoed before removal (GRADE of evidence: very low; Strength of recommendation: strong). ## Consensus reached: 100% agreement Comprehensive documentation with photos or video is considered good practice. A study comparing lesion assessment between US and Japanese expert endoscopists demonstrated a significant difference in the interpretation of flat lesions, including the identification of lesion depression.Misclassification may have implications for subsequent management (eg, endotherapy vs surgery). The use of imaging before therapy may allow for more accurate lesion assessment by additional multidisciplinary specialists without the need for repeat endoscopy.2. We suggest that a size estimate of LNPCPs should be made, ideally by measuring against an open snare (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 100% agreement Pathological estimation appears to be the most accurate method of assessing lesion size, but size estimation during endoscopy is important for deciding upon surveillance intervals and important also when considering the malignant potential of an NPCP and technical considerations such as deciding on en bloc or piecemeal resection or the resection plane.There is extensive evidence that visual size estimation during endoscopy continues to be inaccurate. A 1997 study including 61 LNPCPs, using pathological size estimation as a reference, reported that 20% of lesions were inaccurately estimated.A 2013 study (n=230) found that 62.6% of lesions were mis-sized by >33%, with 47.8% of lesions undergoing inappropriate surveillance because of this.The use of measurement tools has been shown to improve the accuracy of endoscopic size estimates.A readily available modality is the use of an open snare and their use as a size reference may improve accuracy. 3. We recommend that the Paris classification should be used wherever possible to describe polyp morphology (GRADE of evidence: low; Strength of recommendation: strong). ## Consensus reached: 100% agreement A Paris classification model for the description of polyps based on morphology was described in 2002.This was further revised in 2003 to enable the evaluation of superficial lesions with respect to the depth of submucosal invasion. Lesions were classified as protruding (0-I; incorporating pedunculated and sessile polyps), non-protruding and non-excavated (0-II; flatfurther divided as elevated (IIa), flat (IIb) and depressed (IIc)) and excavated (0-III).Lesion morphology appears to accurately predict the risk of malignancy. Non-protruding depressed lesions were highlighted as having an increased risk of malignancy.The initial finding of increased risk of submucosal invasion with Paris 0-IIc lesions compared with sessile lesions (n=3680, 61% vs 3%) has been repeated (n=479) (IIc or IIa +c: 31.8% vs IIb: 11.1% vs Is: 7.5% ( p=0.001)). Furthermore, these lesions also correlate with Kudo Pit Pattern type V, a more established indicator of likely malignancy.This demonstrates the reliability of the Paris classification in predicting malignancy and its use in guiding optimal management.The use of pit pattern classification has been well described and is a robust method of delineating between hyperplastic and adenomatous polyps, and also accurate in predicting deep malignant submucosal invasion based on polyp surface characteristics.A finding of a 'type V' pit pattern is strongly associated with a risk of deep submucosal malignancy compared with other pit pattern types.10 Subclassification of type V pit pattern to V I (irregular arrangement) and V N (amorphous structure) can further stratify malignancy risk. The increased association of type V N pattern with malignancy was confirmed by a finding of malignancy in 100% of these lesions in data from a 2008 Japanese analysis, compared with a reported rate of malignancy of approximately 30% in type V I lesions. Further subclassification of the type V I pattern to mildly irregular and severely irregular has been proposed owing to a marked difference in malignancy incidence between the two groups (7-17% and 56-85%, respectively). While a learning curve is required to interpret pit patterns, and the potential for interobserver variation exists, the use of training modules suggests that pit pattern recognition can be achieved even by inexperienced endoscopists.Enhanced imaging techniques may help to improve diagnostic accuracy when assessing NPCPs. NBI is a form of digital image enhancement that uses narrowband filters and high-intensity blue light to enhance surface mucosal and vascular pattern visualisation. A multicentre RCT (n=667) found that NBI had greater accuracy than both standard and high definition white light endoscopy at correctly predicting polyp histology with a sensitivity of 90% (95% CI 85.3% to 93.4%, p<0.001) and accuracy of 82% (95% CI 77.4% to 85.4%, p<0.001).The importance of NBI is also reflected in its inclusion in the NICE classification system, which has demonstrated accuracy in identifying deep submucosal invasion. In addition, it has high availability and it appears that it can be used by inexperienced endoscopists with appropriate training. A Japanese study demonstrated 90% accuracy (95% CI 85.1% to 93.3%) by a student group using the system. Both NBI and magnifying chromoendoscopy seem to be accurate in delineating between neoplastic and non-neoplastic polyps. A study comparing both modalities with white light endoscopy reported a diagnostic accuracy of >90% compared with white light endoscopy (59%).The utility of magnifying chromoendoscopy has also been confirmed by a large prospective study (n=4215), which demonstrated the accuracy of magnifying chromoendoscopy at estimating the depth of invasion of early colorectal neoplasms using combined mucosal and morphological patterns. The sensitivity, specificity and diagnostic accuracy of the invasive pattern to differentiate mucosal cancer or superficial invasion (sm1) (<1000 mm) from deeper invasion (sm2-3) (≥1000 mm) was reported as 85.6%, 99.4% and 98.8%, respectively.Recent European Society of Gastrointestinal Endoscopy (ESGE) guidelines adopt a similar position by recommending the use of conventional or virtual (NBI) magnified chromoendoscopy to predict the risk of invasive cancer and deep submucosal invasion.5. We suggest that if a lesion may be amenable to endoscopic removal, biopsies should be used with caution, as there is a risk of submucosal tethering due to scarring, rendering the lesion unresectable. Where biopsies are required because of concern about cancer, they should be targeted to the area exhibiting features indicative of cancer, avoiding flat areas and the lesion periphery. Tunnelling biopsies (biopsy through biopsy) should not be used (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 92.3% agreement Taking biopsy specimens of the colonic mucosa can result in fibrosis and subsequent non-lifting, also associated with malignancy and previous endoscopic resection attempts, making successful endoscopic removal more difficult to achieve.Multiple studies have reported that taking biopsy specimens can complicate the removal of colorectal lesions by compromising the submucosal lift from a fluid injection owing to submucosal fibrosis from a post-biopsy scar. A Korean study demonstrated a significantly reduced rate of submucosal elevation in a biopsy group compared with a non-biopsy group (n=42, 77% vs 45%, p=0.03).A delay between carrying out biopsies and subsequent endotherapy may also increase the difficulty in achieving successful resection. A 2008 study reported that previous biopsies significantly increased the incidence of the non-lifting sign, especially over 21 days after the biopsy (n=76, OR=16.208, 95% CI 1.024 to 256.442, p=0.048).All lesions assessed less than 21 days after biopsy did lift, however, suggesting an attempt at resection should be made as soon as possible after biopsy. These factors suggest that caution is required with biopsy use, especially when malignancy is not suspected and prompt repeat endoscopy cannot be guaranteed.Obtaining biopsies of a polyp may not contribute towards obtaining an accurate diagnosis. A 2005 study of 532 polyps asserted that colorectal biopsies were inadequate for grading of colorectal neoplasia, finding that the histopathological diagnosis was underestimated in up to 10% of cases while advanced neoplasia was underestimated in up to 60% of cases.Although important, histopathological assessment appears less significant in the management of benign polyps than with malignancy, in which the pathological assessment, including depth of invasion (by Haggitt level, Kikuchi level and quantitative measures), differentiation, lymphovascular invasion, tumour budding etc, are all important in the consideration of subsequent management. The GDG considered the major histopathological considerations for LNPCPs as described below. Where malignancy is suspected, careful targeting should be used to improve diagnostic accuracy and minimise submucosal fibrosis in the event of subsequent endotherapy.Endoscopic management: pre-procedure 1. We recommend that adequate planning should be undertaken (including length of time booked for procedure, endoscopist and nursing staff skills and endoscopic equipment) so that before an attempt at advanced polypectomy, the endoscopist has a high level of confidence that complete resection can be achieved in a single procedure (GRADE of evidence: very low; Strength of recommendation: strong). ## Consensus reached: 100% agreement Given the potential complexity of advanced polypectomy, adequate planning is required. In addition to the exclusion of malignancy and potential complications related to endotherapy, an important aim, where possible, is to attempt complete endoscopic resection in a single session.The significance of single session completion is reflected by its regular reporting as an important outcome in large volume trials while the ACE study demonstrated significantly lower treatment success with previously attempted lesions (75.4%) than with treatment-naïve lesions (91%) (OR=3.75, 95% CI 1.77 to 7.94, p=0.01). Key to achieving this aim is ensuring that adequate time is allocated for the procedure, an appropriate endoscopist is selected, optimal assessment has been undertaken (such as within a complex polyp MDM) and that all relevant professionals and equipment are readily available, which may not be the case at the time of detection.2. We recommend that antiplatelet drugs such as clopidogrel and prasugrel, and newer antiplatelet agents such as ticagrelor should be stopped at least 7 days before resection in accordance with BSG Antiplatelet Guidelines (GRADE of evidence: moderate; Strength of recommendation: strong). ## Consensus reached: 92.3% agreement Clopidogrel and prasugrel are classified as thienopyridines and have a different antiplatelet mechanism than aspirin. The BSG, ESGE and American Society of Gastrointestinal Endoscopy (ASGE) advise their cessation based on an increased haemorrhage risk.A meta-analysis of five observational studies concerning clopidogrel use with polypectomy compared 574 patients who continued clopidogrel therapy before polypectomy with 6169 control patients. A significantly increased risk of delayed post-polypectomy bleeding (RR=4.66, 95% CI 2.37 to 9.17, p<0.00001) was demonstrated.This concurred with another study where the incidence of delayed bleeding after polypectomy was over three times higher in the clopidogrel group (n=375, 3.5% vs 1%, p=0.02) but immediate bleeding incidence was similar in both groups.Prasugrel and newer antiplatelet agents such as ticagrelor appear to be more potent than clopidogrel and also require cessation. An RCT comparing prasugrel with clopidogrel (n=13 608) found that prasugrel was associated with a significantly higher rate of major bleeding (2.4% vs 1.8%, HR=1.32, 95% CI 1.03 to 1.68; p=0.03).Pharmacological studies have shown that clopidogrel, prasugrel and newer agents such as ticagrelor may affect platelet aggregation for up to 7 days and so cessation at around 7 days before LNPCP endotherapy appears appropriate. 3. We recommend that warfarin should be stopped at least 5 days before resection of LNPCPs and the INR should be confirmed as <1.5 before the procedure, in accordance with BSG Anticoagulation Guidelines (GRADE of evidence: moderate; Strength of recommendation: strong). We suggest that general recommendations about the management of newer anticoagulants which have differing properties, such as rivaroxaban and dabigatran, cannot currently be made owing to a lack of evidence. Appropriate specialist advice should be sought in this situation (GRADE of evidence: very low; Strength of recommendation: weak). ## Consensus reached: 92.3% agreement Cessation of warfarin before endotherapy is advocated by both the BSG and ASGE. A study of 1657 patients undergoing colonoscopic polypectomy showed that warfarin was strongly associated with PPB (OR=13.37, 95% CI 4.10 to 43.65, p<0.001).A single dose of warfarin can be detectable up to 120 h after ingestion and therefore cessation 5 days before endoscopy has been recommended with an INR established as near normal (<1.5).Newer anticoagulants such as dabigatran, rivaroxaban and apixaban are being used increasingly instead of warfarin as they do not require regular monitoring. In addition they have a much shorter half-life (dabigatran: 14-17 h, rivaroxaban: 4-9 h) meaning that they may be stopped closer to the time of endoscopy than warfarin. As they are renally excreted, caution is required with their use in the context of renal impairment, especially before endoscopic polypectomy, with earlier cessation likely to be needed to achieve normal patient clotting function.In the absence of evidence-based recommendations, obtaining specialist input about the management of these drugs before and after endoscopy is advised. 4. We recommend that patients should consent to the risk of thromboembolic events such as stroke and venous thromboembolism when stopping anticoagulants before endoscopic resection (GRADE of evidence: very low; Strength of recommendation: strong). We suggest that advice given should be tailored to a patient's individual risk with a 'bridging regimen' of low molecular weight heparin given to high-risk individuals in accordance with BSG guidelines. The risk of bleeding versus risk of thromboembolic episode should also be explained (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 85.7% agreement In certain 'high-risk' situations, temporary antithrombotic cessation may not be possible. The risk of embolism in patients with mechanical cardiac valves causing major morbidity, such as peripheral ischaemia, neurological deficit and mortality, is reduced from 4 per 100 patient years to 2.2 per 100 patient years and 1 per 100 patient years with antiplatelet and anticoagulant therapy, respectively.Bridging therapy with low molecular weight (LMW) heparin is advocated in this scenario owing to a reduction in risk of major embolism with temporary antithrombotic withdrawal. A prospective study of 224 high-risk patients with LMW heparin bridging therapy reported only two cases of thromboembolism due to warfarin cessation (0.9%, 95% CI 0.2% to 3.2%).In patients taking antiplatelet therapy such as clopidogrel for a drug-eluting cardiac stent, withdrawal of this also poses an increased risk of stent occlusion, major embolism and death.Endoscopic therapy may be delayed until a safer time is possible for antithrombotic withdrawal, but this may vary on an individual basis.In patients taking temporary anticoagulant therapy for venous thromboembolism, endotherapy may need to be delayed until treatment is completed or until antithrombotic therapy has been established for at least 1 month and temporary withdrawal does not appear to pose a significantly increased thromboembolic risk. In the event of permanent anticoagulant therapy (eg, for recurrent venous thromboembolism), bridging therapy will be required and specialist input may also be of use in this case.In patients with 'low-risk' conditions for thromboembolic events, such as uncomplicated atrial fibrillation or bioprosthetic cardiac valves, the practice of temporary antithrombotic therapy cessation for up to 5 days before endoscopy appears safe. A study of 1024 patients in which warfarin was stopped before endotherapy reported an incidence of thromboembolism of 0.4% if warfarin was stopped for <5 days compared with 2.2% in patients whose warfarin was stopped for >7 days.However, individual patient risk should be assessed. An analysis of 987 patients undergoing endoscopic procedures with anticoagulant cessation reported an incidence of stoke of approximately 1%, increasing to 2.93% in the presence of multiple comorbidities ( p=0.004-0.04).5. We suggest that where cessation of anticoagulants or antiplatelet medications is contraindicated owing to comorbidity, or where there is uncertainty, appropriate specialist advice should be sought. If the anticoagulation/antiplatelet medication is temporary and the lesion has been adequately assessed as being of low risk for cancer, deferral of resection until after this medication can be discontinued may be appropriate (GRADE of evidence: very low; Strength of recommendation: weak). ## Consensus reached: 100% agreement In complex situations, such as patients requiring advanced polypectomy who have metallic cardiac valves or atrial fibrillation with a cardiomyopathy, cessation of drugs such as warfarin or clopidogrel may be necessary and bridging therapy with aspirin or LMW heparin may be appropriate.The timing of medication cessation or change may vary and in these situations cardiology and/or haematology input is appropriate. If antithrombotic drugs are being given for a finite period-for instance, clopidogrel with cardiac drug-eluting stent insertion within 12 months, or warfarin for a recently diagnosed pulmonary embolism, it may be more appropriate to defer endotherapy to a time when antithrombotic therapy has finished or where temporary cessation is less likely to result in complications.Evidence to support this view are the results of a study (n=2223) of patients receiving antiplatelet therapy after cardiac stent insertion reporting a HR for stent thrombosis of 89.78 (95% CI 29.90 to 269.60, p<0.001) with premature withdrawal of antiplatelet medication.As previously discussed, with reported malignancy transformation rates of 3% a year for lesions >1 cm this approach appears safe.The increasing use of newer anticoagulant and antiplatelet drugs may result in an endoscopist being unfamiliar with a particular drug. In this case, or if a problem with antithrombotic medication is anticipated, it should be considered good practice to ensure that appropriate specialist advice has been obtained.6. We suggest that the evidence for the cessation/continuation of low-dose aspirin in the context of LNPCPs is weak and the decision should be individualised according to patient risk (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 100% agreement Conflicting reports about the safety of continuing aspirin before advanced polypectomy have been published. While it appears that many endoscopists stop aspirin before polypectomy, UK and US guidelines advise that it can be continued. Multiple casecontrol studies have suggested that aspirin does not increase haemorrhage risk in colonoscopy and polypectomy.An example includes a case-control study of 20 636 patients undergoing colonoscopy with polypectomy, which showed no significant difference with aspirin use in bleeding (40%) and non-bleeding groups (33%) (n=20 636, OR=1.41, 95% CI 0.68 to 3.04, p=0.32).Another example is a 2008 study demonstrating a similar frequency of PPB in aspirin and control groups (41% vs 39%; n=4592; p=0.80).Although specific LNPCP data are limited, a Japanese study examining the risk of bleeding with aspirin with ESD (n=582) showed similar levels of PPB with both aspirin interruption (15.4%) and cessation groups (16.1%), suggesting that aspirin continuation is safe.Given conflicting data and opinion, it does appear appropriate to manage aspirin use according to individualised patient risk, such as a scenario that an LNPCP presents a high risk of PPB. 7. We recommend that when obtaining consent for the endoscopic resection of LNPCPs, written information in plain English should be given. Management options including endoscopic therapy, surgery and conservative management should be discussed. For endoscopic therapy, patients should be informed of the potential need for subsequent check procedures and surveillance endoscopy. The risks of postprocedure bleeding (both immediate and delayed), perforation and residual polyp/recurrence should be explained (GRADE of evidence: very low; Strength of recommendation: strong). ## Consensus reached: 92.9% agreement Consent should adhere to the standards outlined by the Department of Health and the General Medical Council for obtaining valid informed consent. 36 106 107 Principles of obtaining valid informed consent for any procedure include that a patient should understand and retain the information given to them, acknowledge the potential ramifications of a treatment and be aware of all management options for a condition, including conservative management.Discussions should include the potential risk of complications, the possibility of having malignancy within the polyp despite previous benign histology and radiology, and the benefits of a day-case procedure as opposed to a procedure involving a hospital admission.Patients may decide to have no therapeutic management, despite the risk of subsequent malignancy. This may be appropriate in elderly patients or those with comorbidities that reduce life expectancy more imminently than a malignant colonic polyp.The most serious complications related to advanced polypectomy procedure such as EMR and ESD are bleeding, perforation and incomplete resection. Reported figures for EMR are far higher than with standard polypectomy where rates of up to 1 in 100 and 1 in 500 have been reported for delayed bleeding and perforation respectively.The incidence of perforation with EMR appears to range between 0.5% and 1.3% while severe PPB has been reported in approximately 3-10% of cases in large-volume studies. Information pertaining to the risk of serious complications and alternative treatment may be given in a written form and this practice appears to be in place across various centres.Early recurrence with the need for additional treatment is also a prominent concern with the use of piecemeal endotherapy, with a 2014 meta-analysis examining piecemeal endoscopic resection suggesting that early recurrence occurs in up to 20% of cases.It would be appropriate to advise patients that early recurrence does not represent treatment failure as lesion clearance has been achieved in the vast majority of cases with follow-up endotherapy in almost all reported studies. The potential for late recurrence after 12 months, which may suggest treatment failure, should also be mentioned. Recent estimates from studies with large follow-up numbers after 12 months suggest a figure of between 4% and 7%. Data from LNPCP management within the BCSP (n=436) 5 mm reported 6% recurrence at 12 months, similar to figures of up to 6.9% which have been reported in other case series (figures 4-9). Endoscopic management: peri-procedure 1. We recommend that carbon dioxide should be used in preference to air insufflation during colonoscopy to improve patient comfort and safety (GRADE of evidence: high; Strength of recommendation: strong). ## Consensus reached: 100% agreement There is evidence that carbon dioxide (CO 2 ) insufflation improves patient comfort during colonoscopy in comparison with air insufflation, especially with longer procedures such as advanced polypectomy. A trial of 219 patients found that CO 2 was associated with significantly reduced pain ( p=0.014) and bloating ( p<0.001) in comparison with air insufflation as well as increased patient satisfaction (p=0.04).Another study showed that CO 2 use was associated with significantly reduced post-procedure admission after endoscopic polypectomy (OR=0.39, 95% CI 0.16 to 0.95, p=0.04). 114 CO 2 insufflation has also been associated with increased patient safety. As CO 2 is non-inflammable, the risk of combustibility with the use of diathermy and APC (both of which are important components of advanced polypectomy) is eliminated as oxygen is required for an explosion.The improved experience for the patient may allow longer procedure times, previously limited by patient discomfort, enabling single session resection. 2. We recommend that the use of contrast agents such as indigo carmine or methylene blue in the submucosal injection solution is considered to help demarcate a lesion, its resection margins, and to outline a clear submucosal plane (GRADE of evidence: low; Strength of recommendation: strong). ## Consensus reached: 100% agreement The use of contrast agents, to enhance lesion demarcation and a visualisation of post-resection margins in order to aid ascertainment of complete resection is well established. This appears especially relevant with serrated lesions where the resection margins appear more difficult to delineate. For example, almost half of serrated lesions where complete resection was considered to have occurred were found to have residual tissue in the CARE study.A study of 445 patients described how the use of indigo carmine facilitated the recognition of deeper planes of resection and identification of tissue deep to the submucosa, enabling the identification and management of all cases of post-resection perforation at the earliest opportunity.An association between methylene blue and potential DNA damage to colonocytes, reported in laboratory-based work, has no supporting clinical evidence.3. We suggest that the addition of low-concentration adrenaline to the submucosal injection solution may be considered to keep the resection field clear during endoscopic resection (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 100% agreement The use of adrenaline in submucosal injection solutions has been advocated to reduce the risk of immediate PPB. A 2001 study demonstrated reduced immediate PPB with a 1:10 000 adrenaline-containing solution compared with saline (1/75 vs 7/76, p=0.03) and a 2004 study also reported the same result (1/50 vs 8/50; p<0.05). No improvement has been demonstrated with delayed PPB. Korean study showed that this finding applied to LNPCPs (1/75 vs 7/76, p=0.03). Although the above evidence cites the use of a1:10 000 concentration of adrenaline, the consensus of the GDG is that concentrations less than 1:100 000 are also effective and potentially decrease the risk of cardiovascular ischaemia where large injection volumes are required. 4. We suggest consideration of the use of colloidal-type submucosal injection solutions in preference to normal saline lifting solution for LNPCPs (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 92.3% agreement Available evidence suggests colloidal-type solutions to be optimal for submucosal injection in view of technical and safety factors, with findings of a longer lasting lift facilitating easier resection than saline. Animal model studies show that Suggested management algorithm after large non-pedunculated colorectal polyps (LNPCP) identification. Box A (see; box B (see; box C (see. MDM, multidisciplinary meeting; MDT, multidisciplinary team. colloidal-type solutions such as succinylated gelatin (gelofusin) enable a longer lasting lift (mean of 36 min) and increased en bloc resection. Sodium hyaluronate commonly used for ESD, has also demonstrated superiority over normal saline in porcine models.A 2004 Japanese study group found that sodium hyaluronate produced a longer lasting lift than both normal saline and hypertonic solutions, with later reports citing reduced tissue injury. These findings appear to have been replicated in human studies. In a 2005 study (n=223), glycerol demonstrated a higher en bloc resection rate (63.6% vs 48.9%, p<0.05) and complete resection rate (45.5% vs 24.6%, p<0.01) than saline. . We suggest that endoscopists should be familiar with the range of snares available, although a single optimal snare cannot be recommended (GRADE of evidence: very low; Strength of recommendation: weak). ## Consensus reached: 100% agreement There is no evidence available to suggest an optimal snare for use in advanced polypectomy. Various sizes, shapes and textures of snares are available. Larger snares (>2 cm) are preferred by some operators with the intention of en bloc resection or widefield resection of larger polyps, though operators should be aware that this carries a potentially increased risk of perforation if a large volume and depth of tissue is within the snare. Smaller, thinner (monofilament) snares are often preferred where increased precision is required and spiral or stiffer snares are often used by some operators where gripping of a flat elevated lesion is thought to be optimised.Reports favouring the use of a particular snare such as spiral or crescentic snares appear subjective, limiting the ability to recommend a particular snare. 6. We suggest that a prolonged pure coagulation current should be avoided owing to an increased risk of delayed postpolypectomy bleeding and thermal tissue injury (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 92.3% agreement The choice of polypectomy diathermy settings seems to vary extensively. A North American survey of endoscopic practice in 2004 (n=198) found that blended current (46%) and coagulation current (46%) were more commonly used, with lower reported use of varied (4%) and pure cutting current (3%).A 2013 Israeli survey (n=100) found that 42% used a pure coagulation current, with 38% using blended current and 20% using pure cutting current.A pure cutting current is likely to be related to higher rates of immediate PPB owing to poor haemostasis properties, and the avoidance of its use in endoscopic polypectomy has been advocated by some groups including the ESGE. A cutting current does have good incisional properties, however, enabling high-quality resection specimens and inducing less thermal tissue injury. A 1992 study comparing the use of coagulation current with a form of cutting current in snare polypectomy (n=1485) found the latter to be associated with immediate haemorrhage ( p=0.03).A subsequent multicentre study (n=5152) identified pure cutting current as one of the greatest risk factors for immediate PPB (OR=6.95, 95% CI 4.42 to 10.04). Pure coagulation current appears to be commonly used and has good haemostasis properties. However, higher settings and prolonged use induce higher levels of thermal tissue injury. Porcine models have demonstrated a greater depth of tissue injury with coagulation current than both blended ( p=0.0157) and pure cutting current, ( p=0.0461).The increased risk of tissue injury is of particular concern in the thinner right colon, which is more susceptible to diathermy-induced perforation. The use of blended current or automated current that regulates coagulation and cutting current (such as Endocut) has been advocated as a safer diathermy option with the rationale that they provide adequate incision properties combined with effective haemostasis. A trial comparing blended and microprocessor-controlled automated current (n=148) found that automated current produced less tissue damage than blended current with a conventional electrosurgical generator ( p<0.02) while also producing higher-quality resection specimens ( p=0.024) allowing for more accurate histological evaluation ( p=0.046).These findings suggest that the rationale for the use of an automated current appears sound. 7. We suggest that while en bloc endoscopic snare resection of lesions <20 mm is recommended to reduce the risk of recurrence and to enable more accurate histopathological interpretation, this practice should be used with caution in LNPCPs owing to an increased risk of diathermy-associated thermal injury and perforation (GRADE of evidence: low; Strength of recommendation: weak). Consensus reached: 84.6% agreement En bloc snare resection is desirable owing to reduced recurrence and the ability to obtain more accurate histological analysis. In addition, a study by Kim et al 24 suggests that the risk of incomplete resection in piecemeal resection is significantly higher with lesions >30 mm (n=497, OR=2.688, 95% CI 1.036 to 6.993, p=0.042). A 2014 meta-analysis of 33 studies examining snare removal of NPCPs unequivocally demonstrates lower recurrence with en bloc resection than with piecemeal removal (3% (95% CI 2% to 5%) vs 20% (95% CI 16% to 25%), p<0.0001).Although it is possible to remove some LNPCPs en bloc with snare resection, it may be technically difficult to achieve owing to reduced snare stiffness while uncertainty about the resection plane may lead to concerns about perforation due to lack of control of tissue volume and from thermal injury due to an inability to control the cutting plane. A 2012 Korean study also showed that where EMR was carried out for NPCPs >30 mm, the likelihood of using piecemeal resection increased significantly for technical reasons (OR=7.246, 95% CI 4.672 to 11.235, p<0.001).Where en bloc specimen retrieval is required, such as with suspected malignancy, techniques such as ESD and surgery may be required. However, for benign lesions, piecemeal EMR has been shown to have comparable efficacy, especially when allowing for repeat treatment of recurrence, and with less morbidity. The high complete eradication rates reported by various studies such as 90% by Buchner et al 31 and 96% quoted by Longcroft-Wheaton et al,including 87.5% of SMSA level 4 lesions support this. In addition, while a 2009 study reported lower rates of early recurrence with en bloc TEMS for rectal lesions in comparison with pEMR, it should be noted that late recurrence was similar in both groups when allowing for repeat endoscopic therapy (TEMS: 9.6% vs EMR: 13.8%, p=0.386).8. We recommend that treatment-naïve lesions which fail to lift after adequate submucosal injection should not be subject to attempted resection with conventional snare polypectomy technique (GRADE of evidence: low; Strength of recommendation: strong). Consensus reached: 92.3% agreement Uno et al first described an association between non-lifting lesions in response to a submucosal injection and malignancy in 1994.All cases defined as non-lifting were found to contain malignancy. A 1999 Japanese study also demonstrated an association between the non-lifting sign and deep submucosal invasion (n=60). All lesions with deep submucosal invasion (sm3), lesions associated with a higher rate of lymph node metastases and so requiring surgery, displayed the non-lifting sign, whereas 93.5% of lesions with more superficial submucosal invasion (sm1) were successfully lifted.A later study repeated these findings with only 20% of sm3 lesions lifting as opposed to 82.4% of sm1 lesions ( p<0.05),and a 2007 study reported that the non-lifting sign displayed an accuracy rate of 94.8% (n=271, p<0.05).Correlation between the non-lifting sign in treatment-naïve lesions and deep submucosa invasion with lymph node involvement appears strong. In view of this, while en bloc removal may be possible, the mucosectomy action of snare polypectomy is less likely to be effective in treatment-naïve non-lifting lesions owing to irregularity of the submucosal plane.9. We recommend that during endoscopic piecemeal resection, the snare should be used to resect a lesion completely wherever possible. Thermal coagulation techniques such as APC and soft coagulation may be used as adjuncts when snare resection of small residual fragments of polyp is not possible (GRADE of evidence: low; Strength of recommendation: strong). ## Consensus reached: 100% agreement APC is a non-contact method of thermal coagulation considered safe for use in therapeutic endoscopy. The use of APC as an adjunct to endoscopic snare resection has been supported by various studies. Zlatanic et al 147 reported a 50% reduction of residual adenoma on follow-up endoscopy compared with no APC use (n=77, 100% reduced to 50%). A 2003 study also demonstrated successful endoscopic clearance with the additional APC use in 90% of lesions with incomplete endoscopic snare resection (n=77).A larger study in 2011 commented that the use of APC on visible residual adenoma after piecemeal polypectomy did not reduce lesion recurrence (n=105; OR=0. . This finding may be due to the application of APC to larger areas of tissue but also highlights the fact that APC should not be relied upon as the sole treatment of residual adenoma. A 2002 study examining APC use on post-resection margins reported a reduced rate of adenoma recurrence after piecemeal EMR in lesions where complete resection was thought to have been achieved (1/10 APC, 7/11 no APC; p=0.02). This effect might be due to the treatment of microscopic residual foci at the resection margins not visible to the endoscopist.Thermal coagulation may also be provided by the use of soft coagulation from diathermy applied to tissue via the snare tip. However, no data to definitively support its use have yet been obtained. The use of hot biopsy avulsion has also been described as an ablative technique for flat polyp tissue considered unsnarable, with a small 2014 study (n=20) reporting no residual tissue on surveillance in 85% of cases.10. We recommend careful post-procedure inspection of the resection site and photographic documentation of completeness of resection (GRADE of evidence: low; Strength of recommendation: strong). ## Consensus reached: 100% agreement Imaging of a resection site is important to document and confirm whether complete resection has taken place, and also to confirm exclusion of a perforation. Taking steps to assess for complete resection appears important as incomplete resection seems to be far more prevalent than first thought, even among experienced endoscopists. The CARE study demonstrated increasing rates of incomplete resection with larger lesions. Of 10-20 mm lesions felt to be completely resected at endoscopy, 23.3% were found to be incompletely resected, despite the endoscopist considering complete resection to have taken place, significantly higher than with smaller lesions (17.3% vs 6.8%, p=0.003).A 2014 study demonstrated histological evidence of recurrence in 7% of LNPCPs where complete resection was felt to have occurred both on initial resection and follow-up (n=252).The ASGE recommend photo documentation in the area of a tattoo post-endoscopic resection as it may enable identification of a scar site where no residual tissue is present. . We recommend that with the exception of the rectum or caecum, a tattoo should be applied in accordance with local policy to aid endoscopic follow-up or subsequent surgical resection. As tattooing may cause submucosal fibrosis, the tattoo should be placed at least 30 mm from the lesion (GRADE of evidence: very low; Strength of recommendation: strong). Consensus reached: 92.3% agreement The use of tattoo application with an indelible marker such as Indian ink has been highlighted as an important practice in postendoscopic removal to enable identification of the resection site on follow-up and lesion identification in cases requiring surgical resection. Caution has been advised with the tattoo practice to avoid complicating endoscopic resection. Various case series have reported sublesional submucosal fibrosis resulting from tattoo application, thus compromising subsequent endoscopic resection by both EMR and ESD. In view of this, a tattoo should be placed away from a lesion, with a distance of at least 3 cm recommended in one case series.Endoscopic management: post-procedure 1. We recommend that written information about the risk of post-procedure complications (including bleeding risk for up to 2 weeks), together with recommended actions and an emergency phone number should be provided to patients (GRADE of evidence: very low; Strength of recommendation: strong). ## Consensus reached: 100% agreement Patients with serious complications related to polypectomy, such as haemorrhage and perforation, may not present with symptoms until several days after the procedure. An analysis of PPB from 14 575 cases reported a mean presentation time of 5 days after the procedure, with cases occurring up to 17 days after polypectomy, while there have been reports of PPB occurring up to 30 days after the procedure. An analysis of post-colonoscopy perforations found that 24% of cases presented over 48 h after colonoscopy, with 9% presenting after over 15 days.In view of this, the provision of a clear postprocedure plan is important and may expedite appropriate management and improve patient safety. 2. We suggest that recommencement of anticoagulant and antiplatelet therapy after polypectomy should be considered on an individual basis, weighing up the risks of post-procedure bleeding with the risks of a thromboembolic event. Further specialist advice (ideally sought before the procedure) may be appropriate (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 100% agreement While it is ideal that these drugs are restarted as soon as possible after endotherapy to reduce thromboembolism risk, the lack of evidence for restarting antiplatelet agents after advanced polypectomy is recognised, while conflicting evidence exists about the safety of restarting anticoagulants such as warfarin.A study of 94 patients restarting warfarin on the same day of endotherapy reported a delayed bleeding rate of <1%.However, a later study of 173 patients where warfarin was restarted within 7 days after endotherapy had an increased risk of bleeding (OR=5.2, 95% CI 2.2 to 12.5, p<0.001)).Events during endotherapy such as peri-procedural bleeding, in addition to patient factors, may also raise concerns about significant post-polypectomy haemorrhage. In light of this, management, should be considered on an individual basis along with specialist input. 3. We recommend that in the case of piecemeal EMR, initial follow-up should take place within 2-6 months (GRADE of evidence: low; Strength of recommendation: strong). Consensus reached: 92.9% agreement Early follow-up endoscopy after piecemeal resection is advocated owing to potentially high rates of incomplete resection and early lesion recurrence, with histological evaluation often unable to assess for completeness of resection as with en bloc removal.Recurrence levels appear to increase the longer the period of time left before follow-up after the initial treatment and early intervention of recurrent/residual tissue allows for prompt eradication.A Japanese study reported recurrence rates of 18.4%, 23.1% and 30.7% with follow-up at 6, 12 and 24 months, respectively, while a US study reported a similar trend with recurrence almost three times higher after 24 months than at 12 months. Initial follow-up at a later point such as 6 months also appears safe with similar levels of recurrence between 3 and 6 months. However, follow-up may also be appropriate sooner-for example, if malignancy or high-grade dysplasia on histology is found. Follow-up within 6 months is in line with the position of the US Multi-Society Task Force for Colorectal Cancer and the American Cancer Society who recommend that lesions removed piecemeal should be considered for follow-up endoscopy between 2 and 6 month intervals until complete excision.After lesion-specific follow-up has established clearance, further endoscopic surveillance should be consistent with existing BSG polyp surveillance guidelines.4. We recommend that on follow-up, the scar site should be positively identified, scrutinised and photographed. Image enhancement with techniques such as dye spray and digital enhancement may aid detection of residual neoplasia on a polypectomy scar. Areas of possible residual polyp require tissue diagnosis and definitive treatment (GRADE of evidence: low; Strength of recommendation: strong). Consensus reached: 84.6% agreement Evidence suggests that incomplete resection occurs at a higher rate than previously thought. The CARE study found a high incidence of incomplete resection (10.1%) in cases where complete resection was considered to have been achieved, including incomplete resection in almost half (47.6%) of sessile serrated adenomas, with a wide variation of incomplete polyp resection between endoscopists.Further justification for careful analysis of the scar site on follow-up endoscopy are reports of 'late recurrence' in an area where complete resection was believed to have occurred, first described in a 1992 series where almost half of the cases of recurrence occurred where no recurrence had been identified on earlier examination.A 2009 study reported late recurrence of residual adenoma in 4.4% of cases at 12 months' follow-up (n=138). In 7.2% of cases, evidence of residual adenoma was present in biopsy specimens from scar sites where no visible adenoma was seen. Negative biopsy results at early follow-up appeared to be predictive of continued eradication on late follow-up in 97.9% of cases in comparison with the remaining lesions (RR=0.15, 95% CI 0.035 to 0.618, p=0.005).The practice of biopsy retrieval as part of a follow-up resection site examination was supported by an analysis of 252 LNPCPs in which biopsy evidence of residual/recurrent adenoma was found in 7% of cases where no visible adenoma was present, while late recurrence was seen in 10.47% of cases where no adenoma was identified at initial follow-up.Taking biopsy specimens from an apparently clear polypectomy scar site appears justified as it may identify residual tissue that might otherwise remain undetected. Image enhancement may also improve diagnostic accuracy.Magnification endoscopy seems to accurately identify residual tissue. A study of 77 LNPCPs reported similar accuracy to histological evaluation. The sensitivity of magnification endoscopy for predicting residual tissue at resection margins was 98% (95% CI 90% to 100%); specificity was 90% (95% CI 79% to 100%) with an overall accuracy of 94.5% (95% CI 87.2% to 98.6%).Chromoendoscopy was found to accurately predict completeness of endoscopic resection in a 2004 study of 684 lesions (sensitivity 80%; specificity 97%; accuracy 94%).A 2011 study comparing the accuracy of NBI with white light examination for the detection of residual neoplasia found that NBI increased detection of residual neoplasia at the resection site, with 63% of identified lesions found to be more extensive with NBI than initially thought with white light examination.5. We suggest that the management of residual/recurrent polyp tissue can be challenging and should be performed by an endoscopist with complex NPCP experience (GRADE: low; Strength of recommendation: weak). We suggest that the management of ongoing recurrence should be discussed in a complex polyp MDM (GRADE of evidence: low; Strength of recommendation: weak). ## Consensus reached: 100% agreement While a proportion of recurrent/residual polyp tissue can be successfully treated with repeat snare resection, complete eradication at repeat therapy may be much more difficult to achieve, such as with larger areas of recurrence. Repeat treatment with EMR may not be achievable owing to submucosal fibrosis.ESD appears to be a less invasive management option in cases of complex recurrence, with various reports of its efficacy in scar-embedded polyps and subsequent avoidance of surgical resection. A 2009 study reported successful clearance of lesion recurrence with ESD in 15 cases after failed EMR.A Japanese study reported curative resection with ESD in large areas of recurrence (>2 cm) where EMR was not possible,while a UK study also reported successful salvage ESD in 11 of 12 cases.However, it should be noted that these studies are small and ESD availability in the West remains limited. Surgical resection remains an effective treatment while conservative management appears appropriate if patient comorbidities suggest that this will not significantly alter life expectancy. Various factors such as a patient's wishes and comorbidity and availability of treatment modalities may affect management, and access to a multidisciplinary network may optimise management. Surgical Management of LNPCPs While expert endoscopic management is the preferred firstline management in LNPCPs due to superior patient safety, surgical resection still has an important role. Surgery (or ESD where expertise is available) may be preferred for lesions that have a higher risk of malignancy, or where there is a high risk of residual polyp after endoscopic resection. Although morbidity and mortality rates are higher with surgical resection, the results of complete resection are better and there is a reduced need for endoscopic follow-up.Surgical resection is also an effective option where recurrence cannot be managed endoscopically. Even with the most advanced polypectomy techniques such as ESD, deeper submucosal invasion cannot be managed, with surgery often required when it is found at endoscopy. Surgery offers the highest chance of oncologically complete resection for these malignant lesions. ESD compares less favourably in this situation, with a large case series (n=1111) featuring both benign and malignant lesions reporting an en bloc resection rate of 88% and curative rate of 89%. Surgical resection is the only treatment where deep submucosal infiltration and lymph node infiltration may be managed effectively. Reported curative rates for surgical resection are 100% for stage 1 disease with a rate >91% for stage IIIa disease, indicating its efficacy.A proportion of cases with malignancy are found after surgery in lesions previously thought to be benign, although this varies considerably depending on patient selection and operator expertise at assessment. Studies analysing histopathology postsurgical resection in polyps considered benign have an estimated invasive malignancy in up to 22% of lesions. In view of this, where there is diagnostic uncertainty at assessment, surgical resection may be an appropriate management option. In addition, in cases where endoscopic access is considered difficult by an expert advanced endoscopist, with concern about causing complications or achieving a successful resection, surgical therapy may provide a more effective primary option rather than as an additional invasive procedure as secondary treatment.Rectal lesions require special consideration due to the complexity and morbidity associated with both open and laparoscopic resectional surgery in this area and the availability of endotherapy and minimally invasive local resectional surgery such as TEMS. A 1998 study reported (n=591) patients with 3.2% mortality and 30% postoperative morbidity at 30 days with open proctectomy, 183 while a 1999 study (n=681) cited a 0.6% perioperative mortality and 22% postoperative morbidity.A 2010 laparoscopic low anterior resection series (n=132) reported similar morbidity (20.5%).In addition, with low rectal lesions where non-sphincter saving surgery such as an abdominoperineal resection is often used, a permanent stoma will be required.Where suspicion about malignancy exists and en bloc resection is considered desirable to ensure adequate histological analysis, the use of either ESD or minimally invasive local resectional surgery such as TEMS is preferable to conventional resectional surgery; however, ESD availability, as previously discussed, is currently limited. A 2014 meta-analysis of 111 ESD and 10 TEMS series (n=2077) comparing LNPCP management outcomes found en bloc resection to be higher with TEMS (TEMS: 98.7% (95% CI 97.4% to 99.3%) vs ESD: 87.8% (95% CI 84.3% to 90.6%), p<0.001) while the curative resection rate was also superior (TEMS: 88.5% (95% CI 85.9% to 90.6%) vs ESD: 74.6% (95% CI 70.4% to 78.4%), p<0.001).A 2010 meta-analysis of TEMS also demonstrated a significantly reduced postoperative complication rate compared with resectional surgery (n=629, OR=0.16 (95% CI 0.06 to 0.38), p<0.003), while a 2012 study showed significantly reduced morbidity (n=78, 14.6% (TEMS) vs 37.1% (resectional surgery), p=0.046). The available evidence suggests that pEMR is preferable to TEMS for the management of benign rectal NPCPs. A retrospective comparison of TEMS and piecemeal EMR for the management of large rectal NPCPs (n=292) found that while early recurrence rates were lower in TEMS (10.2% vs 31.0%, p<0.001) when allowing for repeat endoscopic therapy on follow-up, late recurrence after 12 months was similar (9.6% vs 13.8%, p=0.386). TEMS was also associated with greater morbidity ( postoperative complications: 24% (TEMS) vs 13% (EMR), p=0.038) and a longer hospital stay (median hospitalisation after the procedure: 3 days (TEMS) vs 0 days (EMR), p<0.001).Another consideration is evidence that pEMR appears to be more cost-effective. International cost analysis suggests that the cost of EMR is around $2000, with subsequent follow-up roughly half this In comparison, the cost of TEMS is estimated to be around $7800. However, TEMS may be indicated as first-line treatment for selected benign rectal NPCPs that occupy significant rectal circumference and are technically difficult to remove with snare retrieval owing to its soft texture and the risk of significant bleeding. Equivalent curative efficacy, reduced morbidity and reduced associated cost justify the preference for pEMR in the management of most benign rectal NPCPs. However, optimal management of complex rectal NPCPs appears ideally suited to complex polyp MDM discussion where all available modalities are potentially available. ## Key performance indicators for the management of lnpcps Ensuring high quality LNPCP management is essential to reduce complications and future cancer risk. The development of KPIs, with defined minimum and aspirational standards, allows a standardised way of monitoring and auditing clinical quality outcomes. Widely varying outcomes have been reported in colonic polyp management, particularly with larger lesions and even between experienced endoscopists.There is evidence of varying management of LNPCPs between different UK centres, which has resulted in outcomes that may be considered suboptimal.Recent data from the BCSP (n=557) demonstrated high levels of piecemeal endoscopic management of malignant polyps where secondary surgical management was subsequently required (16.1%), while almost 80% of NPCPs managed with primary surgery were benign.Given evidence of the efficacy of endotherapy, including for the most complex polyps, it seems likely that many of these lesions might have been managed effectively endoscopically, with lower associated morbidity and mortality risks and reduced cost.The application and monitoring of KPIs, not previously described in LNPCP management, should help to improve quality by identifying potentially suboptimal performance at an earlier stage, reducing patient risk and permitting support and remedial action to be taken. The use of KPIs is intended as a monitoring system with outliers warranting further investigation/analysis. For example, if an outcome can be clearly explained, such as a skilled endoscopist tackling more complex lesions having a higher recurrence/residual rate than a less skilled endoscopist tackling more simple lesions, then this may be acceptable. If, however, endoscopists tackling similarly complex lesions have widely differing outcomes with one endoscopist producing clearly inferior outcomes, the KPI may then call into question the appropriateness for that individual to be managing certain lesions. Various domains for evaluating LNPCP management performance were considered by the writing committee. Potential KPIs within each domain were subsequently formulated. A preliminary round with anonymous voting was then used to assess the suitability of 16 potential KPIs. Seven KPIs were identified within the agreed domains and voted on in accordance with the guideline development process (see. In setting quantitative minimum and aspirational standards, where available, the results from various national and international studies felt to be of suitable design and quality were reviewed as possible reference points. Where it was not felt possible to set a defined standard for a KPI, the phrase "no current standard defined" was used with a view to monitoring outcomes and identifying acceptable minimum standards in the future. As with the guideline statements, LNPCPs refer to non-pedunculated colorectal polyps at least 20 mm in size (tables 7 and 8). ## Key performance indicators and standards for the management of lnpcps In view of the increased cost, morbidity and mortality with surgical management, endoscopic removal is considered first-line management for LNPCPs, as detailed earlier in these guidelines. There is, however, wide variation in the UK between difference centres for management of LNPCPs with regards to cases managed primarily with endotherapy and surgery.The GDG agreed that evaluation of the proportion of patients with LNPCPs managed surgically (excluding primary surgical management for cancer) would identify: ▸ patients with benign LNPCPs undergoing surgery where endoscopic management might have been possible; ▸ patients with LNPCPs which ultimately proved to be cancers where primary endoscopic therapy was attempted, but who later required surgery. Although the GDG recognised that both these situations may occur even in expert hands, it was felt that determining and monitoring this proportion would provide useful additional information on decision-making in the management of LNPCPs. The GDG felt that this KPI could be analysed at both an individual and overall service level: ▸ Level of agreement for KPI: 91.7% ▸ Level of agreement for standard: 92% The presence of recurrence and/residual tissue is a marker for assessing success of endotherapy in keeping with international literature reporting outcomes of LNPCP management. The GDG considered the measurement of 12-month (late) outcomes to be more appropriate than measurement of 3-month (early) outcomes, as the former relates more directly to health outcomes and is consistent with the standardised use of 12 months as an outcome of treatment success internationally. In addition, 12-month surveillance is commonly undertaken with lesions removed both en bloc and piecemeal. Residual polyp tissue seen on early endoscopic follow-up may be treated on repeat endoscopy giving eradication rates comparable to en bloc resection techniques. In addition, analysis at 12 months allows measurement of 'late recurrence' which has been reported in cases where no recurrence was found at initial endoscopic follow-up in multiple studies. ▸ Level of agreement for KPI: 100% ▸ Level of agreement for standard: 100% It is essential that patients receive high-quality management and the risk of harm is minimised (table 10). Perforation and PPB are more commonly associated with advanced polypectomy than with diagnostic colonoscopy and polypectomy of smaller polyps.The reported incidence of perforation after LNPCP resection is 0.5-1.3%, whereas for diagnostic polyps and standard polypectomy the risk or perforation is quoted at 1:1000 and 1:500, respectively. 7 9 36 PPB following resection of LNPCPs is the commonest complication with a reported incidence of 2.9-7.2%. As potentially life-threatening complications that may warrant emergency treatment, perforation and PPB seem appropriate markers of patient safety. ESD practice in the UK is felt to be too limited to set minimum standards while separate NICE guidance covers this modality. Thus, the GDG agreed that both safety KPIs for ESD ( perforation and PPB) should be considered as auditable outcomes. Perforation is defined as: 'air, bowel contents or instrumentation outside the bowel lumen' PPB is defined as: rectal bleeding within 30 days of the procedure resulting in any of the following: ▸ Minor procedure aborted unplanned post-procedure medical consultation unplanned hospital admission, or prolongation of hospital stay, for ≤3 nights ▸ Intermediate haemoglobin drop of ≥2g transfusion unplanned admission or prolongation for 4-10 nights intensive therapy unit admission for 1 night interventional procedure (endoscopic or radiological) ▸ Major surgery unplanned admission or prolongation for >10 nights -ITU admission >1 night ▸ Fatal death 36 Endotherapy perforation rate ▸ Level of agreement for KPI: 100% ▸ Level of agreement for standard: 92% Post-polypectomy bleeding rate ▸ Level of agreement for KPI: 92.3% ▸ Level of agreement for standard: 85% Given the potentially high rate of malignancy in LNPCPs, an aim to manage lesions within the NHS 62-day target was considered desirable by the GDG. However, it was recognised that the need for prompt treatment needed to be balanced with ensuring any treatment was performed by an appropriately skilled clinician. It was also recognised that delays might occur both in assessment/referral as well as in providing treatment. 6 47 200 ▸ Level of agreement for KPI: 100% ▸ Level of agreement for standards: 84% There is evidence that increased procedure numbers and experience are associated with better outcomes and reduced adverse events. In addition, it is common practice in other disciplines to consider undertaking a minimum number of procedures to maintain acceptable standards as it allows meaningful measurement of other KPIs. For example, the BCSP mandates a minimum number of 150 colonoscopies per year. The GDG acknowledged there was no clear evidence of the annual incidence of LNPCPs and therefore felt they could not propose a minimum number of procedures per year per endoscopist. Nevertheless, the GDG felt it important to monitor procedural volume per endoscopist. ▸ Level of agreement for KPI: 92.3% ▸ Level of agreement for standard: 92% ## Advanced polypectomy training and accreditation The GDG discussed ways to improve training in the management of LNPCPs during a round table meeting. Owing to the lack of an evidence base it was not felt to be possible to create guidelines for training and the aim was therefore to formulate a reference model for training in advanced polypectomy techniques. ## Entry requirements for training There was agreement that reaching a minimum number of diagnostic colonoscopy procedures was required to allow development of essential basic colonoscopy and therapeutic skills before entering advanced polypectomy training. There was broad opinion that handling and decision-making skills develop after around 250-350 colonoscopies, with further development after an extensive period of independent practice. Evidence that increased endoscopic experience is associated with improved performance and a reduced rate of adverse events reinforced this view. A minimum number of 500 independent ( postcertification) colonoscopies was felt to be a suitable number to ensure that adequate experience has been achieved in both observed and independent practice. There was unanimous opinion that snare polypectomy experience and skill were the key identifiers of endoscopists suitable for advanced training and that competency in snare polypectomy of smaller lesions (up to 2 cm) needed to be established. This may be assessed with a formal assessment tool such as the 'DOPyS' assessment tool.In addition to formal assessment, evidence of regular snare polypectomy experience with lesions >1 cm in the preceding year was considered desirable as well as performance data for all colonoscopy practice in that period. ## Training programme An apprenticeship programme such as a dedicated fellowship in a recognised advanced endoscopy centre was considered to be the preferred model for delivering advanced polypectomy training to trainees, whereas non-trainees such as consultants wishing to develop advanced polypectomy skills would require a period of mentorship. The availability of fellowships in specific regions may be linked to population demands. An agreed appropriate learning curve starts with a trainee continuing to develop individual colonoscopy skills while watching and assisting their mentor resect large lesions. During this period, trainees may gain significant experience and develop their technique on colonic lesions between 10 and 19 mm in size before progressing to larger lesions and piecemeal resection. At this point trainees would be encouraged to bring cases to dedicated training lists. LNPCP location and accessibility also confers increased lesion complexity in addition to size, and rectal lesions where the bowel wall is thicker and access is easier may be an ideal starting point for obtaining hands-on experience. Trainers and mentors would be required to ensure that their performance data (KPIs) met minimum standards before supervising fellows. ## Certification Dividing certification into provisional and full certification was strongly supported. Achieving provisional certification would be based on outcomes data and mentor opinion and would be the start of independent practice-that is, the trainer not in the room. Full certification would be obtained based on achieving satisfactory KPIs while provisionally certified in addition to mentor opinion, and maintenance of full certification status would be dependent on achieving satisfactory KPIs. ## Other potential training modalities Training workshops were suggested as a modality for reinforcing technical and decision-making skills obtained during a fellowship programme while simulator and tissue simulator models allow hands-on exposure in a safe setting. There is also growing support for the use of live animal training models. In the UK, the BSG have indicated their support for this modality.	None	https://gut.bmj.com/content/gutjnl/64/12/1847.full.pdf	These guidelines provide an evidence-based framework for the management of patients with large non-pedunculated colorectal polyps (LNPCPs), in addition to identifying key performance indicators (KPIs) that permit the audit of quality outcomes. These are areas not previously covered by British Society of Gastroenterology (BSG) Guidelines. A National Institute of Health and Care Excellence (NICE) compliant BSG guideline development process was used throughout and the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to structure the guideline development process. A systematic review of literature was conducted for English language articles up to May 2014 concerning the assessment and management of LNPCPs. Quality of evaluated studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist System. Proposed recommendation statements were evaluated by each member of the Guideline Development Group (GDG) on a scale from 1 (strongly agree) to 5 (strongly disagree) with >80% agreement required for consensus to be reached. Where consensus was not reached a modified Delphi process was used to re-evaluate and modify proposed statements until consensus was reached or the statement discarded. A round table meeting was subsequently held to finalise recommendations and to evaluate the strength of evidence discussed. The GRADE tool was used to assess the strength of evidence and strength of recommendation for finalised statements. KPIs, a training framework and potential research questions for the management of LNPCPs were also developed. It is hoped that these guidelines will improve the assessment and management of LNPCPs.
f749f463c71aa34fd5c656555b2021c88d68d501	pubmed	None	This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. The reconstructive needs following ablative surgery for head and neck cancer are unique and require close attention to both form and function. The vast experience accrued with microvascular reconstructive surgery has meant a significant expansion in the options available. This paper discusses the options for reconstruction available following ablative surgery for head and neck cancer and offers recommendations for reconstruction in the various settings.Recommendations- Microsurgical free flap reconstruction should be the primary reconstructive option for most defects of the head and neck that need tissue transfer. (R) - Free flaps should be offered as first choice of reconstruction for all patients needing circumferential pharyngoesophageal reconstruction. (R) - Free flap reconstruction should be offered for patients with class III or higher defects of the maxilla. (R) - Composite free tissue transfer should be offered as first choice to all patients needing mandibular reconstruction. (R) - Patients undergoing salvage total laryngectomy should be offered vascularised flap reconstruction to reduce pharyngocutaneous fistula rates. (R) # Introduction The problems of reconstructive surgery for the head and neck are variable and can be very complex. [bib_ref] Important aspects of head and neck reconstruction, Hanasono [/bib_ref] [bib_ref] Microvascular reconstruction: evidence-based procedures, Cannady [/bib_ref] These guidelines have been divided into the management of the loss of skin, the maxilla, the mandible, including the associated soft tissues, the oropharynx and the laryngopharynx. There is very little level 1 evidence relating to the reconstruction of head and neck defects. Mandibular reconstruction techniques are fairly standard but some controversy remains regarding the midface and maxilla because of the complexity of the defects and the possibility of using a dental or facial prosthesis. Most reconstructions are performed primarily following tumour extirpation, but secondary reconstructions are also undertaken to treat problems such as fistulae or osteoradionecrosis. Modern techniques aim for one stage reconstruction utilising vascularised tissues with a high success rate and good overall results. Priorities of reconstruction include restoring oral cavity lining, maintaining oral competence, maintaining function of speech and swallowing and providing an acceptable aesthetic result. Choice of reconstructive options depends on patient comorbidities, factors relating to the surgical defect, any future possible treatments including radiotherapy and donor site morbidity. No appropriately powered randomised controlled trials exist to determine flap selection in most instances and this is usually determined by the expertise of the individual surgeon. Patient factors include prior treatments, especially surgery and radiotherapy and the patient's overall health including medical and social history. Multiple tissue types often require to be reconstructed. ## Oral cavity soft tissues Oral soft tissues include tongue, floor of mouth, buccal mucosa and the retro-molar trigone extending to the tonsillar area. It is rare that only one of these areas is involved. Reconstructive access is usually determined by the extent of surgical resection and may involve a lip-split and mandibular osteotomy, although a peroral approach is usually possible. Microsurgical techniques provide the mainstay of oral soft tissue reconstructions as they allow importation of large volumes of healthy tissue from sites distant to prior surgical or radiotherapy fields. Flaps commonly used include the radial forearm flap (RFF) and the anterolateral thigh (ALT) flap. Less commonly the latissimus dorsi, rectus abdominus and flaps based on the scapular and/or para-scapular axis are utilised. More recently, the medial sural artery perforator flap (MSAP) and the superficial circumflex iliac artery perforator flap are being used. The first two represent the workhorse flaps in this field and will be discussed separately. The RFF allows for importation of a large, thin, pliable flap with excellent reliability and simplicity of harvest. [bib_ref] The radial forearm flap in intraoral reconstruction: the experience of 60 consecutive..., Soutar [/bib_ref] Multiple skin paddles can be designed and the flap can be raised as a cutaneous, fasciocutaneous, fascial, adipofascial, osseo-fascial or osseo-cutaneous flap (see below). The principal disadvantage of this flap is the poor donor site aesthetics when skin grafting is required. The ALT flap allows for importation of very large tissue volumes and is versatile. [bib_ref] A review of the advantages of the anterolateral thigh flap in head..., Chana [/bib_ref] Fascio-cutaneous and fascial flaps can be raised, along with muscle and fascia lata if required. The flap has a long pedicle, but can be technically challenging to raise. It is a relatively thick flap which can be thinned. If multiple perforating vessels are available, then the flap can be raised with two skin paddles. Donor site morbidity is minimal and use of the ALT is increasing in most reconstructive centres. If microsurgery is considered, inadvisable local or regional flaps are still used. Within the oral cavity local mucosal flaps can be useful to help close small defects. Regional flaps such as pectoralis major and deltopectoral can be effective in importing tissue, but are not generally considered as a first choice. ## Mandible Reconstruction of the mandible must address the site and size of the bony defect, associated soft tissue loss and the desirability of dental rehabilitation. Free tissue transfer is the mainstay of mandibular reconstruction as it allows importation of bone which can be tailored to fit the desired shape, is well vascularised and is amenable to osseo-integration. Several flaps are commonly used with high success rates, including the fibula flap, deep circumflex iliac artery (DCIA) flap, scapular flap and RFF. [bib_ref] Survival of microvascular free flaps in mandibular reconstruction: a systematic review and..., Markiewicz [/bib_ref] The fibular flap allows harvest of a long piece of bone which is of adequate height for osseo-integration and can be osteotomised several times for contouring. [bib_ref] Harnessing the potential of the free fibula osteoseptocutaneous flap in mandible reconstruction, Wallace [/bib_ref] [bib_ref] Technical considerations of fibular osteocutaneous flap dissection, Collin [/bib_ref] This is now made easier with the availability of software to plan the osteotomies at the mandible and on the fibula prior to transfer. It is relatively easy to harvest as an osseus or osteoseptocutaneous flap, with or without muscle. This versatility means it is the workhorse for mandibular reconstruction in most centres. One drawback of the flap is its relative lack of height. The DCIA flap provides for a high bony segment and the natural curve of the ilium lends itself to lateral mandibular defects where an osteotomy may not be necessary. The donor site defect can be problematic and its skin paddle is usually reserved for external use although muscle can be incorporated for oral reconstruction. The scapular flap allows for harvest of a relatively small amount of bone. The main advantage of this flap is the large volume of skin and muscle (latissimus dorsi) which can be used. The bone is a good height, but two-team flap harvesting is generally not possible. Radial forearm flap is rarely used for bone reconstruction as only a small volume of bone of low height can be harvested. There is a risk of subsequent fracture of the radius. A new classification of the mandibular defect has been described based on the four corners of the mandible which are both angles and both canines : 8 - Class I (70 mm)/Ic (84 mm): Subcondylar region to the ipsilateral canine and class Ic includes the condyle. Most of the flaps described above will work well as the length of this defect is around 7-8 cms and so all bone donor sites are adequate. In the lateral defect the height of the reconstruction is less problematic. - Class II (85 mm)/IIc (126 mm): Hemimandibulectomy from subcondylar region including ipsilateral canine and class IIc includes condyle. The iliac crest can work well as the shape of the ipsilateral hip may reduce osteotomy preparation and a scapula may not be sufficiently long for a class IIc when soft tissue is seldom an issue. - Class III (100 mm): Includes both canines, but neither angle. The choice of flap depends more on the plan of rehabilitation and height of chin support. The fibula flap can be double-barrelled to increase height, but scapula and radius are often difficult to implant successfully for complete oral rehabilitation. - Class IV (152 mm)/IVc (168 mm): This is an extensive mandibulectomy including at least one angle and both canines. The fibula flap is usually the best option for faithful reconstruction, but the mandible is often best made smaller for such major resections especially if there is loss of maxillary teeth. Dental rehabilitation is a key part of mandibular reconstruction and pre-operative liaison with an appropriate team including consideration of osseo-integrated implants is mandatory. ## Maxilla and midface The level of evidence is very weak in all areas of reconstruction, but more particularly in the maxilla and midface because of the differing complexity of the defects, and the potential for skull base involvement. Throughout this section, it is necessary to refer to the classification suggested in [fig_ref] FIG. 2: Classification of the maxillary and midface defects [/fig_ref]. [bib_ref] Reconstruction of the maxilla and midface: introducing a new classification, Brown [/bib_ref] The choice of a prosthetic option or reconstruction depends on the nature of the defect. In class I and II defects an obturator is a reasonable option, but this becomes less favourable as the orbital adnexae are involved (class III), orbital exenteration (class IV) and the midface defects of an orbitomaxillary (class V) or nasomaxillary (class VI) nature. This refers not only to the vertical component but also to the extent of the dental or alveolar part of the resection relevant to the prosthodontist in deciding on appropriate obturation. Other classifications suggested include those by Okay et al., but there is no distinction between classes III and IV. All cases involving the loss or ablation of the maxilla and/or midface should be discussed in a multidisciplinary setting. The choice of reconstruction or prosthetics requires discussion among the ablative and reconstructive teams, the prosthodontist, maxillofacial technician, the patient and the family. There are clear advantages in simplifying the surgery and using prosthetic options, but this choice becomes more difficult to deliver and for the patient to cope as the defect becomes larger and more complex. Class I: This includes resections of the alveolar bone not resulting in an oroantral fistula and these can either be left to granulate or treated with a local flap. Also included are defects involving the junction of the hard and soft palate usually obturated or reconstructed with a soft tissue flap, and minor maxillectomies which may occur following the removal of small inverted papillomas which generally do not require rehabilitation. Class II: This is the standard hemimaxillectomy not involving the orbital floor or adnexae. Obturation is often very successful for this form of defect as the orbit does not require support and if the defect is not too large there is less of a problem for the patient in terms of retention and stability of the prosthesis. In more extensive cases (classes IIc-d), it is possible to gain very good retention with an implant-retained prosthesis, although reconstruction with the fibula flap has also shown good outcomes. A vascularised bone with greater height, such as the DCIA flap which includes the iliac crest and internal oblique muscle, will give better support to the peri-nasal area. The scapula flap can be supplied by the circumflex scapular artery which supplies the lateral scapula (scapula flap) through peri-osteal perforators along its length or the angular branch of the thoracodorsal artery which supplies the scapula tip. The advantage of the scapula tip option is that the pedicle is considerably longer than the circumflex scapula artery option which is a great advantage in the maxilla and midface as the recipient vessels are more distant. Class III: In these cases, there is loss of the orbital support and often a part of the nasal bones may also require reconstruction. There is good consensus in the literature that the restoration of orbital support with vascularised tissue (pedicled or free flap) is essential to ensure healing of the bone graft and reduce the soft tissue problems such as epiphora and ectropion. The iliac crest with internal oblique provides the best solution if an implant-retained prosthesis is planned, but the scapula tip flap using latissimus dorsi muscle is also a good option with a more reliable pedicle. The fibula is also described for this defect but considerable skill in the adaptation of this flap for the defect is required with variable results. The rectus abdominus with non-vascularised bone is also an option but is associated with a high ectropion rate and there is a risk of bone loss if radiotherapy is required. The vastus lateralis based on the descending branch of the lateral circumflex femoral artery is another option. Obturation alone will result in facial collapse, poor support of the orbit and a high risk of vertical orbital dystopia and ectropion. In children, the scapula tip will probably be the best option as the iliac crest has a cartilaginous cover and the vessels are much smaller. Class IV: Reasonable results can be achieved with a soft tissue flap alone such as rectus abdominus or vastus lateralis but this will result in poor definition of the orbital defect and some facial collapse. The choice is similar to class III in that the iliac crest with internal oblique offers better implant options but the scapula tip flap is also a good option. Class V: In the orbitomaxillary defect, the main aim is not to obturate the orbital space with too much soft tissue so as to allow space for an orbital prosthesis. The temporalis or temporoparietal flap are ideal, but in more extensive defects it is worth considering the radial or ALT in a thinner patient. Class VI: If there is loss of the facial skin between the orbits and nasal bones, then free tissue transfer is probably essential. The composite RFF can be ideal if harvested with fascia to line the nasal side of the radial strut and the skin to restore the face. The composite radial can be augmented with a glabella or forehead flap. A classical rhinectomy can be rehabilitated with a prosthesis and of course the surgeon can check the margins of resection and resect more tissue if required. There are very successful full rhinectomy reconstructions performed which can give a permanent biological solution if preferred. In this defect attention must be paid to the restoration of the nasal bones with vascularised tissue to prevent complications during and following radiotherapy. ## Oropharyngeal reconstruction The oropharynx can be divided into the walls of the oropharynx (lateral and posterior), the base of the tongue and the soft palate. The oropharynx is a muscular tube connecting the larynx and hypopharynx to the oral cavity. The role of reconstruction is to try and maintain the function of the residual tissue. From a functional point of view the most difficult area is the posterior tongue which allows normal movement of the epiglottis and maintains swallowing and speech. The use of transoral robotic and laser resections without reconstruction may give better functional results than reconstructing this muscular tube with non-sensate skin such as the radial forearm flap. ## Reconstruction of the soft palate The most commonly described method of soft palate reconstruction involves the use of the RFF often in combination with a local flap such as the superiorly based pharyngeal flap or the superior constrictor advancement flap. Some suggest the use of a folded RFF which is de-epithelialised in order to be sutured to the de-epithelialised posterior pharyngeal wall, but a superiorly based pharyngeal flap can be utllised to provide the nasal lining with good results. [bib_ref] Functional outcome in soft palate reconstruction using a radial forearm free flap..., Brown [/bib_ref] [bib_ref] Use of free tissue transfers in head and neck reconstruction, Kim [/bib_ref] The free flap is used in the horizontal part of the defect only if it is possible to close the posterior tongue to narrow the pharynx and maintain its function. ## Reconstruction of the pharyngeal walls and tonsillar regions Placing free tissue transfers will disrupt the muscular tube and probably decrease function. For this reason, transoral robotic and laser resections are preferred to address these tumours where possible. ## Reconstruction of the posterior tongue Most surgeons do not claim to be able to restore function in this region if more than half of the posterior tongue requires resection [fig_ref] TABLE I METHODS: OF SOFT PALATE RECONSTRUCTION [/fig_ref]. ## Pharyngo-laryngectomy reconstruction Partial pharyngeal defects Partial pharyngeal defects with more than 3.5 cm of 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 myocutaneous flap. Free flaps, such as radial forearm free flaps, may also be used. If the pharyngeal mucosal remnant is very narrow (<1 cm in width), then it is often better to excise the remnant and undertake a total circumferential reconstruction. Total circumferential pharyngolaryngectomy defects Lower anastamosis above clavicles. Where the lower anastamosis of a total circumferential pharyngolaryngectomy reconstruction would lie above the clavicle, several options exist: 12 jejunal free flap (JFF), gastroomental free flap (GFF), tubed radial forearm free flap (RFFF) and tubed anterolateral thigh free flap (ALTF). All of the above options carry the risk of free flap failure, anastamotic leaks, anastamotic strictures, donor site morbidity, failure of voice rehabilitation, swallowing problems and a small peri-operative mortality rate. Previously untreated cases. 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. Good swallowing and voice rehabilitation have also been reported. Alternatives include the JFF 13 and the RFF. Swallowing problems due to hyper-peristalsis and a 'wet' sounding voice are common with JFF, which also carries a morbidity rate due to abdominal complications (≈5 per cent). Radial forearm flap carries lower donor morbidity rates, but higher stenosis and leak rates than JFF. Tubing of the RFF over a salivary bypass tube appears to decrease fistula rates. 14 Post-chemoradiotherapy (salvage) cases. In general, reconstructive free flap surgery in the salvage setting carries higher risks of complications due to the deleterious effects of chemoradiotherapy on tissue vascularity and wound healing. In such cases, limited case series suggest that use of GFFs may have an advantage due to the availability of the omentum. This can be wrapped around the anastamotic site to decrease the possibility of leakage and also improve the overlying skin quality. Additional vascularised tissue can be included with the ALT as a chimaeric flap to resurface the neck in cases where there is poor quality skin or contracted skin that would not safely close post-operatively. Any of the other options mentioned previously, for example JFF, RFF, may also be used in salvage surgery. Lower anastamosis below clavicles. If the resection extends to below the level of the clavicles, then a gastric pull through or colonic transposition flap may be used. Both these techniques carry significant morbidity and mortality due to the need to enter three visceral cavities. Gastric pull through carries a mortality rate of 5-15 per cent, morbidity of 30-55 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 reach than gastric pull through, and is therefore useful for tumours that extend up high into the oropharynx. Vascularised tissue after salvage laryngectomy Pharyngocutaneous fistulae (PCF) are known to occur in nearly one-third of patients who undergo salvage total laryngectomy after chemoradiation. Pharyngocutaneous fistulae have severe impact on duration of admission and costs, quality of life and can even cause severe complications such as bleeding, infection and death. Recent meta-analyses suggest that there is a clear advantage in using vascularised tissue from outside the radiation field in the laryngectomy defect, either as a buttress or to augment the circumference of the pharynx. [bib_ref] Vascularized tissue to reduce fistula following salvage total laryngectomy: a systematic review, Paleri [/bib_ref] [bib_ref] Preventing pharyngo-cutaneous fistula in total laryngectomy: a systematic review and meta-analysis, Sayles [/bib_ref] This intervention reduces the risk of PCF by one-third to a half. ## Recommendations ## Midface and maxilla - Multidisciplinary decision-making should include the patient, surgeon and dental prosthodontist - Prosthetic options reduce the morbidity of treatment and can give excellent results but reconstructive options should be considered as the defect becomes larger and more complex ## Oropharynx - Using local tissue only to restore the constrictor tube is essential. Free tissue transfer is best reserved for the reconstruction of the soft palate - Functional results for posterior tongue reconstruction are disappointing - The greater role played by transoral surgery will reduce the need for reconstruction in this area ## Pharyngolarynx - Partial pharyngeal defects may be closed primarily or using a pedicled myocutaneous, usually a pectoralis major flap or with a free flap - Total circumferential defects where the lower anastamosis is above the clavicle can be reconstructed with several free flaps. In previously untreated patients, anterolateral thigh free flaps, tubed over a salivary bypass tube, appear to carry lowest complication rates. In post-radiotherapy patients, limited evidence suggests that gastromental free flaps may have some advantages - Tubing over and use of a salivary bypass tube appears to decrease complication rates with anterolateral thigh and radial forearm free flaps - Total circumferential defects where the lower anastamosis is below the clavicle may be reconstructed by gastric pull through or colonic transposition Salvage laryngectomy - Use of vascularised tissue to buttress or augment the pharynx in patients undergoing salvage total laryngectomy reduces pharyngocutaneous fistula rates [fig] FIG. 2: Classification of the maxillary and midface defects. Classes I-VI relate to the vertical component of the defect including orbitomaxillary (class V) and nasomaxillary (class VI) when often the palate and dental alveolus are intact. Classes a-d relate to the increasing size of the palatal and dento-alveolar part of the defect indicating increasing difficulty in obtaining good results with obturation. [/fig] [table] TABLE I METHODS: OF SOFT PALATE RECONSTRUCTION [/table]	None	None	None
fd67bcf2b33f4805a21e0abe723b65f2b2771993	pubmed	Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome	Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome # Introduction Increased attention to intra-abdominal pressure (IAP), along with changes in the clinical management of critically ill or injured patients, have led to an exponential growth in research relating to intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) in recent years. Milestones have included the incorporation of the World Society of the Abdominal Compartment Syndrome (WSACS; www.WSACS.org), and the Society's publication of IAH and ACS expert consensus definitions in 2006, clinical practice guidelines in 2007, and recommendations for research in 2009. Changes in the management of critically ill surgical and/or medical patients have included increased use of damage control surgery and resuscitation , percutaneous catheter-based and other minimally invasive therapies, early goal-directed therapy for severe sepsis , and a heightened appreciation of the risks of overresuscitation. In light of such developments, the WSACS reviewed the literature and updated their proposed 2006 consensus definitions and 2007 management statements. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system for clinical practice guideline developers was used to provide consistency in identifying and rating the quality of available evidence and the strength of management suggestions and recommendations. Although the results of our update is reported concisely here, interested readers may refer to the parent report for details (Supplement 1; see electronic supplementary material, ESM). # Methods ## Evaluation of existing 2006 consensus definitions and risk factors In concordance with the levels of agreement appropriate for consensus, all 2006 expert consensus definitions for which more than 80 % of the members voted to accept ''as is'' were retained, while all those with less than 50 % acceptance were rejected. Definitions with only 50-80 % agreement were revised through ongoing discussion until complete consensus was obtained. Where extensive discussion among subspecialists or other experts was required, special sub-committees were created, including a dedicated Pediatric Guidelines Sub-Committee who reviewed the adult guidelines to determine their generalizability to pediatrics. We also searched the literature to determine which IAH or ACS risk factors proposed in 2006 are now supported by evidence and developed a consensus open abdomen classification system. Further details are presented in Supplement 2 (see ESM). ## Development of consensus management statements We followed GRADE recommendations for guideline developers in order to generate management statements related to IAH/ACS. Using this approach, guidelines committee members first developed structured clinical questions and then defined patient-important outcomes with the assistance of an independent GRADE methodological advisor (R.J.). Questions were based on polling of the WSACS Executive to redundancy and were formulated according to the Patient, Intervention, Comparison, Outcome, and study Design (PICO) format. Systematic review teams subsequently conducted systematic or structured/semi-structured reviews and prepared evidence profiles for each of the identified patient-important outcomes as suggested by GRADE. ## Grading of evidence and development of management statements After each systematic review team had created their initial evidence profile, formal face-to-face meetings among all guideline committee members were held on two separate days immediately preceding and following the Fifth Scientific Congress of the WSACS in Orlando, FL, USA in August 2011. At the Management Guidelines Meeting, each systematic review team formally presented their search methods and evidence profile. In accordance with GRADE guidelines, they then made recommendations to the panel regarding the direction (for/against/no recommendation) and strength (recommend/suggest) of the proposed statement . Ultimately, the quality of evidence for each outcome was rated along a four-point ordinal scale in which each evidence grade was symbolized by a letter from D to A: very low (D), low (C), moderate (B), and high (A). Further details are presented in Supplements 3 and 4 (see ESM). # Results ## Existing consensus definitions and risk factors The 2013 WSACS consensus definitions are presented in. Changes from the previously published 2006 definitions, and the pertinent rationale for such, are outlined in Supplement 5 (see ESM). Risk Factors for IAH and ACS are shown in . ## Classification of the open abdomen Critical complications which should be considered in managing the open abdomen include: (1) fixation of the abdominal contents (especially of the viscera to the peritoneal sidewalls) and (2) development of enteroatmospheric fistulae (EAF). To facilitate comparison of patient groups with similar determinants of outcomes and complications, a classification scheme of open abdomen complexity is References are shown if the presented risk factor is supported at least to some degree by primary literature. Those unsupported by primary literature are based on clinical judgment and/or pathophysiological rationale. The patient populations included in these studies included major trauma patients, general intensive care unit patients, severe acute pancreatitis patients, severe extremity injury patients, and surgical intensive care unit patients. Moreover, some of these studies addressed only patients that were mechanically ventilated, whereas others included mixed cohorts of patients with different ventilation statuses APACHE-II acute physiology and chronic health evaluation-II, PEEP positive end expiratory pressure, SOFA sequential organ failure assessment presented. The rationale for creation of this classification system is outlined in Supplement 6 (see ESM). ## Pediatric guidelines sub-committee: definitions A dedicated pediatric sub-committee evaluated the adult definitions for use among children. A summary of the final accepted pediatric definitions is presented in. For the four definitions rejected, new definitions were proposed that are specific to pediatric use. The rationale for these definitions is outlined in Supplement 7 (see ESM). ## Structured clinical questions and consensus management statements Consensus management statements are summarized in. Each of these statements are denoted below to indicate whether they were unchanged from previous guidelines, a new guideline, or revised from previous guidelines. An associated summary of overall management and medical management algorithms are presented in Figs. 1 and 2, respectively. The summary of findings and rationale for each of the following management statements is described in the supporting Supplements (see ESM). Should we measure IAP? Should we measure it via the bladder? Should we use an IAP measurement protocol? (Supplement 8; see ESM) As clinical examination is inaccurate for detecting raised IAP, IAH and ACS research and management rely upon accurate serial or continuous IAP measurements. Although there is an increasing number of IAP measurement techniques, trans-bladder measurement remains a commonly used method, and was recommended by the WSACS in 2006 due to its simplicity and low cost. . We suggest using a protocol to try and avoid a positive cumulative fluid balance in the critically ill or injured patient with, or at risk of, IAH/ACS after the acute resuscitation has been completed and the inciting issues have been addressed [GRADE 2C] 7. We suggest use of an enhanced ratio of plasma/packed red blood cells for resuscitation of massive hemorrhage versus low or no attention to plasma/packed red blood cell ratios [GRADE 2D] 8. We suggest use of PCD to remove fluid (in the setting of obvious intraperitoneal fluid) in those with IAH/ACS when this is technically possible compared to doing nothing [GRADE 2C]. We also suggest using PCD to remove fluid (in the setting of obvious intraperitoneal fluid) in those with IAH/ACS when this is technically possible compared to immediate decompressive laparotomy as this may alleviate the need for decompressive laparotomy [GRADE 2D] 9. We suggest that patients undergoing laparotomy for trauma suffering from physiologic exhaustion be treated with the prophylactic use of the open abdomen versus intraoperative abdominal fascial closure and expectant IAP management [GRADE 2D] 10. We suggest not to routinely utilize the open abdomen for patients with severe intraperitoneal contamination undergoing emergency laparotomy for intra-abdominal sepsis unless IAH is a specific concern [GRADE 2B] 11. We suggest that bioprosthetic meshes should not be routinely used in the early closure of the open abdomen compared to alternative strategies [GRADE 2D] ## No recommendations 1. We could make no recommendation regarding use of abdominal perfusion pressure in the resuscitation or management of the critically ill or injured 2. We could make no recommendation regarding use of diuretics to mobilize fluids in hemodynamically stable patients with IAH after the acute resuscitation has been completed and the inciting issues have been addressed 3. We could make no recommendation regarding the use of renal replacement therapies to mobilize fluid in hemodynamically stable patients with IAH after the acute resuscitation has been completed and the inciting issues have been addressed 4. We could make no recommendation regarding the administration of albumin versus not, to mobilize fluid in hemodynamically stable patients with IAH after acute resuscitation has been completed and the inciting issues have been addressed 5. We could make no recommendation regarding the prophylactic This measure has previously been suggested as a more accurate predictor of visceral perfusion and a better endpoint for resuscitation than IAP or mean arterial pressure (MAP) alone. Should we treat or prevent IAH? (Supplement 10; see ESM) Intra-abdominal hypertension (IAH) has consistently been associated with morbidity and mortality in observational studies. However, it remains uncertain as to whether treating or preventing this condition improves patient outcomes. # Statement We RECOMMEND efforts and/or protocols to avoid sustained IAH as compared to inattention to IAP among critically ill or injured patients (New Management Recommendation 4 [GRADE 1C]). ## How should we manage iah/acs? In addition to decompressive laparotomy for ACS, numerous medical and minimally invasive therapies have been proposed or studied that may be beneficial for patients with IAH or ACS. Approaches or techniques of potential utility include sedation and analgesia, neuromuscular blockade, body positioning, nasogastric/ colonic decompression, promotility agents, diuretics and continuous renal replacement therapies, fluid resuscitation strategies, percutaneous catheter drainage (PCD), and different temporary abdominal closure (TAC) techniques among those requiring an open abdomen. ## Non-invasive options: sedation and analgesia (supplement 11; see esm) While sedation and analgesia have been incorporated into previous IAH/ACS management algorithms, it remains unclear if they alter outcomes among those with IAH/ACS. # Statement We SUGGEST that clinicians ensure that critically ill or injured patients receive optimal pain and anxiety relief (Unchanged Management Suggestion 1 [GRADE 2D]). ## Neuromuscular blockade (supplement 12; see esm) Through a reduction in abdominal muscular tone and an increase in abdominal compliance, neuromuscular blockade may reduce IAP among those with IAH and/or ACS. # Statement We SUGGEST brief trials of neuromuscular blockade as a temporizing measure in the treatment of IAH (Unchanged Management Suggestion 2 [GRADE 2D]). ## Body positioning (supplement 13; see esm) Body positioning may change IAP by altering the zero reference for IAP measurement and/or the external forces on the abdominal cavity [32,. # Statement We SUGGEST that the potential contribution of body position to elevated IAP be considered among patients with, or at risk of, IAH or ACS (Unchanged Management Suggestion 3 [GRADE 2D]). ## Nasogastric/colonic decompression (supplement 14; see esm) While the routine use of enteric tubes post-operatively has not been associated with benefit after uncomplicated surgery, there are anecdotal reports that gastric and colonic distension can induce marked IAH commensurate with ACS. # Statement We SUGGEST liberal use of enteral decompression with nasogastric or rectal tubes when the stomach or colon are dilated in the presence of IAH/ACS (New Management Suggestion 4 [GRADE 1D]). ## Promotility agents (supplement 15; see esm) Studies have reported that treatment with neostigmine may be effective at inducing colonic decompression among those with colonic pseudo-obstruction. However, no data exist on the effects of pharmacologic promotility therapy on IAP or outcomes among those with IAH/ACS. # Statement We SUGGEST that neostigmine be used for the treatment of established colonic ileus not responding to other simple measures and associated with IAH (New Management Suggestion 5 [GRADE 2D]). ## Should we keep fluid balance neutral or even negative among icu patients? (supplement 16; see esm) An increased or positive fluid balance has been associated with third space fluid accumulation and organ dysfunction in animal models. However, it remains unknown whether strategies that target a neutral or even negative fluid balance after the initial resuscitation of critically ill patients may be linked with improved clinical outcomes. # Statement We SUGGEST using a protocol to try to avoid a positive cumulative fluid balance in the critically ill or injured with, or at risk of, IAH/ACS after the acute resuscitation has been completed and the inciting issues have been addressed (New Management Suggestion 6 [GRADE 2C]). ## Diuretics (supplement 17; see esm) Although diuretics are commonly used to improve fluid balance among the critically ill, it remains unknown whether they improve outcomes among those with IAH or ACS. # Statement We could make NO RECOMMENDATION regarding the use of diuretics to mobilize fluids in hemodynamically stable patients with IAH after acute resuscitation has been completed and the inciting issues have been addressed. ## Renal replacement therapies (supplement 18; see esm) Renal replacement therapies are increasingly being used to modify fluid balance among the critically ill. # Statement We could make NO RECOMMENDATION regarding the use of renal replacement therapies to mobilize fluid in hemodynamically stable patients with IAH after acute resuscitation has been completed and the inciting issues have been addressed. ## Albumin (supplement 19; see esm) Albumin is frequently administered to critically ill patients in order to expand plasma volume and improve oncotic pressure. # Statement We could make NO RECOMMENDATION regarding the administration of albumin versus not, to mobilize fluid in hemodynamically stable patients with IAH after acute resuscitation has been completed and the inciting issues have been addressed. Should we use damage control resuscitation? (Supplement 20; see ESM) Damage control resuscitation is increasingly being used among critically injured patients . This type of resuscitation is characterized by permissive hypotension, limitation of crystalloid intravenous fluids, and delivering higher ratios of plasma and platelets to red blood cells [8]. # Statement We SUGGEST use of an enhanced ratio of plasma/packed red blood cells for resuscitation of massive hemorrhage versus low or no attention to plasma/packed red blood cell ratios (New Management Suggestion 7 [GRADE 2D]). ## Minimally-invasive options If the medical management approaches suggested above do not alleviate IAH, then clinicians will need to consider whether invasive treatments may be necessary. ## Should we use pcd? (supplement 21; see esm) Although paracentesis has long been a diagnostic and therapeutic procedure among those without documented IAH, the insertion of an indwelling PCD catheter in an attempt to improve IAP and associated patient-important outcomes among those with IAH/ACS was only first suggested in 2001. # Statement We SUGGEST use of PCD to remove fluid (in the setting of obvious intra-peritoneal fluid) in those with IAH/ACS when this is technically possible compared to doing nothing (Unchanged Management Suggestion 8 [GRADE 2C]). We also SUGGEST using PCD to remove fluid (in Decompressive laparotomy historically constituted the standard method to treat severe IAH/ACS and to protect against their development in high risk situations (e.g., following damage control laparotomy for significant intraperitoneal injury). It has been reported to result in an immediate decrease in IAP and in improvements in organ function. However, decompressive laparotomy is associated with multiple complications and overall reported patient mortality is considerable (up to 50 %), even after decompression. # Statement We RECOMMEND decompressive laparotomy in cases of overt ACS compared to strategies that do not use decompressive laparotomy in critically ill adults with ACS (Unchanged Management Recommendation 5 [GRADE 1D]). ## Use of the open abdomen after trauma damage control laparotomy (supplement 23; see esm) The damage control approach to trauma involves an abbreviated resuscitative surgical approach with the primary goal being rapid control of hemorrhage and contamination with restoration of metabolic function at the expense of normal anatomy [8,. Damage control laparotomy is typically a component of a larger damage control approach that includes damage control resuscitation. Although it remains difficult to prove that this approach improves mortality and other outcomes, it has been associated with unexpected patient survival. # Statement We SUGGEST that patients undergoing laparotomy for trauma suffering from physiologic exhaustion be treated with the prophylactic use of the open abdomen versus closure and expectant IAP management (New Management Suggestion 9 [GRADE 2D]). ## Damage control laparotomy for non-trauma acute care surgery patients (supplement 24; see esm) While damage control techniques are being used among non-trauma acute care surgery patients (which largely includes emergency general surgery), very little evidence exists to support their use, or to support prophylactic open abdominal management afterwards. # Statement We could make NO RECOMMENDATION regarding the prophylactic use of the open abdomen in non-trauma acute care surgery patients with physiological exhaustion versus intra-operative abdominal fascial closure and expectant IAP management. ## Damage control surgery for patients with intraabdominal sepsis (supplement 25; see esm) Intra-abdominal sepsis is a particularly devastating and common form of sepsis, which is commonly associated with development of IAH/ACS. # Statement We SUGGEST NOT to routinely utilize the open abdomen approach for patients with severe intra-peritoneal contamination undergoing emergency laparotomy for intra-abdominal sepsis unless IAH is a specific concern (New Management Suggestion 10 [GRADE 2B]). ## Definitive abdominal closure While the open abdomen method is a valuable, life-saving tool, the longer the abdomen is open, the greater the potential for morbidity. Thus, specific strategies should be utilized from the first laparotomy that consider prevention of visceral adhesions, loss of soft tissue coverage, lateralization of the abdominal musculature and its fascia, malnutrition, and enteric fistulae. The detailed management of the open abdomen is beyond the scope of this document, for which other recent reviews are available. Should we attempt to achieve same-hospital-stay closure of the open abdomen? (Supplement 26; see ESM) As the inability to achieve primary fascial closure after damage control laparotomy has been associated with increased morbidity and reduced quality of life among critically ill adults, efforts to close the abdominal fascia before discharge could potentially lead to improved outcomes.. It may also remove fluid and pro-inflammatory cytokines from the peritoneum, which may reduce abdominal third space volume, the systemic inflammatory response, and resultant organ dysfunction . However, others have reported concerns over associations between NPWT and recurrent ACS or intestinal or enteroatmospheric fistulae, especially among those with limited intraabdominal fluid available for removal. Advances in tissue recovery and engineering have driven production of a large range of bioprosethic mesh prostheses that provide new options for abdominal wall reconstruction. It has been suggested that these meshes can be used to achieve earlier abdominal fascia closure among those with an open abdomen as they may allow for an increased intra-peritoneal domain without enteric fistula formation. # Statement We SUGGEST that bioprosthethic meshes SHOULD NOT be routinely used in the early closure of the open abdomen compared to alternative strategies (New Management Suggestion 11 [GRADE 2D]). ## Pediatric iah and acs management The Pediatric Sub-Committee of the WSACS reviewed the main management guidelines in regard to their applicability and suitability for children. They accepted six guidelines as is, rejected none, but could not make recommendations regarding the suitability for children in the remaining six. Their specific opinions are presented in. # Discussion In this manuscript, the WSACS presented updated consensus definitions and management statements related to IAH/ACS. It was identified that there were topics for which future review was required, including the most accurate/meaningful reference-standard locations for IAP measurement and the definition of ''normal'' values of IAP across various patient populations. Moreover, although the Pediatric Sub-Committee reviewed and made recommendations regarding the appropriateness of the updated consensus definitions and management statements for pediatric patients, further work in this area is needed. Similarly, normal values of IAP among obese and pregnant patients have not yet been adequately defined, and the influence of IAH and ACS in these patients is somewhat poorly understood. Thus, further work among these patient populations is urgently needed. Finally, as overt ACS becomes less common, further research must be performed in order to delineate what role IAH without ACS plays in gut ischemia, bacterial translocation, feeding intolerance, anastomotic and wound breakdown, and neurological dysfunction. The GRADE system was used to formulate the updated consensus management statements. GRADE is practical in requiring clinical judgements to be made in the context of weighing potential benefits and harms, the burdens of therapy both to the patient and society, and involved costs, with the overall assessment of the quality based on the entire body of evidence, rather than any particular study. Therefore, in the context of making recommendations, the quality of evidence ultimately reflects the degree of confidence that a panel of expert clinicians has in the estimates of effect size. The combined, collective experience is therefore reflected in the RECOMMEN-DATIONS and SUGGESTIONS, wherein the evidence is reflected in the quality of evidence assessment. With this background, these guidelines should be used as guides for any institution or clinician to initiate their care of the critically ill, at all times evaluating the patients' outcomes ideally in a formal research study or at least in an organized fashion. However, these guidelines should not be used as performance measures or quality assurance criteria to censure any physician or institution. In utilizing these guidelines, clinicians should be aware that there are ongoing developments in medical knowledge. The panelists made great efforts to review the literature broadly, and to be aware of ongoing research that could influence recommendations. However, the reviewers focused on completed peer-reviewed studies that were available in the public domain. Although some studies could have been missed, we feel it unlikely that the exclusion of the results of these studies would significantly alter our provided recommendations. Nonetheless, it is probable that new knowledge will require future revision of this work. Given the lack of high-quality evidence to base decision-making, this is desirable, and thus users are reminded to use these guidelines in the context of knowing their patients, acting at the bedside, and considering new data as it becomes available. ## Conflicts of interest	None	https://link.springer.com/content/pdf/10.1007/s00134-013-2906-z.pdf	None
fc36b13048a45f93c1e62e5a46c62f4735bbae21	pubmed	SEOM clinical guidelines for endometrial cancer (2017)	SEOM clinical guidelines for endometrial cancer (2017) Endometrial cancer (EC) is the most common gynecological cancer in developed countries. Most patients are diagnosed at an early stage with a low risk of relapse. However, there is a group of patients with a high risk of relapse and poor prognosis. Despite the recent publication of randomized trials, the adjuvant treatment of high-risk EC is still to be defined and there are many open questions about the best approach and the right timing. Unfortunately, the survival of metastatic or recurrent EC is short, due to the poor results of chemotherapy and the lack of a second line of treatment. Advances in the knowledge of the molecular abnormalities in EC have permitted the development of promising targeted therapies. # Introduction EC is the most common gynecological cancer in developed countries. Although most EC patients have a favorable prognosis, those either with high-risk early disease or advanced stage at diagnosis have a survival below 50%. The most important risk factors identified in EC are obesity, long-lasting endogenous or exogenous hyperestrogenism (polycystic ovary, tamoxifen therapy, anovulation, and nulliparity), hypertension and diabetes mellitus. In addition, women with Lynch syndrome (LS, or hereditary nonpolyposis colon cancer) are at a markedly increased risk of EC. ## Diagnosis Abnormal uterine bleeding is the most frequent symptom of EC. Particular suspicion should be held for postmenopausal women or for those over 40 years with high-risk factors. Transvaginal ultrasound (TVUS) is considered the firstline imaging technique to be performed. In postmenopausal women, TVUS evaluation of the endometrial thickness has a high accuracy for EC diagnosis using a cut-off value of 3 mm . When an endometrial thickness is identified, an endometrial biopsy should be performed. Endometrial sampling is the gold standard for histologic diagnosis. If bleeding persists or recurs after endometrial sampling with benign findings, hysteroscopy should be performed. The role of preoperative studies is to establish risk groups and to define the surgical management. A chest radiograph should be performed as a part of the initial assessment. Contrast-enhanced MRI is the best method for detecting myometrial invasion or cervical involvement, when compared with non-enhanced MRI, ultrasound, or CT scan. MRI is also the best imaging modality, compared with CT or positron emission tomography (PET) with or without CT, for detecting lymph node metastases. There is no evidence for the clinical usefulness of CA 125 in the pretreatment evaluation of EC . ## Hereditary endometrial cancer The majority of ECs are associated with sporadic mutations. The genetic mutations associated with LS are responsible for 2-5% of all the ECs, mainly affected by the MLH1 and MSH2 genes. The estimated lifetime risk of EC varies between 18% in MLH1 and 30% in MSH2 mutation carriers [bib_ref] Cancer risks for MLH1 and MSH2 mutation carriers, Dowty [/bib_ref]. The Amsterdam II criteria and revised Bethesda Guidelines can be used to identify women with LS. The incidence of EC was significantly lower in the largest retrospective cohort study in women with the germline MLH1, MSH2 or MSH6 mutation, who underwent risk-reducing surgery versus those who did not [bib_ref] Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch..., Schmeler [/bib_ref]. Molecular screening for LS should be performed in women with Amsterdam or Bethesda criteria and women with EC before 50 years [II, A]. Prophylactic surgery with hysterectomy and bilateral salpingo-oophorectomy should be offered in women with LS mutations who have completed childbearing . ## Screening There are no high-quality data to support the efficacy of screening for reducing EC mortality. Routine screening of asymptomatic women at average or increased risk of EC is not recommended [II, A]. In women with LS, screening should be offered in asymptomatic women who have not completed childbearing or women that refused prophylactic surgery beginning at the age of 30-35 or 5-10 years prior the earliest age of first diagnosis of Lynch-associated cancer in the family. Annual endometrial sampling [II, A], TVUS with endometrial aspiration and serum CA 125 are usually recommended to be performed every year [IV, B]. ## Pathology and molecular biology of endometrial carcinoma WHO's classification of EC defines seven different types of tumor: endometrioid carcinoma (~ 80% of EC), usual type and variants, mucinous adenocarcinoma (1-9% of EC), serous carcinoma (< 10% of EC), clear cell carcinoma (< 5% of EC), neuroendocrine carcinoma, mixed carcinoma and undifferentiated and dedifferentiated carcinoma. Endometrioid adenocarcinoma (EEC) and their variants are the prototype of type I EC. The usual type EEC encompasses a spectrum of neoplasms with variable histological differentiation that ranges from well-differentiated tumors (grades 1 and 2) to solid and poorly differentiated carcinomas (grade 3). EEC with squamous differentiation accounts for 25-50% of all EEC. Serous carcinoma (SC) is the prototype of type II EC. SC is a very aggressive tumor, which arises occasionally in endometrial polyps. SC is usually associated with deep myometrial and extensive lymphovascular invasion. Tumor cells are usually positive for p53, p16, IMP2, IMP3. Clear Cell Carcinoma (CCC ) shows clear cells and a combination of patterns such as solid, papillary, glandular, and tubulocystic. HNF-1 beta, AMACR and Napsin A immunostaining are usually expressed. ## 3 SC or CCC may coexist with EEC. When more than one of these components is present at least in 5% of the tumor, it is diagnosed as a mixed carcinoma. The molecular genetic alterations of EEC (type I) differ from those of SC (type II), and cDNA analysis shows different gene expression profiles. Whereas EEC shows microsatellite instability (MI) and mutations in the PTEN, PIK3CA, K-RAS and CTNNB1 genes, SC have alterations of p53, chromosomal instability, as well as other molecular alterations (STK15, p16, E-cadherin, and C-erbB2) [bib_ref] Molecular pathology of endometrial carcinoma, Matias-Guiu [/bib_ref] [fig_ref] Table 1: Molecular features of endometrioid and serous endometrial cancer EEC Endometrioid endometrial cancer,... [/fig_ref]. The Cancer Genome Atlas Research Network (TCGA) has recently performed an integrating genomic characterization of EC [bib_ref] Integrated genomic characterization of endometrial carcinoma, Network [/bib_ref]. Interestingly, exome sequence analysis revealed four groups of ECs: Group 1, with EEC with mutations in POLE, and showing high mutation rates (ultramutated), associated with good prognosis; Group 2, including EEC with microsatellite instability (hypermutated), and Group 3, tumors including EEC with low copy number alterations, showing similar progressionfree survival rates. Group 4 (serous-like) including SC, but also EEC (usually grade 3), exhibited p53 mutations, and worse prognosis. Results show that there is a group of EEC, that are molecularly and prognostically similar to SC. Combining POLE mutational analysis with immunohistochemical analysis of p53 and mismatch repair markers (PMS-2 and MSH-6) have been proposed to classify the tumors in the four TCGA groups, particularly for high-grade EEC and SC, as a surrogate approach to apply TCGA to clinical practice. However, validation is needed. ## Staging and risk assessment EC is surgically staged. The staging is based on FIGO 2009 [fig_ref] Table 2: Fertility preservation could be offered in reproductive age patients with low-risk EC,... [/fig_ref] [bib_ref] Revised FIGO staging for endometrial cancer, Lewin [/bib_ref]. The most important prognostic factors identified in EC are: FIGO stage, histological subtype, grade, depth of myometrial invasion, lymphovascular space invasion (LVSI), and age. According to the risk of relapse, EC has been subdivided into four risk categories [fig_ref] Table 3: ESMO risk groups to guide adjuvant therapy use LVSI lymphovascular invasion, EEC... [/fig_ref]. In the near future, the molecular advances could be used for outcome prediction and may aid in optimal distinction of the risk groups. ## Surgical treatment ## Early stages All patients with newly diagnosed disease should be considered for surgery. The standard surgical approach of endometrioid EC in early stages is total hysterectomy without vaginal cuff with bilateral salpingo-oophorectomy and with or without lymphadenectomy. Peritoneal cytology, although recommended is not mandatory for FIGO staging. Lymphadenectomy (LND) provides prognostic information. Two randomized controlled trials have shown no overall survival (OS) benefit from LND in early-stage EC [bib_ref] Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical..., Benedetti Panici [/bib_ref] [bib_ref] Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a..., Kitchener [/bib_ref]. Decisions about whether to perform lymphadenectomy and to what extent can be made based on the preoperative findings or based on the intraoperative study of the hysterectomy. Criteria indicative of low risk for nodal metastases are less than 50% of myometrial invasion, tumor less than 2 cm or grade 1 and 2. Sentinel lymph node mapping (SLNM) provides important information to tailor adjuvant therapy and reduces LNDrelated morbidity and long-term sequelae of unnecessary adjuvant treatments, although published results are singleinstitution series or multi-institutional collaborations, without a prospective randomized trial. Laparoscopic approach has a lower rate of surgical complications and similar outcomes than laparotomy. Robotic approach could be an alternative to laparoscopic approach, with less estimated blood loss and outcomes comparable to laparoscopy. In non-endometrioid early stages, due to their high propensity to disseminate in the upper abdomen, complete staging including abdominal cavity review, bilateral salpingo-oophorectomy, pelvic lymphadenectomy, para-aortic lymphadenectomy up to the renal vein, omentectomy and peritoneal biopsies with maximal surgical debulking is recommended. The standard surgical approach of endometrioid EC in early stages is laparoscopic [I, A] with total hysterectomy, without vaginal cuff and bilateral salpingo-oophorectomy . In low-risk EC, LND is not recommended [II, A]. In intermediate and high-risk group, LND is recommended to guide surgical staging and adjuvant therapy . SLNM in EC is promising and being performed in many centers, but still can not be recommended as standard treatment. In nonendometrioid early stages, complete staging and maximal surgical debulking is recommended [IV, A]. ## Advanced stages A complete staging with maximal surgical debulking is recommended in patients with good performance status and resectable tumor . Palliative surgery could be considered in patients with good performance status and metastasic disease [IV, A]. ## Fertility sparing therapy Reproductive age women with low-risk EC should be advised about fertility sparing options. To recommend fertility preservation, it is important to exclude evidence of myometrial invasion, extrauterine disease or non-endometrioid histologies. Progestin therapy (medroxyprogesterone acetate; 400-600 mg/day or megestrol acetate; 160-320 mg/ day or an intrauterine device containing levonorgestrel) is the only available option in these patients, but there are no studies that compare progestin therapy vs standard therapy. Close follow-up and confirmation of lesion regression are mandatory. ## Adjuvant treatment Adjuvant treatment for patients with early-stage disease is tailored according to the risk group and the most important prognostic factors. ## Adjuvant radiotherapy Pelvic radiation (PRT) after surgery in stage I EC provides locoregional control, but there is no improvement in OS or disease-free survival (DFS) [bib_ref] Adjuvant radiotherapy for stage I endometrial cáncer, Kong [/bib_ref]. A randomized trial comparing vaginal brachytherapy (VBT) and observation in women with stage IA, grade 1 and 2 endometrioid EC have shown no OS benefit in VBT group and VBT was associated with an increase in genitourinary symptoms [bib_ref] Intravaginal brachytherapy in FIGO stage I low-risk endometrial cancer: a controlled randomized..., Sorbe [/bib_ref]. The results of PORTEC-2 trial, that compared VBT and PRT [bib_ref] Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer..., Nout [/bib_ref] in the high-intermediate-risk group, showed that there were no differences in pelvic or vaginal recurrences, DFS and distant metastasis, but the VBT group suffered significantly lesser toxicities than the PRT group. VBT in combination with PRT was compared to VBT only in patients with intermediate risk in a randomized trial [bib_ref] Pettersson B. External pelvic and vaginal irradiation versus vaginal irradiation alone as..., Sorbe [/bib_ref]. Addition of PRT improved locoregional control, but had no impact on OS and was associated with increased acute gastrointestinal and urinary toxicity. Postoperative RT has been considered standard in high-risk EC group, although a comparative study of adjuvant radiation versus no treatment in this group of patients has not been conducted. ## Adjuvant chemotherapy Results of prospective randomized trials comparing PRT to chemotherapy (CT) in high-risk EC have shown that CT reduced the risk of distant recurrences, but did not improve OS and the local control was poor. These observations have provided the rationale for a combined CT/RT approach. The role of adjuvant combined treatment with PRT and CT in EC has been studied in patients with intermediate and high risk. The pooled analysis of NSGO-EC-9501/EORTC-55991 and MaNGO ILIADE-III trials demonstrate that combined treatment (four cycles of platinum-based CT, given either before or after RT) improve DFS and show a trend towards improved OS [bib_ref] Sequential adjuvant chemotherapy and radio-therapy in endometrial cancer: results from two randomised..., Hogberg [/bib_ref]. The limitation of these studies is that 25-40% of the patient population was stage III or incompletely surgically staged. The type of CT used and the number of cycles are other concerns that preclude generalization of these results. The recent results of the two randomized trials have shown no benefit for adjuvant CT over PRT in high-intermediate and high-risk EC. In PORTEC-3 trial, PRT was compared with chemoradiation (two cycles of cisplatin with PRT, followed by four cycles of carboplatin and paclitaxel), with no difference in OS or DFS, but adverse events were more frequent with CT/RT. However, in stage III, there was an improvement in DFS with CT/RT with no improvement in OS [bib_ref] Final results of the international randomized PORTEC-3 trial of adjuvant chemotherapy and..., Boer [/bib_ref]. In GOG 249, CT (carboplatin-paclitaxel) plus VBT have demonstrated similar DFS as PRT, but more acute toxicity [bib_ref] Randomized phase III trial of pelvic radiation therapy (PXRT) versus vaginal cuff..., Mcmeekin [/bib_ref]. The results of GOG 258, a randomized trial that compared CT vs CT-RT in stages III to IVA, I-II serous or clear cell EC have shown no differences in DFS [bib_ref] A randomized phase III trial of cisplatin and tumor volume directed irradiation..., Matei [/bib_ref]. In PORTEC-3 and GOG 258, completion rate of CT was lower after radiation and most recurrences were distant. For these reasons, in stage III EC, we recommend adjuvant CT followed by PRT, rather than the combination. The results of protocol ENGOT-EN2-DCGC will definitively address the benefit of chemotherapy in high-risk early stages. Adjuvant treatment recommendations with the level of evidence and grade of recommendations are summarized in . ## Treatment of metastatic and advanced disease Surgery or radiation (in non-irradiated area) are options in patients with isolated centropelvic recurrence or single metastasic site [IV, A]. In patients with extrapelvic relapse, CT or hormonal therapy (HT) are palliative options. ## Hormonal treatment HT could be an option in endometrioid EC. The response rate (RR) with progestagens in first line is ~ 25%, while the RR described with tamoxifen or aromatase inhibitors is ~ 10%. Predictors of response are low histological grade, prolonged time to relapse, the location and extent of extrapelvic disease and positive hormone receptor. Hormone receptor status should be determined before initiating hormonal therapy, although its role as a predictor of response to hormonal treatment has not been clearly demonstrated [bib_ref] Hormone therapy in advanced and recurrent endometrial cancer: a systematic review, Decruze [/bib_ref]. The treatment of choice is a progestational agent (megestrol acetate 160 mg QD or medroxyprogesterone acetate 200 mg QD) [III, A]. Endocrine therapy is recommended as a therapeutic alternative for those patients with G1-2 tumors, hormone receptor positive and no rapid progressive disease [IV, A]. ## 3 Low risk EEC (stage I G1-2, <50% myometrial invasion, LVSI negative) ## No adjuvant treatment [i,a] Intermediate risk (stage I, G1-2, >50% myometrial invasion, LVSI negative) ## Adjuvant vbt [i,b] High intermediate risk ## Chemotherapy The most active drugs in EC are doxorubicin, platinum agents and paclitaxel. Doxorubicin was compared with doxorubicin plus cisplatin (AP) in FIGO III and IV EC in two large randomized trials. The combination arm showed better RR and PFS, but no benefit in OS. Doxorubicin plus paclitaxel combination was compared to AP, and no significant differences were found in RR, DFS or OS. AP combination was compared with doxorubicin, cisplatin and paclitaxel (TAP) in advanced EC, with an improvement in RR, PFS and OS that was shown in the TAP arm, but with bad tolerability [bib_ref] Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus..., Fleming [/bib_ref]. The GOG 209 trial compared carboplatin-paclitaxel (CT) versus TAP. There were no differences in OS or DFS (in the CT arm: PFS 12-14 m, OS 32 m). The better toxicity profile of CT regimen made it the standard scheme for advanced disease, but also for adjuvant treatment [bib_ref] Randomized phase III non inferiority trial of first line chemotherapy for metastatic..., Miller [/bib_ref]. Available options after the first-line therapy are limited. The evaluated drugs are paclitaxel (RR 20%), liposomal doxorubicin (RR 9.5%), ifosfamide (RR 15%), oxaliplatin (RR 13. %) and ixabepilone (RR 12%). Carboplatin and paclitaxel is the standard option in metastatic or advanced endometrial cancer [I, A]. There is no standard CT for second line. 1 3 ## Targeted therapies The identification of molecular abnormalities in EC, as described previously, has permitted the development of new drugs as target therapies. Antiangiogenic drugs and mTOR/ PI3K inhibitors are the most promising agents. EGFR and Her-2 neu inhibitors have had disappointing results. Up to now, no approved targeted therapies are available for EC. ## Antiangiogenic drugs Bevacizumab has been evaluated as a monotherapy agent in phase II trials, resulting in a RR of 15.1%, PFS 4.2 and OS 10.5 months and, in combination with paclitaxel and carboplatin with a RR of 73%. Latest phase II randomized trials (GOG86P and MITO END-2) have shown an interesting activity in combination with carboplatin and paclitaxel in first line, in advanced or metastatic EC [bib_ref] A randomized phase II study of paclitaxel/carboplatin/bevacizumab, paclitaxel/carboplatin/temsirolimus and ixabepilone/carboplatin/bevacizumab as initial..., Aghajanian [/bib_ref] [bib_ref] Randomized phase II trial of carboplatin-paclitaxel (CP) compared to carboplatin-paclitaxel-bevacizumab (CP-B) in..., Lorusso [/bib_ref]. Phase III trials with bevacizumab combination are ongoing. ## Mtor inhibitors Several phase II trials have been reported with mTOR inhibitors. The largest randomized study observed a PFS of 3.6 months for the experimental arm versus 1.9 months for the hormonotherapy treatment group. These drugs have shown low RR (0-25%), but the clinical benefit is secondary to long disease stabilization. Preclinical data have suggested that mTOR inhibition reverses hormonal resistance. A phase II trial with letrozole and everolimus has been reported with 32% of RR. ## Follow-up Most EC relapses occur within 3 years after primary treatment. The pelvis is the most common site of recurrence, most of them in the vaginal vault, whereas distant relapses account for only one-third of all the cases. Most patients with EC will have a low risk of recurrence and more than one-half of all the recurrences will be detected with examination and symptoms. Recurrent EC has poor prognosis, regardless of the time of detection, with the exception of local relapse. There are no prospective studies that have evaluated the role of the surveillance in EC. The most consistently used method is the physical examination which includes a thorough speculum, pelvic, and rectovaginal examination. Cytology does not add any clinical benefit [bib_ref] Posttreatment surveillance and diagnosis of recurrence in women with gynaecologic malignancies: society..., Salani [/bib_ref]. The CA-125 level should not be used routinely in patients with EC, but may be appropriate in selected patients with advanced disease, serous histology or a higher CA-125 level at diagnosis [bib_ref] Follow-up in gynecological malignancies: a state of art, Zola [/bib_ref]. The routine use of chest RX is not recommended. Pelvic US and CT may play a role in the evaluation of patients with symptoms, advanced stages or clinical signs of recurrence. All recommendations for the diagnosis, treatment and follow-up of EC are summarized in [fig_ref] Table 4: SEOM guidelines recommendations for the management of endometrial cancer Diagnosis TVUS and... [/fig_ref]. ## Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethical approval This article does not contain any studies with human participants 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. [table] Table 1: Molecular features of endometrioid and serous endometrial cancer EEC Endometrioid endometrial cancer, SC Serous carcinoma [/table] [table] Table 3: ESMO risk groups to guide adjuvant therapy use LVSI lymphovascular invasion, EEC endometrioid endometrial cancer, EC endometrial cancer [/table] [table] Table 2: Fertility preservation could be offered in reproductive age patients with low-risk EC, but there is no standard option [V, A]. Progestins are the recommended treatment[IV, B]. [/table] [table] Table 4: SEOM guidelines recommendations for the management of endometrial cancer Diagnosis TVUS and endometrial sampling should be considered the standard approach [II, B] Women with EC should have contrast-enhanced MRI and chest RX before surgery [IV, A] In advanced stages, a complete staging with maximal surgical debulking is recommended in patients with good performance status and resectable tumor [III, B]. Palliative surgery could be considered in patients with good performance status and metastasic disease [IV, A] Fertility preservation could be offered in reproductive age patients with low-risk EC, but there is no the standard option [V, A]. In the intermediate-high-risk group, VBT is recommended in patients with surgical staging and node negative [III, B]. CT can be evaluated [III, B]. In patients with no surgical nodal staging, PRT and VBT is recommended [III, B] In high-risk early stages, endometrioid EC, VBT [III, B] or PRT [III, B] are recommended. In early stages with non-endometrioid histologies VBT [IIIB] or PRT [I, B],CT can be evaluated [III, B]. The recommendation in stage III optimally debulked is CT, followed by PRT [I, B] Treatment of advanced or recurrent disease Surgical or local treatment (radiation in non-irradiated area) are options in patients with isolated centropelvic recurrence or single metastasic site [IV, A] Endocrine therapy is recommended as a therapeutic alternative for those patients with well-differentiated tumors or a long disease-free interval [IV, A] Carboplatin and paclitaxel is the standard option in metastatic or advanced endometrial cancer [I, A]. There is no standard CT for second line Follow-up Physical examination with a thorough speculum, pelvic, and rectovaginal examination is the most effective method for the detection of EC recurrences [IV, A] Cytology evaluation and chest RX are not recommended in asymptomatic women, imaging test should be reserved for patients with suspected recurrence [IV, A] [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs12094-017-1809-9.pdf	None
fff78fb7d54848ff9f30d884989da40239f4269f	pubmed	7th Brazilian Guideline of Arterial Hypertension: Chapter 10 - Hypertension in Children and Adolescents	7th Brazilian Guideline of Arterial Hypertension: Chapter 10 - Hypertension in Children and Adolescents Arterial hypertension was identified as the major source of combined mortality and morbidity, representing 7% of global disability-adjusted life years. 1 The adoption of the BP definitions and normalization of the "National High Blood Pressure Education Program" (NHBPEP) 2004 2 has standardized the BP classification in the pediatric population. The percentage of children and adolescents diagnosed with AH is estimated to have doubled in the past two decades. The current prevalence of AH in the pediatric population is around 3% to 5%, 3-5 while that of PH reaches 10% to 15%, 3,4,6,7 and such values are mainly attributed to the large increase in childhood obesity.8The etiology of pediatric AH can be either secondary, most often associated with nephropathies, or primary, attributed to genetic causes with environmental influence, predominating in adolescents. Pediatric AH is usually asymptomatic, but as many as 40% of hypertensive children have LVH at the initial diagnosis of AH. Although oligosymptomatic in childhood, LVH is a precursor of arrhythmias and HF in adults.In addition, pediatric AH is associated with the development of other changes in target organs, such as increased carotid IMT, arterial compliance reduction, and retinal arteriolar narrowing. Early diagnosis and treatment of childhood AH are associated with a lower risk for AH and for increased carotid atheromatosis in adult life. [bib_ref] Ideal cardiovascular health in childhood and cardiometabolic outcomes in adulthood: the Cardiovascular..., Laitinen [/bib_ref] Therefore, periodical BP measurements in children and adolescents are recommended, even contradicting the U.S. Preventive Services Task Force's suggestion, which considers the evidence of benefits of primary AH screening in asymptomatic children and adolescents insufficient to prevent CVD in childhood or adulthood. ## Definitions and diagnosis ## Definition and etiology Children and adolescents are considered hypertensive when SBP and/or DBP are greater than or equal to the 95 th percentile for age, sex and height percentile, on at least three different occasions.Prehypertension in children is defined as SBP/DBP ≥ the 90 th percentile < the 95 th percentile, and in adolescents as BP levels ≥ 120/80 mm Hg and < the 95 th percentile. Stage 1 AH is considered for readings between the 95 th percentile and the 99 th percentile plus 5 mm Hg, while stage 2 AH, for readings > stage 1. The height percentiles can be obtained by using Centers for Disease Control and Prevention's (CDC) growth charts. In addition, normal and high BP levels for children and adolescents are available in mobile apps, such as PA Kids and Ped(z). In the pediatric population, WCH and MH can be diagnosed based on established normality criteria for ABPM.After a detailed clinical history and physical examination, children and adolescents considered hypertensive should undergo investigation. The younger the child, the greater the chance of secondary AH. Parenchymal, renovascular and obstructive nephropathies account for approximately 60-90% of the cases, and can affect all age groups (infants, children and adolescents), being more prevalent in younger children with higher BP elevations. Endocrine disorders, such as excessive mineralocorticoid, corticoid or catecholamine secretion, thyroid diseases and hypercalcemia associated with hyperparathyroidism, account for approximately 5% of secondary AH cases. Coarctation of the aorta is diagnosed in 2% of the cases, and 5% of secondary AH cases are attributed to other etiologies, such as adverse effects of vasoactive and immunosuppressive drugs, steroid abuse, central nervous system changes, and increased intracranial pressure. Primary AH is more prevalent in overweight or obese children and adolescents with family history of AH. Currently, primary AH seems to be the most common form of AH in adolescence, being, however, a diagnosis of exclusion, and, in that population, secondary causes should be investigated whenever possible. ## Diagnosis ## Method for bp measurement Measuring BP in children is recommended at every clinical assessment after the age of 3 years, abiding by the standards for BP measurement.Children under the age of 3 years should have their BP assessed on specific situations.For BP measurement, children should be calm and sitting for at least 5 minutes, with back supported and feet on the floor, having refrained from consuming stimulant foods and beverages. The BP should be taken at heart level on the right arm, because of the possibility of coarctation of the aorta. [fig_ref] Table 1 -: Specific recommendations for BP measurement in children and adolescents• Auscultatory method [/fig_ref] shows the specific recommendations for auscultatory BP measurement in children and adolescents. Whenever BP is high on the upper limbs, SBP should be assessed on the lower limbs. Such assessment can be performed with the patient lying down, with the cuff placed on the calf, covering at least two-thirds of the knee-ankle distance. The SBP reading on the leg can be higher than that on the arm because of the distal pulse amplification phenomenon. A lower SBP reading on the leg as compared to that on the arm suggests coarctation of the aorta. [fig_ref] Table 2 -: Blood pressure levels for boys by age and height percentile2 [/fig_ref] show the BP percentiles by sex, age and height percentile. [fig_ref] Figure 2 -: Blood pressure levels for girls, from birth to the age of 1... [/fig_ref] show BP values for boys and girls, respectively, from birth to the age of 1 year based on data from the Report of the Second Task Force on Blood Pressure Control in Note: Adolescents with BP ≥ 120/80 mm Hg should be considered prehypertensive, even if the 90 th percentile value is greater than that. This can occur for SBP in patients older than 12 years, and for DBP in patients older than 16 years. For children/adolescents, ABPM is indicated to investigate WCH and MH, and to follow prehypertensive or hypertensive patients up.The prevalence of WCH has been reported as between 22% and 32%. The use of ABPM should be restricted to patients with borderline or mild AH, because patients with high office BP readings are more likely to be hypertensive. [bib_ref] Evaluation of white coat hypertension in children: Importance of the definitions of..., Sorof [/bib_ref] ## Anamnesis A careful recollection of data on birth, growth and development, personal antecedents, and renal, urological, endocrine, cardiac and neurological diseases should be performed. The following patterns should be characterized: physical activity; dietary intake; smoking habit and alcohol consumption; use of steroids, amphetamines, sympathomimetic drugs, tricyclic antidepressants, contraceptives and illicit substances; and sleep history, because sleep disorders are associated with AH, overweight and obesity. In addition, family antecedents for AH, kidney diseases and other CVRF should be carefully assessed. ## Physical examination On physical examination, BMI should be calculated. [bib_ref] Blood pressure: effect of body mass index and of waist circumference on..., Guimarães [/bib_ref] Growth delay might suggest chronic disease, and persistent tachycardia might suggest hyperthyroidism or pheochromocytoma. Pulse decrease on the lower limbs leads to the suspicion of coarctation of the aorta. Adenoid hypertrophy is associated with sleep disorders. Acantosis nigricans suggests insulin resistance and DM. Abdominal fremitus and murmurs can indicate renovascular disease. 18 ## Complementary tests Laboratory and imaging tests are aimed at defining the etiology of AH (primary or secondary) and detecting TOD and CVRF associated with AH [fig_ref] Table 4 -: Initial investigation of children and adolescents with AHComplete blood countRenal function and... [/fig_ref].Target-organ assessment should be performed in all children and adolescents with stage 1 and 2 AH. Sleep study by use of polysomnography or home respiratory polygraphy is indicated for children and adolescents with sleep disorders detected on anamnesis.To investigate secondary AH, see Chapter 12. [fig_ref] Table 5 -: Complementary tests to confirm the etiology of secondary AH in children and... [/fig_ref] shows some tests for children and adolescents suspected of having secondary AH. ## Therapeutic aspects In children and adolescents with confirmed AH, therapeutic management is guided by the AH etiology definition, CV risk assessment, and TOD characterization. ## Nonpharmacological management Nonpharmacological management should be introduced to all pediatric patients with BP levels above the 90 th percentile. 2 (GR: IIa; LE: C). It includes body weight loss, a physical exercise program, and dietary intervention.Body weight reduction yields good results in the treatment of obese hypertensive children, [bib_ref] Blood pressure and physical fitness in a population of children-the Odense Schoolchild..., Hansen [/bib_ref] similarly to physical exercise, which has better effect on SBP levels. [bib_ref] Blood pressure and physical fitness in a population of children-the Odense Schoolchild..., Hansen [/bib_ref] Regular aerobic activity is recommended as follows: moderate-intensity physical exercise, 30-60 minutes/day, if possible, every day. Children with AH can practice resistance or localized training, except for weight lifting. Competitive sports are not recommended for patients with uncontrolled stage 2 AH.Dietary intervention can comprise sodium restriction, [bib_ref] Changing sodium intake in children: the Minneapolis Children's Blood Pressure Study, Gillum [/bib_ref] and potassium and calcium supplementation; the efficacy in that population, however, is yet to be proven. [bib_ref] Blood pressure response to potassium supplement in normotensive adults and children, Miller [/bib_ref] ## Pharmacological management Pharmacological therapy should be initiated for children with symptomatic AH, secondary AH, presence of TOD, types 1 and 2 DM, CKD and persistent AH nonresponsive to nonpharmacological therapy. 2 (GR: IIa; LE: B). The treatment is aimed at BP reduction below the 95 th percentile in non-complicated AH, and BP reduction below the 90 th percentile in both complicated AH, characterized by TOD and comorbidities (DM, CKD), and secondary AH. 2 (GR: IIa; LE: C). The treatment should begin with a first-line antihypertensive agent, whose dose should be optimized, and, if target BP level is not attained, other pharmacological groups should be added in sequence. A recent systematic reviewhas identified neither a randomized study assessing the efficacy of antihypertensive drugs on TOD, nor any consistent dose-response relationship with any drug class assessed. The adverse events associated with the use of antihypertensive agents for children and adolescents have been usually of mild intensity, such as headache, dizziness, and upper respiratory tract infections. All classes of antihypertensive drugs seem safe, at least in the short run.The only randomized, double-blind, controlled study, by Schaefer et al., comparing the efficacy and safety of drugs of parallel groups and assessing hypertensive children on enalapril or valsartan, has shown comparable results regarding the efficacy and safety of both drugs. [bib_ref] Efficacy and safety of valsartan compared to enalapril in hypertensive children: a..., Schaefer [/bib_ref] In secondary AH, the antihypertensive drug choice should be in consonance with the pathophysiological - When using the oscillometric device, it requires validation. - Detection of AH by use of the oscillometric device requires confirmation with auscultation. - Use appropriate cuff size; air bag width: 40% of arm circumference in the middle point between the acromion and olecranon, and air bag length: 80-100% of arm circumference. - Conditions under which children < 3 years old should have BP measured: neonatal intensive care; congenital heart diseases, kidney diseases, treatment with drugs known to raise BP, and evidence of increased intracranial pressure. [fig_ref] Table 1 -: Specific recommendations for BP measurement in children and adolescents• Auscultatory method [/fig_ref] principle involved, considering the comorbidities present. For example, non-cardioselective BBs should be avoided in individuals with upper airway reactivity, because of the risk for bronchospasm. [bib_ref] Beta-adrenergic blocking drugs in the treatment of hypertension, Prichard [/bib_ref] In pregnancy, ACEIs and ARBs are contraindicated, because of their potential for fetal malformation. [bib_ref] Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors or angiotensin receptor..., Bullo [/bib_ref] The use of those drugs for childbearingage girls should be always accompanied by contraceptive guidance. [bib_ref] Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors or angiotensin receptor..., Bullo [/bib_ref] [bib_ref] Rational use of antihypertensive medications in children, Ferguson [/bib_ref] For renovascular AH, of ACEIs or ARBs are indicated in association with vasodilators and DIUs. In cases of coarctation of the aorta, in the preoperative period, the initial drug is usually a BB. If the AH persists postoperatively, the BB can be maintained, replaced or associated with an ACEI or ARB. For AH associated with DM and CKD, an ACEI or ARB is initially used. The use of ACEI and ARB relaxes the efferent arteriole, reducing the glomerular capillary hydrostatic pressure, and posing a risk for AKI in situations of hypovolemia. Similarly, those drugs are contraindicated for patients with bilateral renal artery stenosis. [bib_ref] Pregnancy outcome following exposure to angiotensin converting enzyme inhibitors or angiotensin receptor..., Bullo [/bib_ref] [bib_ref] Rational use of antihypertensive medications in children, Ferguson [/bib_ref] [bib_ref] Effect of antihypertensive drugs on blood pressure and proteinuria in childhood, Simonetti [/bib_ref] For obese adults, ACEIs, ARBs, CCBs, BBs and DIUs are effective in reducing BP. [bib_ref] Best strategies for hypertension management in type 2 diabetes and obesity, Allcock [/bib_ref] In adults, ACEIs and ARBs seem to reduce the risk of developing DM and to increase insulin sensitivity. [bib_ref] Does it matter how blood pressure is lowered in patients with metabolic..., Sharma [/bib_ref] [bib_ref] The effects of telmisartan treatment on the abdominal fat depot in patients..., Murakami [/bib_ref] [fig_ref] Table 6 -: Most frequently used oral drugs for management of pediatric chronic arterial hypertension2 [/fig_ref] shows the updated pediatric doses of the most frequently prescribed hypotensive agents to treat CAH. [bib_ref] Rational use of antihypertensive medications in children, Ferguson [/bib_ref] Hypertensive crisis Hypertensive emergency is characterized by acute BP elevation associated with TOD, which can comprise neurological, renal, ocular and hepatic impairment or myocardial failure, and manifests as encephalopathy, [fig_ref] Table 1 -: Specific recommendations for BP measurement in children and adolescents• Auscultatory method [/fig_ref] convulsions, visual changes, abnormal electrocardiographic or echocardiographic findings, and renal or hepatic failure. [bib_ref] First-attack pediatric hypertensive crisis presenting to the pediatric emergency department, Yang [/bib_ref] Hypertensive urgency is described as BP elevation above the 99 th percentile plus 5 mm Hg (stage 2), associated with less severe symptoms, in a patient at risk for progressive TOD, with no evidence of recent impairment. Oral drugs are suggested, under monitoring, with BP reduction in 24-48 hours.In HE, the BP reduction should occur slowly and progressively: 30% reduction in the programed amount in 6-12 hours, 30% in 24 hours, and final adjustment in 2-4 days. [bib_ref] The emergency management of severe hypertension, Adelman [/bib_ref] Very rapid BP reduction is contraindicated, because it leads to hypotension, failure of self-regulating mechanisms, and likelihood of cerebral and visceral ischemia. [bib_ref] Management of hypertensive emergencies, Deal [/bib_ref] The HE should be treated exclusively with parenteral drugs. In Brazil, the most frequently used drug for that purpose is SNP, which is metabolized into cyanide, which can cause metabolic acidosis, mental confusion, and clinical deterioration. Thus, SNP administration for more than 24 hours requires monitoring of serum cyanide levels, especially in patients with renal failure. [bib_ref] The emergency management of severe hypertension, Adelman [/bib_ref] [bib_ref] Management of hypertensive emergencies, Deal [/bib_ref] After patient's stabilization with SNP, an oral antihypertensive agent should be initiated, so that the SNP dose can be reduced. The use of SNP should be avoided in pregnant adolescents and patients with central nervous system hypoperfusion. Special clinical conditions can be managed with more specific hypotensive agents for the underlying disease. Patients with catecholamine-producing tumors can be initially alpha-blocked with phenoxybenzamine, or prazosin if the former is not available, followed by the careful addition of a BB. After BP control and in the absence of kidney or heart dysfunction, a sodium-rich diet [fig_ref] Table 7 -: Major pediatric drugs and doses used to control hypertensive emergency 2,95,96 IV [/fig_ref] shows the most frequently used drugs in pediatric HE. [bib_ref] Pediatric hypertensive emergencies, Baracco [/bib_ref] [fig] Figure 2 -: Blood pressure levels for girls, from birth to the age of 1 year 97 [/fig] [table] Table 1 -: Specific recommendations for BP measurement in children and adolescents• Auscultatory method. • Use 1 st Korotkoff sound for SBP, and 5 th Korotkoff sound for DBP. [/table] [table] Table 2 -: Blood pressure levels for boys by age and height percentile2 [/table] [table] Table 3 -: Blood pressure levels for girls by age and height percentile2 [/table] [table] Table 4 -: Initial investigation of children and adolescents with AHComplete blood countRenal function and electrolytes (including calcium, phosphorus and magnesium)Renal US with Doppler of renal arteries [/table] [table] Table 5 -: Complementary tests to confirm the etiology of secondary AH in children and adolescentsMeasurement of urine electrolytes, proteinuria and urine creatinine Plasma levels of renin (or plasma renin activity) and aldosterone, salivary cortisol test, PTH, TSH, free T4 and T3Hemoglobin electrophoresisSpecific auto-antibodies: FAN, anti DNA, ANCA p, ANCA c Urine catecholamines and metanephrines (or plasma metanephrine) and MIBG scintigraphy [/table] [table] Table 6 -: Most frequently used oral drugs for management of pediatric chronic arterial hypertension2 [/table] [table] Table 7 -: Major pediatric drugs and doses used to control hypertensive emergency 2,95,96 IV: intravenous; IM: intramuscular; min: minute; h: hour. [/table]	None	None	Arterial hypertension was identified as the major source of combined mortality and morbidity, representing 7% of global disability-adjusted life years.1 The adoption of the BP definitions and normalization of the “National High Blood Pressure Education Program” (NHBPEP) 20042 has standardized the BP classification in the pediatric population. The percentage of children and adolescents diagnosed with AH is estimated to have doubled in the past two decades. The current prevalence of AH in the pediatric population is around 3% to 5%,3-5 while that of PH reaches 10% to 15%,3,4,6,7 and such values are mainly attributed to the large increase in childhood obesity.8 The etiology of pediatric AH can be either secondary, most often associated with nephropathies, or primary, attributed to genetic causes with environmental influence, predominating in adolescents.
ee305a8a4733c1f8f1fba7f64561d6e86183b55a	pubmed	UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care	UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care # Introduction The requirement for the consensus guidelines on this topic was highlighted by a national survey of physician and nurse attitudes to transition conducted by the Adolescent and Young Persons (AYP) Section of the British Society of Gastroenterology (BSG). There is currently no European consensus guideline available for clinicians working in this field, although in 2015 the Italian Societies of Gastroenterology published a position statement,as have the North America Society for Paediatric Gastroenterology, Hepatology and Nutrition in 1993.The guideline proposal was reviewed and accepted by the Clinical Services and Standards Committee (CSSC) in 2014. Members of the guideline committee were selected after an open invitation for expressions of interest and divided into multidisciplinary subgroups. The authors drafted a preliminary guideline document following the 'BSG Guideline Advice' document. The draft guidelines were submitted for review by BSG AYP Section, CSSC and BSG Council and revised in response to their comments. ## Data sources and search strategy A systematic literature search was undertaken by a medical librarian (RF) using four relevant databases, Medline (via Ovid), Embase, Web of Science and CINAHL, aiming to capture all relevant studies across disciplines including paediatric and adult gastroenterology from 1980 to September 2014. MeSH search terms relating to digestive system diseases ("gastrointestinal disease", "hepatological disease", "liver disease", "digestives system disease"), transition to adult care ("transition clinic", "transition" "transition process", "transition care", "transfer"), adolescent ("adolescen", "young adult" (were entered and combined, and limited to 'adolescent' and 'young adult' (see online supplementary appendix 1)). Following this, section working groups reviewed all relevant articles and any additional records identified through other sources in an iterative way, drawing on clinical expertise in the field to draw on key publications related to AYP transition in non-GI or hepatology disorders. *Denotes terms where truncation has been used. ## Study eligibility and selection criteria Members of the guideline group determined study eligibility for inclusion in the final consensus. Studies were initially screened independently by all members of each subgroup. Decisions regarding study inclusion were made by consensus within each subgroup, with final decisions regarding study inclusion made by the relevant chair. Studies were included if (a) published in full and (b) written in English. Studies were excluded if (a) they were case studies or not empirical studies (eg, narrative reports) and (b) they were only published in abstract. Additional studies of interest were identified by hand searches of bibliographies and cited references and by consultation with clinical experts in the field. ## Data extraction and quality assessment Of 639 studies identified, a formal assessment of quality was conducted using the GRADE system. Assessing the quality of the guidelines: the Agree II instrument The Agree II instrument is the recognised and accepted method of assessing the quality of clinical guidelines.Six domains are listed and the position of the current guideline in these domains is stated: 1. Scope and purpose The aim of the guideline is to provide clinical guidelines based on current available literature for the care of AYP as they progress from paediatric health services through to adult care, for clinicians and other health professionals in gastroenterology and hepatology. ## Guideline development group membership and stakeholder involvement Membership of the guideline development group included paediatric and adult gastroenterologists and hepatologists, specialist nurses and dieticians who were selected after an open call for participation was published in the BSG newsletter. The group also included patient and parent members as well as representatives from appropriate patient organisations who were invited to participate by the chairperson. The guideline development group had three face-to-face meetings where the scope and remit of the guideline was planned and progress reviewed at key stages. The guideline development group was divided into four multidisciplinary subgroups; patient populations, risks of poor transition, models of transition and, finally, the patient and parent perspective (see online supplementary appendix 2). Each subgroup had a nominated chairperson (RKR, DRG, SS and PJS, respectively) with the responsibility of overseeing the review of relevant literature and production of draft recommendations and accompanying text for publication for that section (see online supplementary appendix 2). ## Rigour of development The guideline development group met regularly for discussion via face-to-face meetings and teleconferences during the period from September 2014 to September 2015. The guidelines rely on a formal assessment of study quality that was conducted using the GRADE system. GRADE was used to determine (a) quality of studies included into high (A), moderate (B), low (C) or very low (D); and (b) assess guideline recommendations and classify them as either STRONG or WEAK (tables 1 and 2). In the guideline, we have stated the recommendations and the associated GRADE of evidence together. Practice points were included based on expert clinical experience and consensus of opinion rather than these being supported by clinical research, as used in European Crohn's and Colitis Organisation (ECCO) and European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPAGHAN) guidelines. Face-to-face meetings were held to agree the recommendations. Areas of disagreement about the recommendation grade were subject to discussion and, where necessary, voting by members of the guidelines group with consensus achieved when >80% were in agreement. Practice points were used where formal recommendations were not possible due to a paucity of appropriate research, but where the guideline development group felt there was enough expert clinical experience and consensus for these to be included. The guidelines were subject to peer review by the CSSC and BSG Council for consideration of publication in July 2016. This involved five expert reviewers providing detailed feedback to the Guideline Development Group. The review resulted in the writing committee (AJB, PJS, JOL, SAM) undertaking changes and improvement in the structure and content of the guideline that underwent subsequent approval by the Chair of the CSSC. The updated guideline was reviewed by all members of the Guideline Development Group prior to submission for publication in September 2016. ## Clarity and presentation Recommendations are intended to be specific to particular areas of transition and the process of transition in order to provide clinicians and allied health professionals with guidance to facilitate development of transition facilities with a local setting and context. ## Applicability Within the guidance we have discussed organisational changes that may be required to apply the recommendations and identified areas suitable for monitoring, audit and service improvement. 6. Editorial independence and conflict of interest Guideline group members have declared any conflicts of interest, which are detailed at the end of the guideline. ## Patient populations involved in ayp transition transition for gi disease areas Until recently, there has been a lack of transition services for AYP patients with chronic GI and liver diseases in the UK. The most frequent GI areas where transition arrangements exist are IBD followed by chronic liver disease comprising both transplanted and non-transplanted patients. A very small number of patients with complex nutritional needs are transferred or transitioned on an ad hoc basis although there are not dedicated clinics for these patient groups in the UK. Until recently, the majority of patients with coeliac disease and other common GI illnesses (constipation, GORD), together with simple functional GI disorders, have been transferred from paediatric to adult care or discharged from paediatric care with the expectation that the primary care physician will refer to an appropriate adult consultant if required. However, after the initial evidence search for this guideline was completed in 2016 the first consensus guidelines regarding transition in coeliac disease recommend structured transition for this patient group,and there has been recent interest in transition Individual studies included in the guideline are formally assessed using the GRADE system 1 with the quality of the body evidence rated, from 'high' (A) to 'very low' (D) Modify the initial quality of a body of evidence ## Prevalence of gi disease in this population While published data exist on the prevalence of specific GI and liver disease in AYPs, the actual numbers of patients who move from paediatric to adult care with or without transition annually have not been recorded systematically. This is important as it will determine the potential impact of recommendations to implement a transition service for a specific disease. An estimate based on extrapolation from audits, surveys or expert opinion is provided in table 3. Due to the comparatively larger sizes of the patient populations-transition has to date been more frequently undertaken in the IBD and liver disease patient populations, but is of increasing importance in other GI diseases such as coeliac diseaseand in complex functional GI disorders. However, the true requirement for transition care among AYP with GI disease has still to be accurately defined and data on the number of transition clinics currently supporting AYPs through the transition process are not available to be able to estimate any shortfall in service provision. However, these figures are likely to be underestimating the true prevalence of AYPs requiring formal transition into adult services. The demand for specialist nutrition for paediatric GI and surgical disorders has risen in recent years, suggesting that increasing numbers of AYP patients may survive and require transition to adult services. Furthermore, the number of complex enteral nutrition patients will be significantly higher than those requiring parenteral nutrition support. Children with complex motility disorders will make up a small proportion of these patientsand therefore may require formal transitioning into adult care with multidisciplinary support given their symptomatology, nutrition support and psychological comorbidity can be difficult to manage. ## Disease course and differences between ayp and adults For specific GI diseases, there are documented variations in prognosis and clinical course when the disease presents in childhood compared with adulthood. This has clear relevance for the AYP transition process in these diseases. There are also clear differences in diagnostic and therapeutic IBD management dependent on age at diagnosis with a higher use of exclusive enteral nutrition in children with Crohn's disease and general anaesthetic use for endoscopy in children compared with sedation in adults. Furthermore, children presenting with IBD have a more extensive disease phenotype and rapid early progression, although there no clear differences reported in the rate of disease complications.Although the clinical course of coeliac disease presenting in childhood is often more severe than that presenting later in life, it is difficult to predict outcomes dependent on age at diagnosis with sparse research in this area. There are no studies that assess the benefit or risk of good versus poor disease control during the transition from paediatric to adult care. However, there are differences in management as in children the diagnosis of coeliac disease is often based on serology with supportive investigations without the need for duodenal biopsy, whereas histological evaluation is always recommended in adults.The use of psychological management for functional GI illness in paediatrics is higher than adult practice. Outside the GI tract, the most common indication for liver transplant in children is for congenital reasons (biliary atresia) compared with acquired liver disease in adulthood. ## Recommendations and practice points We recommend that AYP with IBD, coeliac disease and chronic liver disease should be involved in formal transition arrangements (GRADE recommendation: strong (C)). ## Practice points ▸ AYP with other chronic GI and liver conditions, including complex functional disorders, are likely to benefit from formal transition arrangements and may be incorporated into existing transition services. ▸ HCPs involved in the management of AYP should be aware of the differences between classification, diagnostic methods, treatment and natural history of relevant paediatric and adult chronic GI and liver diseases dealt with in transition clinics. ▸ Centres should audit their population of AYP with chronic GI and liver diseases to determine the prevalence and service requirements for transition. ▸ HCPs involved in the management of AYP with chronic GI and liver diseases should receive appropriate training in transition care such as the pitfalls and benefits of transition and strategies to improve transitional care. ▸ AYPs should be transitioned once they have finished or are in the later stages of puberty. Patients with growth issues should be transitioned once the growth issues are resolved. ## Risk of failing transition or poor transition Transition to adulthood is a complicated process for most AYP and is particularly so where AYP have chronic illnesses and ongoing health needs. The transition process has increasingly been recognised as covering a vulnerable period where unaddressed healthcare needs may have long-term consequences. 21 ## Inadequate transition arrangements and adverse outcomes Inadequate transition arrangements have been associated with a number of adverse outcomes over a wide range of medical conditions including diabetes, heart disease 24 and haematological disorders.These consequences include delayed and inappropriate care, poor communication with AYP and their families, as well as emotional and often financial stress for patients, their families and healthcare systems. Following solid organ transplantation, inadequate transition has been associated with worsening adherence,increased graft lossand higher mortality.There have been few specific studies in gastroenterology and hepatology, but similar conclusions are emerging. Inadequate transition in IBD is associated with clinic nonattendance and non-adherence with medication, restricted growth potential and an increased likelihood of requiring surgery.In coeliac disease, inadequate transition arrangements are associated with dietary non-adherence, anaemia and reduced bone density.As the AYP grows into adulthood, considerations of further education and employment become important. There is some emerging data on the relevance of a coordinated transition during adolescence in chronic disorders, which may have impact on the future work and employment. ## Benefits of successful transition in other chronic diseases There is evidence to support the benefits achieved by successful transition programmes in chronic diseases in various disciplines. For AYP with diabetes, successful transition has been shown to result in improved objective measures of glycaemic control, better engagement with screening programmes, improved outpatient attendance and engagement with adult providers in addition to decreased hospitalisation with diabetic ketoacidosis.In juvenile idiopathic arthritis and congenital heart disease, successful transition was associated with improved selfknowledge and improved disease knowledge among parents and carers. These were accompanied by increased satisfaction with the process and better quality of life. In renal diseases, an integrated paediatric-adult clinical transition service was associated with a striking reduction in the rate of graft loss among the patients with renal transplants.Evidence to document the impact of successful transition in gastroenterology and hepatology is more sparse. A recent UK study in 72 patients (diagnosed with IBD in paediatric care and then transferred to adult care service) who either went through a formal transition programme versus no formal programme has shown that establishment of a transition programme resulted in improvements in drug adherence, clinical attendance and growth with a reduced need for surgical intervention on retrospective analysis of their medical records.The same study also showed a trend towards improved growth pattern in the transition patients. A French group that performed a retrospective survey in 48 AYPs who had been transitioned from paediatric to adult care showed that a structured transition programme results in improved patients and carer satisfaction.Another study in which 81 AYPs with a chronic illness (34 IBD, 13 cystic fibrosis and 34 type 1 diabetes mellitus) were randomised to either a 2-month web-based text delivered health educational programme or a control group that received written materials health-related topics to read has shown disease management, health-related self-efficacy (one's belief in one's ability to accomplish a specific health-related task) and patient-initiated communications were all improved by the use of a generic disease management tool. ## Recommendations We recommend the use of structured transition programmes to improve control of chronic GI disease in AYP (GRADE recommendation: strong (C)). We suggest that the use of structured transition programmes may increase disease related knowledge in patients and carers/ parents (GRADE recommendation: weak (C)). We suggest that a structured transition programme may improve psychological outcome and health-related quality of life in chronic GI diseases (GRADE recommendation: weak (D)). We suggest that the use of a structured transition programme may reduce adverse outcomes such as hospitalisation, surgery and radiation exposure in GI disease (GRADE recommendation: weak (C)). ## Improvements in adherence and compliance Following liver transplantation non-adherence to immunosuppression is a major cause of graft loss and mortality. Non-adherence increases throughout adolescence and may worsen when transfer is complete.The use of a dedicated transplant coordinator results in better adherence and improved self-management of healthcare needs. Thus, AYPs who had moved from paediatric to adult care after liver transplant with the support of a liver transplant coordinator had more appropriate tacrolimus levels and enhanced healthcare management parameters compared with a historical comparison group.Medication adherence in IBD also appears to be increased following a structured transition programme. ## Recommendation We recommend the use of structured transition programmes to enhance adherence to medications, clinic attendance and clinical outcomes including organ survival in liver transplantation (GRADE recommendation: strong (C)). ## Models of ayp transition The implementation of existing AYP transition models vary with differences in approach and outcome dependent on coordination between the relevant HCPs. Various models have been proposed and evaluated, but it remains unclear which transition model is associated with the best outcomes for AYP.Combined care during transition Surveys of different transition programmes in a variety of medical disciplines have reported that combined clinic visits with input from both paediatric and adult HCPs are clinically beneficial and endorsed by patients. However, the exact format of transition may be highly variable and may include combined adult/paediatric clinics and/or joint multidisciplinary clinics or 'virtual' transition clinics. ## Recommendation We suggest that an overlap between paediatric and adult gastroenterology care is a core element of every structured transition service (GRADE recommendation: weak (C)). Benefit from AYP transition clinics in GI/liver diseases Transition models incorporating a joint paediatric-adult clinic that have been associated with improvements in clinically relevant endpoints have been reported sparsely in gastroenterology and hepatology but there is supporting evidence from other chronic diseases that affect AYPs. For example in patients with renal transplant, a transition model in which the use of a single referral letter for transfer was replaced by an integrated paediatric-adult clinical service was associated with a reduction in the rate of graft loss.However, no significant enhancement of adherence, patient satisfaction or clinician's subjective assessment of graft stability was reported in another small study of renal transplant recipients.In type 1 diabetes, significant improvements in HbA1c, rate of screening for complications of the disease and attendance at clinic appointments have been described in patients undergoing a structure transition planned and coordinated with the adult team compared with those in whom a letter of referral was used to transfer patients to the adult services.In a single-centre study from the UK where the transition clinic involved use of combined clinics with paediatric and adult gastroenterology teams and using assessment of readiness to transfer using tools, there were indicators for improvement in clinically relevant outcomes such as adherence, surgery rates and growth and development.In a further study from France, the majority of patients attending a joint paediatric and adult IBD clinic view a joint clinic as being beneficial in transferring information from their medical records and in building confidence in their new adult physician. ## Different transition models The published guidance for specific models of transition lacks a strong evidence base and originates from expert opinion as a result of weak studies involving small patient numbers, bias and multiple methodological flaws within the data sets. However, a theoretical framework, entitled the Chronic Care Model (CCM), describes how teams comprised of individuals from different disciplines should approach the care of patients with chronic health conditions.It identifies the components of care that are relevant to transfer. The CCM also identifies the major barriers to a successful transfer including a lack of coordination between adult and paediatric services, a lack of planning and resistance of patient and families to transition of their healthcare. These themes were also identified in the UK survey on transition care among paediatric and adult gastroenterologists involved in care of AYPs. 1 A description of the application of this model to a paediatric liver transplant population has been published and illustrates how a theoretical framework can be applied to implement organisational change.In a systematic review of practices that promote continuity between child and adult services, recurring themes within the literature were identified from which core principles of transition could be established. From this, four models of transition were outlined (direct, sequential, developmental and professional).In the 'direct' model, the focus is primarily on relations between services and addresses continuity of information between them, rather than focusing on the AYPs' personal growth and development. The 'sequential' model is more flexible and recognises that the AYPs' needs are changing and that they require some preparation if they are to adjust to adult care successfully. A 'developmental' transitional model starts from the premise that the AYP will need some help in acquiring the skills and support systems necessary to use or experience adult care effectively, with an active focus on personal growth and development. Finally, in contrast to the other models, the 'professional' model focuses on the expertise from within one service type (adult or paediatric) and not on the AYP. This may be important in conditions with a short life expectancy or where expertise is heavily located within one service, for example, cystic fibrosis, so is less applicable to chronic GI disease. These models are not mutually exclusive with this guideline reflecting aspects of all of these models in our recommendations but no evidence to support a particular type exclusively. ## Recommendation We suggest that while there are numerous models of transition there is no evidence to support a particular type (GRADE recommendation: weak (C)). ## Essential components of ayp transition clinics It is important to design the transition process to be flexible and dependent on patient factors including chronological age, current disease activity, adherence with medical therapies, views of AYP, view of the parents/carers and self-advocacy skills of the patient. The crucial role of a named transition coordinator (eg, for patients with IBD the paediatric IBD nurse who will remain a constant contact and organise the transition process) is a recurring theme in the literature and often scored as the key component of the programme in many surveys. A systematic review of transition services between paediatric and adult healthcare identified three core areas that require attention when developing a successful transition service. These comprised interventions aimed at staffing requirements (transition coordinator) and service delivery (separate young adult clinics, out-of-hours telephone support and enhanced follow-up) and patients (educational programmes and skills training). ## Ayp transition coordinator The AYP transition coordinator is frequently a specialist nurse, often, but not exclusively based within the paediatric service. However, an expanded role of the transition coordinator has also been described and applied to patients who have undergone liver transplantation.In this model, the transition coordinator continues to work with the patients after transfer to the adult services to help address gaps identified in the patients' healthcare management. ## Assessment of readiness to transfer Several tools that assess the readiness to transfer have been described some of which are disease-specific.The Transition Readiness Assessment Questionnaire is a generic tool that has a high internal consistency and validity.The University of North Carolina TR(x)ANSITION Scale is a tool for assessing the effectiveness of a transition process.It uses a semistructured interview with the patient with use of the medical records to verify data. It has a high inter-rater reliability. These tools tend to focus on patients' knowledge of disease and skills. Psychometric data are not frequently collected. Data demonstrating the ability of these tools to predict outcomes of transition are lacking.The involvement of parents who can overestimate AYP self-efficacyand have higher levels of anxiety than the AYP is deemed important. 64 ## Disease-specific education programmes A number of tools may be used to facilitate disease education for transitioning patients. The 'IBD passport' (a wallet-sized card containing personal and medical information about the patient) has been identified as such a tool for transitioning AYPs with IBD 65 by identifying the areas of weakness in which AYPs and parents require education and support such as awareness of disease pathogenesis, disease location, characteristics, medications and health resources available to them. In a pilot study of a disease-specific education programme in liver transplant recipients, a two-session education programme was associated with improvements in adherence to immunosuppressant medications and a reduction in elevated alanine aminotransferase (ALT) levels.In the first session, the focus was on educating the patient and parents on their disease and the medication regimens necessary to achieve disease control, while the second session focused on practical aspects of taking responsibility for one's care in relation to taking medications, scheduling appointments, communicating directly to healthcare providers and attending appointments alone. The use of education programmes to facilitate the transition process has been described in other chronic conditions. Disease-specific education programmes and skills training have been associated with improvement in HbA1c, acute complications, self-management skills and disease-specific knowledge in patients with diabetes transitioning to the adult services.However, no improvement in quality-of-life scores was demonstrated. In patients with juvenile idiopathic arthritis, an age-adjusted structured transition programme that featured a disease-specific programme of education was associated with an improvement in disease-specific quality of life and continuous improvements in knowledge of patients and their parents.No impact was demonstrated on independent health behaviours. Furthermore, disease education for HCPs is a vital component of successful transition. A survey of adult and paediatric gastroenterologists in IBD identified suboptimal training in adolescent care in 65% and 59% respectively as a barrier to successful transition. 1 ## Recommendation We recommend an effective transition model (figure 1) may benefit from inclusion of the following elements (GRADE recommendation: strong (D)): A. flexible timing of transition B. a named transition coordinator to oversee the process C. individualisation of the transition model based on local expertise, staffing, resources and geography D. assessment of readiness for transfer E. disease-specific education programme. We have suggested a transition pathway (figure 2) within this guideline incorporating many of the recommendations and practice points into a practical overview. ## Use of technology in ayp transition programmes Recent studies have highlighted the impact and interest in web-based and mobile technologies to assist in the transition process. Such technologies offer several unique advantages including potential for individualisation of the health message being delivered, anonymity, rapid access, low cost and ability to overcome most geographical barriers. With wireless technologies now being ubiquitous and text messaging being one of the main forms of communication by adolescents today, we suggest that such technology should be incorporated into the design of transition models to enable good, rapid communication with health providers for reporting of symptoms, obtaining essential medications, ensuring appointments are not missed, as well as providing links to educational materials and useful websites and support forums. In AYP with type I diabetes, the use of mobile phone interventions have resulted in improved clinic attendance, supported intensive insulin regimens and reduced progression from ketosis to diabetic ketoacidosis in those with poor glycaemic control.A transition intervention for chronic disease (MD2Me) has been tested in a number of chronic diseases including IBD.This intervention uses technology-based communication between the healthcare team and patients (web-based and text message-based intervention) to enhance access to the healthcare team and to provide disease management and skills-based interventions. In a randomised controlled trial, this has been shown to improve health-related self-efficacy, performance of disease management tasks and patient-initiated communications. However, no beneficial impact was demonstrated for quality-of-life measure, functional performance or for disease status. ## Recommendations We recommend information technology as an effective and costefficient tool to facilitate transition (GRADE recommendation: strong (C)). We recommend that AYP's self-efficacy is enhanced by the use of virtual intervention and electronic communication (GRADE recommendation: strong (C)). ## Audit of transition programmes and research into their impact In view of the inability to recommend one specific transition model for any specific service, we suggest regular clinical audit of the transition process to identify weaknesses and facilitate improvements in the process for the benefit of HCPs, patients and carers alike. This would benefit from agreeing on key performance indicators for transition generally that are then complemented by disease-specific indicators. Audit should include assessment of the number of eligible patients that access a transition programme in addition to an assessment of the impact of the programme and patient satisfaction. The impact can be assessed using validated measures of disease-related knowledge and tools that assess progress through the transition process. Research into the impact of a successful transition programme is also required, which may include standard transition workshops that take place prior to and during the transition process.The rate of hospital admissions, use of support services, attendance at outpatient clinic appointments, requirement for steroids, adherence to medications and patient satisfaction would all be potential outcome measures for assessment of the impact of a transition intervention.Qualitative studies that assess the outcome of transition from a patient and parent perspective are also important. It is unlikely that a controlled trial in this area will be performed due to methodological difficulties in designing an appropriate trial as well as ethical concerns of allocating a group of patients to 'no transition' when all expert consensus suggests that this is inferior. Therefore, it is likely that research will assess outcomes between centres that offer transition compared with those that do not. This will always suffer from bias. ## Recommendation We recommend regular audit of the transition service in order to improve the service, outcomes and assess key performance indicators (GRADE recommendation: strong (D)). ## Patient and carer/parent perspective in ayp transition addressing patient and carers/parents readiness during transition Anticipation of the timing of transition for AYPs has been identified as one of the most important factors for its success. AYPs with non-GI chronic disease report frustration at inflexibility regarding a determined age of transfer. In a study of 28 AYPs with a variety of chronic conditions, AYPs did not identify self-management as an indicator of readiness for transition and some transition occurred before they were willing, or understood the need.In patients with cystic fibrosis up to 12 months post transition, AYPs felt that paediatric HCPs were more concerned with the clinical parameters than the emotional factors associated with transition, reporting feeling neglected in this period while waiting for the move and being uncertain as to who was responsible for their healthcare needs during this period. ## Patient and carer/parents uncertainty and behaviour during transition AYPs with IBD may feel a sense of abandonment or be uncertain regarding transfer to adult care 79 while parents often feel a sense of anxiety about joining a new healthcare team that may not have been adequately informed about their condition. Furthermore, failure to connect with an adult healthcare provider post transition has been demonstrated to predict future complications in diabetic patients.AYPs often face multiple transitions (education, employment) at this stage in their lives, which may take priority over their healthcare transition resulting in anxiety and uncertainty.In this context, AYP may display regressive behaviour during transitionand as a result transition services should identify this and provide supporting emotional and psychological support. Age, gender or severity of disease does not predict level of concern about transition in cystic fibrosis AYPs and their carers/ parents.The combination of difficult symptoms and use of medications with significant side effects such as corticosteroids results in adolescents with IBD reporting poorer quality of life and an increased prevalence of psychological distress and depression.The most common coping strategy employed by AYP is 'avoidant coping'; where an individual distracts himself or herself with social diversion.This behaviour is associated with disease relapse in adolescents.A number of studies show improvement in adolescents overall psychological well-being with psychological interventions indicating an important role for the psychologist in IBD. ## Recommendation We suggest that HCPs consider concerns of AYP and their carers/parents during transition and identify when additional emotional and psychological support is required (GRADE recommendation: weak (D)). Empowering AYPs self-management: the role of the patient and carers/parents Carers/parents of AYP undergoing transition may find it difficult to cope with their reduced role in medical care and should be actively included where appropriate. Carer/parent protectiveness has been reported as a significant challenge in transition in patient with juvenile idiopathic arthritis.Furthermore, HCPs may perceive AYPs ready to been seen independent of their carers/parents at an earlier age than their carers/parents do.Negotiating the appropriate level of protectiveness with carer/parent should be based on the AYPS self-efficacy and is an important skill for HCPs to appreciate.Addressing motivational issues, teaching problem-solving skills and addressing problematic patterns of family functioning are more likely to benefit individuals displaying intentional nonadherence. AYPs displaying non-adherence may benefit from more frequent appointments, with intensified clinical interventions. ## Recommendations We suggest that HCPs maintain the goal of empowering the AYP to become independent while acknowledging the carer/parent perspectives (GRADE recommendation: weak (C). We recommend that AYPs identified as at risk of non-adherence may benefit from targeted specific educational and organisational interventions (GRADE recommendation: strong (C)). ## Disease-specific information appropriate for developmental age and gender Disease-specific knowledge is an important part of AYP transition but information given is not always pertinent to AYPs stage of development, with information more often geared towards the carers/parents rather than AYPs.AYPs are taking over self-management later than expected from carers/parents, 95 with those >18 years often requiring significant assistance from carers/parents to book clinic appointments and order medications.Furthermore, the age of disease onset and timing of medical interventions may play a role in mastery over healthcare responsibilities. In liver transplantation, younger male recipients struggled more with mastery over their healthcare compared with those transplanted at an older aged and to females in any age group.An organised transition programme should include agespecific educational components to address the deficits in AYP knowledge.Acquisition of skills needed for successful transition should be a stepwise or age appropriate checklist for the AYP. In IBD, a 'transition protocol' has been developed by Hait et al,which is based around developmental milestones to anticipate the changes and normal expectations for AYP for self-management and self-efficacy whereby at different ages (11-13, 14-16, 17-19 and 20-23 years old) a checklist of tasks for the medical team (eg, at 11-13 years old, HCP introduces concept of future independent visits to the HCP) and milestones for the AYP (eg, 14-16 years old, AYP knows their own medical history) are gradually obtained on the protocol. However, this does not recognise the variable rate for maturity and developmental milestones, with its inflexible format being its major limitation. ## Recommendation We recommend that disease-specific information and education be appropriate for the AYPs developmental stage and this should be reassessed over the period of transition (GRADE recommendation: strong (C)). ## Lifestyle, psychosocial health and sexuality Studies in transplant recipients demonstrate that AYPs wish to be treated as adults and prefer healthcare professionals to address them instead of their parents. In addition, these studies have identified that areas that may not be addressed in a paediatric setting such as sexual relationships and recreational drug use are important to AYPs, but they are often reluctant to ask for such information. AYPs are often concerned that their illness will compromise their employment and preclude them from valued jobs. In a qualitative study of cystic fibrosis and congenital heart disease, AYPs and their carers/parents describe seeing the future as uncertain, with particular concern regarding deteriorating health and occupational restrictions in the future. Employment issues are one of the primary sources of stress for cystic fibrosis AYPs in transition.AYPs with GI disease report major concerns regarding body image and HCPs may encounter resistance to the use of corticosteroids in the transition periodAYPs with IBD also describe concerns relating to future fertilityand a sense of potential loss regarding normal gendered roles such as motherhood.Similarly AYPs with juvenile idiopathic arthritis express concern over disclosing illness to sexual partners. Furthermore, AYPs' liver transplant recipients express concern about transmitting illness to descendants with concern regarding immunosuppression on fertility and future children's health and demonstrating a lack of understanding of genetic risk.Furthermore, AYPs may not feel doctors understand the wider impact on their life. ## Recommendation We suggest the transition process addresses the AYP's lifestyle, future health concerns, educational/employment goals, psychosocial health, sexuality and reproduction (GRADE recommendation: weak (D)). ## Surgical perspective There is limited data in relation to transition of AYP in the field of surgery. There are several groups of patients that may benefit from transition from paediatric to adult care: 1. Patients who have undergone surgery in a specialist paediatric unit who require long-term follow-up and have reached an age where care in a paediatric setting is no longer inappropriate. 2. Patients who have been receiving ongoing paediatric medical treatment for a condition requiring surgical intervention at an age on the cusp of needing transition to an adult surgical service. 3. Patients with newly diagnosed conditions needing surgical intervention diagnosed at an age where transition to an adult service is indicated. While it would be possible for AYPs in the above groups to be seen in a regular adult surgical outpatient setting, this would require initiating a new dialogue with the adult surgeon. AYPs and parents/carers may find the adult clinic setting an intimidating experience compared with the more familiar paediatric environment. In a surgical gastroenterological transition clinic, the paediatric surgeon can hand the case over to his adult surgeon colleague. This may entail not only describing in detail the procedures already performed by the paediatric surgeon but also the nuances around any family dynamics and aspects of the patients psyche. This will enable robust transfer of anatomical surgical knowledge and engendering confidence in the receiving surgeon, AYP and parent/carers. In specific cases, it may also be appropriate for the adult surgeon to consider operating jointly with the paediatric surgeon if the AYP is not yet ready for transition. ## Practice point ▸ We suggest that AYPs who require surgical intervention during the transition period have a named adult surgeon in the disciplined concerned involved in their care preoperatively, perioperatively and postoperatively, and that surgeon will form part of the multidisciplinary team in transition care. # Conclusion This guideline provides the framework for healthcare professionals to develop transition services for patients with chronic GI disorders, using the best available research data from the literature related to AYPs with GI disorders and other chronic disorders in which transition between paediatric and adult health services is routinely done. The most significant limitation of this review is that the recommendations are predominantly based on evidence graded as weak due to the paucity of randomised controlled trials in this area. In addition, there is a significant lack of GI-specific data in this expanding field and hence recommendations are based on evidence not exclusively pertainable to GI-specific research. Future studies are needed to improve the strength of recommendations for future revisions of the guidelines. Furthermore, future research must consider design to improve outcome-based data with longitudinal design in order to aid future cost-benefit analysis to be undertaken. Our hope is that this guideline will stimulate more GI-related research in this field so future revisions will be supported by an expanding robust and broad evidence base. ## Scheduled review of guidelines The proposed date for review is 1 August 2021 to take account new developments in this area and as set out in the 'BSG Guideline Advice' document. Every two years the research objectives identified in the guidelines will be reviewed for evidence of additional studies, which may contribute to resolving the objectives. The guidelines are available on the BSG website (http://www.bsg.org.uk) and listed by date of publication. These guidelines are accessible to the public. There is a forum for feedback from BSG members via the forum link in the members' area on the BSG website to ensure there is a facility for feedback after publications. Any publication updates maybe published in Gut as a letter subject to the normal review processes of the journal and are submitted to the CSSC Secretary/Guidelines A rare cause of GI bleeding in a 56-year-old man A 56-year-old man, with a known history of diabetes for 1 year, presented with a 5-day history of melena that was associated with one episode of haematemesis. One month prior, he had completed a course of oral amoxicillin for a dental infection that occurred after a tooth extraction. The only other significant past medical problem was hypertension for 10 years. Physical examination only showed pallor and abdominal examination was normal. Laboratory investigations revealed haemoglobin level of 8.4 g/dL and HbA1C of 7.8%. His upper GI endoscopy showed a diffuse irregular friable exudative ulcerative lesion involving the gastric fundus (figure 1). Endoscopic ultrasonography (EUS) demonstrated disrupted gastric wall layers with wall thickening of 5.1 mm and regional lymph nodes (figure 2). Abdominal CT also showed gastric wall thickening and cluster of regional lymph nodes . Upper GI series showed a focal irregular mucosal pattern with relatively flattened gastric fundus. ## Question What is the most likely diagnosis?Upper GI endoscopy illustrated diffuse irregular friable exudative ulcerative lesion involving gastric fundus. ## Figure 2 Endoscopic ultrasonography demonstrated disrupted gastric wall layers with regional lymph nodes. CT showed thickened gastric wall and cluster of regional lymph nodes.	None	https://gut.bmj.com/content/gutjnl/66/6/988.full.pdf	The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included. These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings; 1. Patient populations involved in AYP transition 2. Risks of failing transition or poor transition 3. Models of AYP transition 4. Patient and carer/parent perspective in AYP transition 5. Surgical perspective
a04253329b606eaf08c917e9fed96d6b098035a4	pubmed	Brazilian guidelines for the diagnosis and treatment of hereditary angioedema	Brazilian guidelines for the diagnosis and treatment of hereditary angioedema Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the ''Associaç ã o Brasileira de Alergia e Imunopatologia -ASBAI'' developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema. # Introduction Why should we study HAE? HAE was first described as a clinical entity by Quincke in 1882, and its hereditary nature was established by Osler in 1888. [bib_ref] Ü ber akutes umschriebenes Hautö dem, Quincke [/bib_ref] [bib_ref] Hereditary angioneurotic edema, Osler [/bib_ref] The biochemical change associated with HAE, C1-INH deficiency, was not identified until 75 years later, in 1963.Sir William Osler (1849-1919), a Canadian physician who lived in the United States and England, was renowned for his many contributions to medicine, including his participation in the description of HAE and for stating that ''Medicine is both a Science and an Art''. To develop evidence-based guidelines is to practice medicine as a science. To follow such guidelines and consensuses while treating patients and their various phenotypes in a personalized manner is to practice medicine as an art. HAE is a disease that is unknown to many health professionals and is therefore underdiagnosed. The prevalence of HAE is approximately 1550,000 (with estimates ranging from 1510,000 to 15150,000); the disease affects various ethnic groups and accounts for 2% of all cases of angioedema. [bib_ref] Five novel mutations in the C1 inhibitor gene (C1INH) leading to a..., Freiberger [/bib_ref] [bib_ref] C1 inhibitor deficiency: consensus document, Gompels [/bib_ref] [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients, Agostoni [/bib_ref] As is true for other autosomal dominant diseases, the children of a patient with HAE have a 50% chance of carrying the anomalous gene. Although a family history is characteristic of the disease and should alert physicians to a possible diagnosis of HAE, in 20-25% of cases, a family history of disease is absent, and new, spontaneous mutations can be observed. [bib_ref] Frequent de novo mutations and exon deletions in the C1 inhibitor gene..., Pappalardo [/bib_ref] Approximately 200 HAE-associated mutations have been identified to date. Although genetic defects are found in patients of both genders with equal frequency, the phenotype is more common in female patients, for whom the disease is more severe. [bib_ref] Hereditary angioedema in women, Bouillet [/bib_ref] The time elapsed between the onset of symptoms and diagnosis, as well as the time between diagnosis and the initiation of treatment, play important roles in HAE-related morbidity and mortality. [bib_ref] Hereditary angioedema: an appraisal of 104 cases, Cicardi [/bib_ref] [bib_ref] Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course, Bork [/bib_ref] [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] Therefore, physicians should be aware of the clinical profile and laboratory tests that confirm a diagnosis of HAE and inform decisions regarding its treatment. The cause of death from HAE is laryngeal edema with asphyxia, and the estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. [bib_ref] Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients, Agostoni [/bib_ref] [bib_ref] Hereditary angioedema: an appraisal of 104 cases, Cicardi [/bib_ref] [bib_ref] Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course, Bork [/bib_ref] [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] [bib_ref] Current management of hereditary angio-oedema (C'1 esterase inhibitor deficiency), Fay [/bib_ref] [bib_ref] Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema..., Bork [/bib_ref] Patients with HAE are commonly hospitalized and admitted to intensive care units, and the disease accounts for 15,000-30,000 emergency room visits per year in the United States. [bib_ref] Hereditary angioedema, Moore [/bib_ref] The two most severe clinical manifestations of HAE are edema of the larynx and edema of the bowel wall. Delayed diagnosis increases morbidity, thereby affecting the quality of life of patients and their families. [bib_ref] The humanistic burden of hereditary angioedema: Impact on health-related quality of life,..., Lumry [/bib_ref] [bib_ref] Self-administration of intravenous C1-inhibitor therapy for hereditary angioedema and associated quality of..., Bygum [/bib_ref] A study involving two families showed that nine out of ten family members who were hospitalized for symptoms of HAE were discharged with diagnoses other than HAE. [bib_ref] Type 1 hereditary angiooedema. Variability of clinical presentation and course within two..., Winnewisser [/bib_ref] In addition to life-threatening edema of the glottis, HAE often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with HAE may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. [bib_ref] Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to..., Bork [/bib_ref] [bib_ref] Ultrasonography in the diagnosis and monitoring of ascites in acute abdominal attacks..., Farkas [/bib_ref] It is estimated that patients with HAE experience some degree of disability 20-100 days per year. [bib_ref] The humanistic burden of hereditary angioedema: Impact on health-related quality of life,..., Lumry [/bib_ref] ## Pathophysiology ## What is the cause of hae? Patients with HAE present with a quantitative or qualitative deficiency of C1-INH, which is a serine protease inhibitor. This enzyme inhibits the C1r and C1s esterases, which bind to and activate C1q. Without such inhibition, the complement system becomes excessively activated. [bib_ref] Hereditary angioneurotic edema: two genetic variants, Rosen [/bib_ref] [bib_ref] Spontaneous activation of the first component of human complement (C1) by an..., Ziccardi [/bib_ref] C1-INH also inhibits the lectin pathway of complement system activation and participates in the regulation of the contact, coagulation, and fibrinolysis systems. Deficiency of C1-INH results in increased bradykinin production. Episodes of angioedema were initially attributed to factors that were formed during complement system activation, including a C2 fragment (C2 kinin) that is associated with vasodilation and increased vascular permeability. [bib_ref] Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2..., Fields [/bib_ref] Recent evidence has shown that bradykinin is one of the principal mediators of HAE. [bib_ref] Plasma bradykinin in angio-oedema, Nussberger [/bib_ref] [bib_ref] Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type..., Han [/bib_ref] [bib_ref] Bradykinin-mediated angioedema, Nussberger [/bib_ref] It has been shown that bradykinin levels are higher in blood drawn from angioedematous sites than in blood drawn from the systemic circulation. [bib_ref] Plasma bradykinin in angio-oedema, Nussberger [/bib_ref] Knockout mice with concomitant deficiencies of C1-INH and bradykinin receptor B2 (BDKRB2) display decreased vascular permeability, which demonstrates that the bradykinin/BDKRB2 pathway plays an important role in the development of angioedema. [bib_ref] Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type..., Han [/bib_ref] ## Classification What are the types of HAE? Currently, HAE is divided into three groups [fig_ref] Table 1 -: Classification of hereditary angioedema [/fig_ref]. Most patients (80-85%) present with type I HAE, with reduced C1-INH synthesis (a quantitative defect). [bib_ref] Detection of C1 inhibitor mutations in patients with hereditary angioedema, Zuraw [/bib_ref] Low serum levels of C1-INH trigger the attacks. In patients who present with type II HAE (15-20%), adequate quantities of C1-INH are produced, although the functional capacity of the protein is partially diminished. [bib_ref] A review of the reported defects in the human C1 esterase inhibitor..., Bowen [/bib_ref] Therefore, the enzyme has a qualitative (i.e., functional) defect. Type III HAE is rarer than types I and II and principally affects females. It is characterized by normal C1-INH levels and activity. [bib_ref] Hereditary angioedema with normal C1-inhibitor activity in women, Bork [/bib_ref] This group includes diseases that vary in their etiopathogenesis; coagulation disorders and links to the endocrine system have been identified in this group. [bib_ref] Hereditary angioedema in women, Bouillet [/bib_ref] [bib_ref] Increased activity of coagulation factor XII (Hageman Factor) causes hereditary angioedema type..., Cichon [/bib_ref] [bib_ref] Oestrogen-dependent hereditary angio-oedema with normal C1 inhibitor: description of six new cases..., Serrano [/bib_ref] Acquired angioedema (AAE), which has a manifestation similar to that of HAE, is noteworthy among the differential diagnoses of HAE. [bib_ref] Acquired deficiency of the inhibitor of the first component of complement: report..., Sheffer [/bib_ref] AAE is characteristically associated with lymphoproliferative and autoimmune diseases in which there is consumption of C1-INH, which is caused by the activation of C1-INH or by the production of anti-C1-INH autoantibodies. [bib_ref] Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and..., Cugno [/bib_ref] ## Diagnosis ## What is the typical clinical manifestation of hae? The patient's clinical history is the principal component of an HAE diagnosis. Patients with HAE present with attacks of nonpruritic edema of the skin and submucosa that affects various organs. [bib_ref] Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course, Bork [/bib_ref] [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] The most commonly affected sites are the face, extremities, genitalia, oropharynx, larynx, and digestive system. However, rarer clinical manifestations, including intense headaches caused by brain edema, urinary retention, and acute pancreatitis, can also occur. [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] [bib_ref] Acute pancreatitis associated with hereditary angioedema, García [/bib_ref] The incidence and severity of the clinical manifestations of HAE vary among individuals. It has been reported that 5% of patients with HAE are asymptomatic, and 25% develop sporadic symptoms. [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course, Bork [/bib_ref] [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Bowen [/bib_ref] A retrospective study analyzing 131,110 attacks in 221 patients with HAE reported that laryngeal edema occurred in less than 1% of the attacks, although over 50% of the patients had previously experienced that symptom at least once. [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] Left untreated, HAE attacks typically last 48-72 h. Although many attacks occur spontaneously, a number of triggering factors have been identified, including minor trauma, stress, infection, menstruation, pregnancy, alcohol consumption, a change in temperature, exercise, the use of angiotensin-converting enzyme (ACE) inhibitors, and the use of estrogen (including contraceptives and hormone replacement therapy). [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course, Bork [/bib_ref] [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Bowen [/bib_ref] Serpiginous erythema can occur as a prodromal manifestation that precedes angioedema in some patients; however, the concomitant presence of pruritic urticaria makes the diagnosis of HAE unlikely. [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course, Bork [/bib_ref] [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Bowen [/bib_ref] However, some cases of HAE coexisting with urticaria have been reported. [bib_ref] Hereditary angioedema and chronic urticaria: is there a possible association?, Jorge [/bib_ref] A family history of clinical manifestations that are similar to those seen in the patient supports a diagnosis of HAE, although this type of family history is absent in approximately 25% of cases. [bib_ref] Frequent de novo mutations and exon deletions in the C1 inhibitor gene..., Pappalardo [/bib_ref] In children, the clinical manifestations of HAE generally develop before six years of age. However, the onset of clinical manifestations in infants is rare, and few cases have been described. Attacks of laryngeal edema are particularly rare before three years of age and tend to occur later than other manifestations. During adolescence, there are substantial changes in disease activity, particularly in girls, for whom disease progression is worse because of their menstrual cycles and their use of contraceptives containing estrogen. [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary Angioedema: New Findings Concerning Symptoms, Affected Organs, and Course, Bork [/bib_ref] [bib_ref] Clinical Characteristics and Outcome of 36 Patients, Tanno [/bib_ref] [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Bowen [/bib_ref] Although the manifestations of type III HAE are similar to those of the other HAE types, there are certain features unique to this type. Symptom onset generally occurs later in life, the course of the disease tends to be more benign, and tongue involvement is common. Purpura is occasionally seen at sites that are affected by angioedema. However, the most striking characteristic of type III HAE is a personal and family history of associations between the disease and female gender and between the disease and estrogen administration. In AAE, the onset of symptoms also occurs later, there is no family history of angioedema, and the associations between AAE and lymphoproliferative diseases and between AAE and autoimmune diseases should be investigated. [bib_ref] Acquired deficiency of the inhibitor of the first component of complement: report..., Sheffer [/bib_ref] [bib_ref] Angioedema due to acquired C1-inhibitor deficiency: a bridging condition between autoimmunity and..., Cugno [/bib_ref] How can laboratory tests confirm the diagnosis of HAE? Individuals who are clinically suspected of having HAE and individuals with a family history of HAE should be investigated [fig_ref] Table 2 -: Laboratory diagnosis of angioedema [/fig_ref]. The principal screening test is the determination of serum levels of C4. [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Bowen [/bib_ref] Quantitative or qualitative C1-INH deficiency leads to the permanent activation of the complement system, accompanied by C4 consumption, even when patients are not experiencing an angioedema attack. In 2-5% of cases, C4 levels normalize during the intercrisis period. [bib_ref] Management of hereditary angioedema in pediatric patients, Farkas [/bib_ref] C3 turnover is greater than C4 turnover. In addition, there are other proteins that, together with C1-INH, regulate the consumption of C3, the levels of which are generally normal in HAE patients. Therefore, the determination of C3 levels is unnecessary except in patients who are suspected of having AAE, principally in the presence of autoimmune diseases. [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Bowen [/bib_ref] In AAE, there is activation and consumption of complement components, and 75% of patients present with reduced serum levels of C1q. [bib_ref] Acquired angioedema, Cicardi [/bib_ref] Therefore, the determination of C1q levels can aid in the differentiation between HAE and AAE. Following (or concomitant with) the determination of serum levels of C4, quantitative and qualitative determinations of C1-INH should be performed. All health professionals and family members who are involved in providing care for patients with HAE must ensure that such tests are available. Although the quantitative determination of C1-INH is a relatively easy test to perform, the determination of functional enzymatic activity (qualitative test) should be performed at a referral laboratory. 6,36-38 Importantly, the determination of functional activity is only necessary when C1-INH levels are normal [fig_ref] Figure 1 -: Diagnostic algorithm of hereditary angioedema [/fig_ref]. If clinical suspicion remains despite normal C4 levels and normal (quantitative/qualitative) C1-INH levels, these tests should be performed again during an angioedema attack. [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Bowen [/bib_ref] If the test results are again normal, a diagnosis of type III HAE is suggested. [bib_ref] Hereditary angioedema with normal C1-inhibitor activity in women, Bork [/bib_ref] What are the diagnostic criteria for HAE? Criteria to standardize the diagnosis of HAE have been proposed . [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] According to these criteria, the presence of HAE is confirmed when patients meet one major clinical criterion and one biochemical criterion. It should be noted that those criteria are not absolute and that the patient's clinical history takes precedence, principally in locations where the laboratory tests are not available and in suspected cases of type III HAE. In selected cases, we can presume a diagnosis of HAE and perform a therapeutic test. ## Treatment ## Guidance To improve the quality of life of patients and their families and to avoid severe complications, the most important initial measure is to provide guidance regarding the course of HAE and the triggering factors for attacks. Patients should be given relevant information (in writing) regarding the disease and the steps that must be taken in the case of an attack (an action plan). There are nonpharmacological approaches that can reduce HAE severity and therefore merit attention. Because of the significant morbidity and mortality associated with HAE, a strategy involving careful treatment and prevention of attacks is essential for appropriate patient management [fig_ref] Table 4 -: General recommendations for the medical treatment of attacks of hereditary angioedema [/fig_ref]. The experience at large centers has demonstrated that 25-40% of patients can develop asphyxia and die if they are left untreated. 7,10-15 ## Prevention of attacks The risk of attacks can be reduced by identifying and eliminating the factors that trigger them. Stress and trauma are clearly triggering factors for edema in HAE, so patients should monitor those factors. High-impact sports and hobbies that pose a risk of trauma should be avoided. To prevent infections, which constitute a trigger of attacks, immunization is indicated. Hepatitis B vaccination is recommended because blood products might be used during the treatment of HAE attacks. ## Drugs that can worsen or prolong an hae attack The drugs that most commonly worsen or prolong the clinical profile of HAE or AAE are ACE inhibitors, angiotensin II receptor antagonists, medications containing estrogen, and certain oral hypoglycemic agents. Because ACE inhibitors increase the half-life of bradykinin, their use should be avoided. [bib_ref] Angiotensin-converting enzyme inhibitor associated angioedema, Byrd [/bib_ref] Angiotensin II receptor antagonists can also worsen the clinical profile of HAE, although they do so less commonly than ACE inhibitors. [bib_ref] Angioedema induced by ACE inhibitors and angiotensin II-receptor antagonists: analysis of 98..., Schuster [/bib_ref] Contraceptives containing progesterone should be preferentially prescribed over those containing estrogen. [bib_ref] Hereditary angioedema, Moore [/bib_ref] [bib_ref] Recurrent episodes of skin angioedema and severe attacs of abdominal pain induced..., Bork [/bib_ref] Sitagliptin phosphate, which is an oral hypoglycemic agent indicated for the treatment of type 2 diabetes, belongs to a class of oral hypoglycemic agents designated dipeptidyl peptidase-4 inhibitors, which can worsen the clinical profile of HAE. [bib_ref] Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema, Brown [/bib_ref] Genetic screening of family members All first-degree relatives of patients with HAE should be screened for HAE. In pediatric patients with a family history of HAE, the HAE diagnostic tests should be performed at six months of age and repeated at one year. [bib_ref] Pediatric hereditary angioedema due to C1-inhibitor deficiency, Farkas [/bib_ref] Patients and their families should receive genetic counseling and guidance regarding the inheritance pattern of the disease. [bib_ref] Hereditary angioedema: a rare but potentially lethal disease, Kamboj [/bib_ref] ## Pharmacological treatment The pharmacological treatment of HAE can be divided into three modalities: long-term prophylaxis, short-term prophylaxis, and treatment of attacks. The therapies recommended here were classified according to the strength of the recommendation, which is based on the level of scientific evidence supporting such a recommendation [fig_ref] Table 5 -: Evidence levels and degrees of recommendation for therapies [/fig_ref]. How should long-term prophylaxis be performed? The objective of long-term prophylaxis in HAE is to reduce the frequency and severity of attacks. These two variables can vary widely. Patients may be asymptomatic or experience attacks twice per week with symptoms that are practically continuous. Therefore, the first question regarding long-term prophylaxis should be whether patients actually require this type of treatment. In general, individuals with frequent symptoms or a history of angioedema attacks involving the upper airways should be treated prophylactically. Patients who are candidates for this type of treatment are those who present with more than one severe attack per month or those who experience more than five attacks per month. [bib_ref] Hereditary angioedema: a current state-of-the-art review, VII: Canadian Hungarian 2007 International Consensus..., Bowen [/bib_ref] [bib_ref] Hereditary and acquired angioedema: problems and progress: proceedings of the third C1..., Agostoni [/bib_ref] [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Bowen [/bib_ref] Although the number and severity of angioedema attacks play important roles in this evaluation, the impact of angioedema episodes on the patient's quality of life is a decisive aspect. Another important point to be considered is whether patients have access to appropriate medical care in the case of a severe episode of angioedema. [bib_ref] Hereditary angioedema: a current state-of-the-art review, IV: short-and long-term treatment of hereditary..., Zuraw [/bib_ref] In Brazil, two treatment modalities are available for longterm prophylaxis: attenuated androgens and antifibrinolytic agents. The most effective and best tolerated therapy for longterm prophylaxis of HAE is attenuated androgens that increase the levels of C1-INH and C4 and reduce the number of attacks of angioedema (grade B recommendation). [bib_ref] Treatment of hereditary angioedema with danazol, Gelfand [/bib_ref] The drugs used include danazol, stanozolol, and oxandrolone, which are less virilizing than methyltestosterone. Oxandrolone is especially recommended for use in children. 52 In Brazil, the most widely used attenuated androgen is danazol, which is also the most widely available (its availability is guaranteed by the High-Cost Drug Program); in addition, well-controlled studies have demonstrated the clinical efficacy of this drug and have shown that it improves biochemical parameters. [bib_ref] Treatment of hereditary angioedema with danazol, Gelfand [/bib_ref] [bib_ref] Management of hereditary angio-oedema with low-dose danazol, Macfarlane [/bib_ref] [bib_ref] Long term therapy of hereditary angioedema with danazol, Hosea [/bib_ref] Treatment with danazol can be started at high doses (600 mg/day), which can later be reduced. Another option is to start at a low dose and increase the dose as needed. Therefore, two protocols have been established: 6 a) Milan Protocol-Initiation at a high dose with a subsequent reduction: The best strategy should be chosen based on the patient's clinical status. Therefore, we should consider whether it is more important to control the angioedema attacks as fast as possible or to minimize the potential adverse effects of the drug. In both protocols, the final dose should be the lowest dose that provides adequate prophylaxis, generally ranging from the administration of 50 to 200 mg/day or on alternate days. [formula] - [/formula] Although androgens increase the levels of C1-INH and C4, symptomatic benefits are generally achieved at doses lower than those required to significantly alter the levels of complement components. Therefore, it is important that the drug dosage is based on the patient's clinical symptoms rather than his or her biochemical parameters. It should be emphasized that androgens are ineffective in controlling attacks of HAE because it takes approximately 48 h for the drugs to begin to take effect. [bib_ref] Hereditary angioedema: the clinical syndrome and its management in the United States, Frank [/bib_ref] Most patients tolerate androgens at the aforementioned doses. However, sustained use at higher doses generally results in significant adverse effects. The adverse effects of androgens are related to the dosage, with the major adverse effects being hepatotoxicity and virilization. [bib_ref] Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison..., Cicardi [/bib_ref] Other adverse reactions include weight gain, headache, menstrual changes, acne, changes in libido, anxiety, mood disorders, hypertension, myopathy, changes in lipid profiles, and hematuria. [bib_ref] Adverse effects of danazol prophylaxis on the lipid profiles of patients with..., Széplaki [/bib_ref] Although there is evidence of changes in patients' lipid profiles, the association between danazol and atherosclerosis is controversial. [bib_ref] Adverse effects of danazol prophylaxis on the lipid profiles of patients with..., Széplaki [/bib_ref] [bib_ref] Effects of short-term and long-term danazol treatment on lipoproteins, coagulation, and progression..., Birjmohun [/bib_ref] Danazolinduced hematuria results from mild cystitis or bladder telangiectasia. [bib_ref] The long-term safety of danazol in women with hereditary angioedema, Zurlo [/bib_ref] These adverse effects tend to disappear after the discontinuation of the drug. In individuals receiving androgens, the hepatic enzyme levels should be evaluated every six months. If liver damage develops, the dose should be reduced or the drug should be discontinued until these tests yield normal results. Because hepatic adenomas and hepatocellular carcinoma have previously been reported as consequences of the use of androgens, liver ultrasounds should also be routinely performed every six months. [bib_ref] Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema, Bork [/bib_ref] [bib_ref] Characterisation of a new C1 inhibitor mutant in a patient with hepatocellular..., Monnier [/bib_ref] The development of liver tumors in patients who are using danazol has been associated with the use of higher doses (400-800 mg), a longer duration of administration, and the lack of monitoring for liver injury. [bib_ref] The effect of long-term danazol prophylaxis on liver function in hereditary angioedema..., Farkas [/bib_ref] Although many patients complain of androgen-induced adverse events, most patients with HAE can benefit, at least moderately, from androgen use, and the risk profile is acceptable. Danazol is contraindicated during pregnancy because there have been documented cases of virilization in female neonates. However, discontinuation of the drug by gestational week eight has been shown to avert that alteration. [bib_ref] The effects of fetal exposure to Danazol, Brunskill [/bib_ref] [bib_ref] Ambiguous genitalia in a term female infant due to exposure to danazol..., Schwartz [/bib_ref] [bib_ref] Transient adrenogenital syndrome due to exposure to danazol in utero, Castro-Magana [/bib_ref] Other contraindications for danazol use include breastfeeding and prostate cancer, as well as kidney, liver, and heart failure. One or more randomized controlled clinical trials of sufficient sample size with a narrow confidence interval Meta-analysis of randomized controlled clinical trials 2 Good quality cohort study Low-quality randomized clinical trial (small sample size and .20% lost to follow-up) 3 Case-control studies Meta-analysis of case-control studies 4 Case series Low-quality cohort studies Low-quality case-control studies 5 Based on expert opinions, experimental studies or physiology Antifibrinolytic agents (epsilon-aminocaproic acid and tranexamic acid) are generally effective (grade B recommendation) in preventing HAE attacks. [bib_ref] Epsilon aminocaproic acid therapy of hereditary angioneurotic edema: A double-blind study, Frank [/bib_ref] [bib_ref] Tranexamic acid therapy in hereditary angioneurotic edema, Sheffer [/bib_ref] [bib_ref] Treatment of hereditary angioneurotic oedema with tranexamic acid. A random double-blind cross-over..., Blohmé [/bib_ref] [bib_ref] Hereditary angio-oedema treated with Eaminocaproic acid, Champion [/bib_ref] [bib_ref] Epsilon-aminocaproic acid (E-ACA) as a therapeutic agent based on 5 year's clinical..., Nilsson [/bib_ref] These drugs antagonize the fibrinolytic system by blocking plasmin formation and inhibiting the proteolytic activity of plasminogen activators and, consequently, clot dissolution. The mechanism by which antifibrinolytic agents prevent HAE attacks remains unknown. Unlike attenuated androgens, antifibrinolytic agents do not increase the serum levels of C1-INH or C4. The therapeutic dose of epsilon-aminocaproic acid is 1 g, administered orally three to four times per day, and it can be as high as 8 g/day. [bib_ref] Hereditary angioedema: the clinical syndrome and its management in the United States, Frank [/bib_ref] Tranexamic acid should be administered at a dose of 0.5-0.75 mg/kg two to three times per day; the drug is more potent than aminocaproic acid and has a lower incidence of adverse effects. [bib_ref] Tranexamic acid: preoperative prophylatic therapy for patients with hereditary angioneurotic edema, Sheffer [/bib_ref] The side effects of antifibrinolytic agents include nausea, diarrhea, vertigo, postural hypotension, fatigue, muscle weakness, cramps, and increased muscle enzyme levels. [bib_ref] Hereditary angioedema: a current state-of-the-art review, IV: short-and long-term treatment of hereditary..., Zuraw [/bib_ref] Other adverse effects that are associated with the inhibition of plasmin include the increased occurrence of thrombosis and increased tumor growth. Because of the risks of teratogenicity, the use of antifibrinolytic agents during pregnancy is restricted. [bib_ref] Hereditary angioedema: a current state-of-the-art review, IV: short-and long-term treatment of hereditary..., Zuraw [/bib_ref] As occurs with attenuated androgens, the time of onset of the therapeutic effects of antifibrinolytic agents is approximately 48 h after administration. Therefore, both classes of drugs are of little use in providing immediate symptom relief. Because anabolic androgens are more effective in controlling HAE, they generally constitute the treatment of choice (grade C recommendation). Antifibrinolytic agents should be reserved for patients who do not tolerate anabolic androgens or for cases in which anabolic androgens are contraindicated. In severe cases for which the maximum dose of androgen is not sufficient to control the attacks, antifibrinolytic agents can be used in combination with androgens. Long-term prophylaxis of HAE is satisfactory for most patients but has the disadvantage of requiring daily medication. In some patients, the use of androgens or antifibrinolytic agents is impractical because of the adverse reactions that they provoke (principally in females) or because of a lack of response. In addition, neither class of drugs is safe for use during pregnancy. Although they are still unavailable in Brazil, C1-INH concentrates, which have a grade B recommendation, have been used elsewhere for the long-term prophylaxis of HAE. [bib_ref] Hereditary angioedema: long-term treatment with one or more injections of C1 inhibitor..., Bork [/bib_ref] [bib_ref] Long-Term Prophylaxis of Hereditary Angioedema with a Pasteurized C1 Inhibitor Concentrate, Tallroth [/bib_ref] [bib_ref] Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema, Zuraw [/bib_ref] Administered intravenously at regular intervals, approximately three times per week, C1-INH concentrates constitute a viable therapeutic alternative for individuals in whom other therapies cannot be used or are ineffective. Regardless of the drug chosen, the effectiveness of each drug depends on treatment adherence, which must be encouraged and evaluated. How should short-term prophylaxis be performed? Short-term prophylaxis is indicated for patients undergoing major surgical procedures (e.g., surgery with orotracheal intubation), other surgical procedures (principally craniofacial procedures), invasive diagnostic procedures (e.g., endoscopy), or major dental procedures (all patients should be informed of the higher risk of attacks during major dental procedures). In addition to prophylaxis, patients should remain under observation for 36 h and should have easy access to rescue medication. [bib_ref] C1 inhibitor deficiency: consensus document, Gompels [/bib_ref] Therapeutic intervention should be performed before the occurrence of events that can provoke HAE attacks. Favorable results have been obtained with the use of attenuated androgens, antifibrinolytic agents, fresh frozen plasma, and C1-INH concentrates . Fresh frozen plasma can be administered intravenously at a dose of 2 U the night before surgery or on the day of surgery (grade D recommendation). Epsilon-aminocaproic acid is effective when it is administered several days before the triggering event (grade C recommendation). Androgens, which have a grade C recommendation, are used three-five days before surgery at doses of 10 mg N kg 21 N day 21 , with a maximum dose of 600 mg/day. [bib_ref] Hereditary Angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment..., Banerji [/bib_ref] For prophylaxis in adults and children, C1-INH concentrates are safe and effective at doses of 500-1,000 U when administered intravenously (grade C recommendation). Some of these products have also been tested and are currently used in pregnant women. Initially, in the 1970s, C1-INH concentrate was established as the emergency treatment for HAE. With the introduction of viral inactivation processes, C1-INH concentrate also became a first-line drug for the prophylaxis of acute HAE attacks. There are two C1-INH concentrates currently in use in the United States: CinryzeH and BerinertH. Because of regulatory issues, CinryzeH is indicated for short-term prophylaxis of HAE but not for the treatment of attacks, and BerinertH is indicated for the treatment of acute HAE attacks. ## How should hae attacks be treated? The treatment of acute HAE attacks depends on their severity [fig_ref] Table 7 -: Parameters for the treatment of acute attacks in patients with hereditary angioedema [/fig_ref]. Severe attacks and attacks involving the respiratory tract require urgent treatment because of the potential for morbidity and mortality. Although episodes of peripheral edema rarely require treatment, the early administration of danazol can shorten the duration of attacks and uncomfortable symptoms (grade D recommendation). Patients who are taking attenuated androgens prophylactically should double the dose for a few days after identifying an attack in any part of the body. [bib_ref] Hereditary Angioedema: a current state-of-the-art review, V: attenuated androgens for the treatment..., Banerji [/bib_ref] Therapy with antifibrinolytic agents, such as tranexamic acid administered orally every 3-4 h, has also been recommended for mild crisis periods (grade C recommendation). Abdominal attacks are extremely painful and can be accompanied by vomiting, diarrhea, or both. When patients present with severe abdominal attacks, symptomatic treatment with the administration of fluids, antiemetics, and analgesics is indicated. Antispasmodics and narcotics may be required to treat intense pain. [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] Dysphonia and dysphagia are indicative of progression to a severe laryngeal attack. Such attacks develop slowly over the course of approximately 8 h on average, and dysphagia and voice changes generally precede laryngeal obstruction. [bib_ref] Hereditary angioedema, Moore [/bib_ref] However, there have been reports of rapid-onset laryngeal edema, and physicians should bear this in mind when evaluating such patients. More severe cases require immediate intubation. In such cases, oxygen therapy is indicated, and pulse oximetry should be monitored. During laryngoscopy and intubation, the need for tracheostomy should be evaluated. [bib_ref] C1 esterase inhibitor deficiency, airway compromise, and anesthesia, Jensen [/bib_ref] In cases of laryngeal edema, it may be prudent to perform prophylactic intubation as an early measure to maintain airway patency and avoid tracheostomy (grade D recommendation). [bib_ref] C1 esterase inhibitor deficiency, airway compromise, and anesthesia, Jensen [/bib_ref] In cases of severe acute attacks, the treatment of choice is C1-INH replacement therapy, which can be achieved by the intravenous infusion of 1,000 U of a C1-INH concentrate (grade A recommendation), by the infusion of recombinant C1-INH, or, as reported recently, by a kallikrein inhibitor or a BDKRB2 antagonist (grade B recommendation). In countries where the aforementioned drugs are not available, fresh plasma or solvent/detergent-treated plasma, which contains C1-INH, can be used (grade D recommendation). However, this type of treatment can worsen HAE attacks because fresh plasma also contains the remaining complement, coagulation, and contact system components. In addition, there are concerns regarding the safety of fresh plasma (e.g., transfusion-related acute lung injury, anaphylaxis, and viral transmission), and the need for a relatively large volume of plasma might be problematic in an emergency setting or in patients who cannot tolerate significant volume expansion. Therefore, when C1-INH concentrate, or bradykinin receptor antagonist, or kallikrein inhibitor are available, they are preferred over plasma transfusion. [bib_ref] International Consensus Algorithm For the Diagnosis, Therapy, and Management of Hereditary Angioedema, Bowen [/bib_ref] [bib_ref] Hereditary angioedema: optimal therapy, Sheffer [/bib_ref] [bib_ref] Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies, Bernstein [/bib_ref] The symptoms generally improve [bib_ref] Hereditary angioedema with normal C1-inhibitor activity in women, Bork [/bib_ref] [bib_ref] Hereditary angioedema: a current state-of-the-art review, IV: short-and long-term treatment of hereditary..., Zuraw [/bib_ref] [bib_ref] Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies, Bernstein [/bib_ref] [bib_ref] Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy, Farkas [/bib_ref] RhucinH, which was developed recently, is a recombinant C1-INH derived from the milk of transgenic rabbits. [bib_ref] Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema, Zuraw [/bib_ref] Although its half-life is only 3 h, RhucinH has been shown to produce a response similar to that produced by other commercially available C1-INH preparations in the treatment of HAE attacks (grade B recommendation). [bib_ref] Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema, Zuraw [/bib_ref] [bib_ref] C1-inhibitor deficiencies (hereditary angioedema): where are we with therapies?, Lock [/bib_ref] Further studies are needed to assess the effects of Rhucin. In addition to C1-INH replacement therapy, blocking the synthesis and effects of bradykinin constitute other pharmacological approaches to HAE attacks. Recent studies have confirmed the efficacy of a kallikrein inhibitor and a BDKRB2 antagonist. The BDKRB2 antagonist, icatibant, is highly specific for BDKRB2, binding to it with the same affinity as bradykinin and inhibiting a variety of BDKRB2-mediated effects. [bib_ref] Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2..., Bork [/bib_ref] The drug is administered subcutaneously, and its plasma halflife is 2-4 h. Icatibant is degraded by peptidases, and the products of icatibant degradation are excreted by the -Drugs used for the short-term prophylaxis and treatment of acute attacks of hereditary angioedema. found that a single dose of icatibant was effective in 90% of the attacks of HAE (grade B recommendation). [bib_ref] Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema, Cicardi [/bib_ref] One perspective that merits investigation is the home treatment of HAE attacks with icatibant. Icatibant has been approved in Brazil, and its use is indicated for the treatment of HAE attacks. Although the drug can be stored at room temperature, in Brazil, it is suggested that the drug be stored at 4˚C. Ecallantide is a high-potency recombinant protease inhibitor that binds to and inhibits kallikrein, thus decreasing bradykinin production. Because of its short half-life when it is administered subcutaneously, ecallantide has been evaluated for use in acute HAE attacks only. Multicenter phase III clinical trials have found a significant reduction in the severity of acute attacks after ecallantide administration compared to a placebo (grade B recommendation). [bib_ref] Ecallantide for the treatment of acute attacks in hereditary angioedema, Cicardi [/bib_ref] Side effects were rare and included dyspnea, oropharyngeal edema, and prolonged prothrombin and thrombin times. There have also been isolated reports of anaphylactic reactions following ecallantide administration; therefore, the use of the drug is restricted to hospital environments. [bib_ref] Hereditary angioedema: a current state-of-the-art review, VI: novel therapies for hereditary angioedema, Frank [/bib_ref] To date, no studies been conducted to compare the efficacy of C1-INH concentrate, icatibant, and ecallantide in the treatment of HAE attacks. [bib_ref] Therapeutic agents for hereditary angioedema, Giavina-Bianchi [/bib_ref] Regarding pharmacological treatment, it should be highlighted that, unlike anaphylaxis and edemas associated with the degranulation of mast cells and basophils, C1-INH deficiency-induced angioedema does not respond significantly to the administration of antihistamines, glucocorticoids, or epinephrine. [bib_ref] C1 esterase inhibitor deficiency, airway compromise, and anesthesia, Jensen [/bib_ref] ## Special situations ## Pediatric patients In pediatric patients, antifibrinolytic agents are the drugs of choice for long-term prophylaxis because of their safety profiles (grade C recommendation). Studies have reported that tranexamic acid is better tolerated than epsilonaminocaproic acid. When these agents are not sufficient, attenuated androgens may be required. The use of minimum maintenance doses for control has been found to have no negative impact on growth, and the only adverse effect that was observed was late menarche with subsequent menstrual irregularity, which was attributed to the use of danazol (200 mg/day). [bib_ref] Clinical management of hereditary angio-oedema in children, Farkas [/bib_ref] During the first two years of prophylaxis, it is recommended that laboratory tests be performed every three-four months and that abdominal ultrasounds be performed every six months. The clinical course of HAE should be monitored, as should any adverse effects of treatment. ## Pregnancy and delivery During pregnancy and, if possible, even before conception, the ideal situation is that no prophylactic drug be used. Attenuated androgens are contraindicated, and tranexamic acid can be used if it is administered with caution (grade C recommendation). The treatment of HAE attacks does not change during pregnancy. Attacks during vaginal delivery are rare. However, when they do occur, they are severe. Regional analgesia is recommended for surgical delivery; general anesthesia and orotracheal intubation should be avoided (grade C recommendation). ## Suspected cases of acute abdomen Some HAE attacks mimic acute surgical abdomen, and negative exploratory laparotomy results are common in such patients. [bib_ref] Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to..., Bork [/bib_ref] [bib_ref] Ultrasonography in the diagnosis and monitoring of ascites in acute abdominal attacks..., Farkas [/bib_ref] However, a diagnosis of HAE raises the concern that if there is a true abdominal emergency requiring surgery, the timing of the surgical procedure may be delayed. # Conclusion The Experts in Clinical Immunology and Allergy of the ''Associaçã o Brasileira de Alergia e Imunopatologia -ASBAI'' developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema. We hope that these guidelines will aid readers in the diagnosis and treatment of HAE, which is a neglected disease. A Portuguese version of this consensus is published in the ''Revista Brasileira de Alergia e Imunopatologia''. [bib_ref] Diretrizes do diagnó stico e tratamento do angioedema hereditário, Giavina-Bianchi [/bib_ref] [fig] Table 3 -: Diagnostic criteria for hereditary angioedema. 36 I -Primary clinical criteria a) Non-inflammatory subcutaneous angioedema lasting longer than 12 h b) Abdominal pain of undefined organic etiology lasting longer than 6 h c) Recurrent laryngeal edema II -Secondary clinical criteria a) Family history of hereditary angioedema III -Biochemical criteria a) Quantitative C1 inhibitor ,50% in two distinct samples b) Functional C1 inhibitor ,50% in two distinct samples c) Mutation in the C1 inhibitor gene [/fig] [fig] Figure 1 -: Diagnostic algorithm of hereditary angioedema. C1-INH: C1 inhibitor, HAE: hereditary angioedema, AAE: acquired angioedema, NL: normal. [/fig] [table] Table 1 -: Classification of hereditary angioedema. [/table] [table] Table 2 -: Laboratory diagnosis of angioedema. [/table] [table] Table 4 -: General recommendations for the medical treatment of attacks of hereditary angioedema. Take a personal and family history of the acute attack profile Use oxygenation and pulse oximetry Hydrate Use antispasmodics and analgesics as needed Avoid the use of angiotensin-converting enzyme inhibitors Increase the dose of chronic medication to control the attack Use acute phase control agents (fresh plasma, C1 inhibitor, bradykinin receptor antagonist, or kallikrein inhibitor) if available [/table] [table] Table 5 -: Evidence levels and degrees of recommendation for therapies. [/table] [table] Table 7 -: Parameters for the treatment of acute attacks in patients with hereditary angioedema. 6,38 C1-INH: C1 inhibitor, ICU: intensive care unit. + indicated. ¡ consider indication. 2 contraindicated.kidneys. Icatibant was initially shown to be effective in treating seasonal allergic rhinitis and asthma. Subsequently, two double-blind, randomized, multicenter trials (the For Angioedema Subcutaneous Treatment trial, parts 1 and 2) [/table]	None	None	Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the “Associação Brasileira de Alergia e Imunopatologia - ASBAI” developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema.
6eb951e64b44fa509227bd222e3b6e1cfb82b822	pubmed	American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation	American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation # Introduction Mental retardation (MR), defined by the World Health Organization (WHO) as an intelligence quotient (IQ) Ͻ 70, is characterized by significantly limited cognitive functioning, coupled with limitations in adaptive skills in two or more of the following areas: social skills, community living, communication, home living, health, self-direction, work, and leisure. [bib_ref] Evaluation of mental retardation: Recommendations of a Consensus Conference: American College of..., Curry [/bib_ref] [bib_ref] Diagnostic yield of the comprehensive assessment of developmental delay/mental retardation in an..., Battaglia [/bib_ref] MR is generally divided into mild (IQ of , moderate (IQ of [bib_ref] Multicolor spectral karyotyping of human chromosomes, Schrock [/bib_ref] [bib_ref] Multiplex-FISH for pre-and postnatal diagnostic applications, Uhrig [/bib_ref] [bib_ref] Spectral karyotyping refines cytogenetic diagnostics of constitutional chromosomal abnormalities, Schrock [/bib_ref] [bib_ref] Karyotyping human chromosomes by combinatorial multi-fluor FISH, Speicher [/bib_ref] [bib_ref] Classifying by colors: FISH-based genome analysis, Fauth [/bib_ref] [bib_ref] American College of Medical Genetics Professional Practice and Guidelines Committee, Sherman [/bib_ref] [bib_ref] Minimal sizes of deletions detected by comparative genomic hybridization, Bentz [/bib_ref] [bib_ref] Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors, Kallioniemi [/bib_ref] [bib_ref] Clinical applications of comparative genomic hybridization, Levy [/bib_ref] [bib_ref] Deletions below 10 megabasepairs are detected in comparative genomic hybridization by standard..., Kirchhoff [/bib_ref] [bib_ref] High resolution analysis of DNA copy number variation using comparative genomic hybridization..., Pinkel [/bib_ref] [bib_ref] Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances, Solinas-Toldo [/bib_ref] [bib_ref] A cytogeneticist's perspective on genomic microarrays, Shaffer [/bib_ref] [bib_ref] Unusual mosaic karyotype resulting from adjacent 1 segregation of t(11;22): Importance of..., Kulharya [/bib_ref] [bib_ref] The characteristic physiognomy and tissue specific karyotype distribution in the Pallister-Killian syndrome, Hunter [/bib_ref] [bib_ref] Pallister-Killian syndrome: Cytogenetic and molecular studies, Peltomaki [/bib_ref] , and severe (IQ of [bib_ref] Analysis of genes and chromosomes by nonisotopic in situ hybridization, Lichter [/bib_ref] [bib_ref] Fluorescence in situ hybridization: Applications in cytogenetics and gene mapping, Trask [/bib_ref] [bib_ref] The annual incidence of DiGeorge/velocardiofacial syndrome, Devriendt [/bib_ref] [bib_ref] Molecular mechanism for duplication 17p11.2-the homologous recombination reciprocal of the Smith-Magenis microdeletion, Potocki [/bib_ref] [bib_ref] Review of recent epidemiological studies of mental retardation: Prevalence, associated disorders, and..., Mclaren [/bib_ref] [bib_ref] The end of the beginning of chromosome ends, Biesecker [/bib_ref] [bib_ref] The highest gene concentrations in the human genome are in telomeric bands..., Saccone [/bib_ref] [bib_ref] Translocation breakpoint mapping and sequence analysis in three monosomy 1p36 subjects with..., Ballif [/bib_ref] [bib_ref] Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating..., Ballif [/bib_ref] [bib_ref] Development and clinical application of an innovative fluorescence in situ hybridization technique..., Knight [/bib_ref] [bib_ref] Perfect endings: A review of subtelomeric probes and their use in clinical..., Knight [/bib_ref] [bib_ref] Clinical studies on submicroscopic subtelomeric rearrangements: a checklist, De Vries [/bib_ref] [bib_ref] The promise and pitfalls of telomere regionspecific probes, Ballif [/bib_ref] [bib_ref] Caution: Telomere crossing, Shaffer [/bib_ref] [bib_ref] Multicolor spectral karyotyping of human chromosomes, Schrock [/bib_ref] ; those cases in which the IQ is below 20 are occasionally defined as profound. [bib_ref] Diagnostic yield of the comprehensive assessment of developmental delay/mental retardation in an..., Battaglia [/bib_ref] [bib_ref] Genetics of mental retardation, Chiurazzi [/bib_ref] The prevalence rate of MR in the general population is estimated to be approximately 1% to 3%, with mild MR occurring 7-10 times more frequently than moderate or severe MR. [bib_ref] Diagnostic yield of the comprehensive assessment of developmental delay/mental retardation in an..., Battaglia [/bib_ref] [bib_ref] The recurrence risks for mild idiopathic mental retardation, Bundey [/bib_ref] [bib_ref] Aetiology of mild mental retardation, Lamont [/bib_ref] Global developmental delay (DD) describes significant delay in two or more of the following areas: cognition, speech/ language, gross/fine motor skills, social/personal skills, and daily living. [bib_ref] Practice parameter: Evaluation of the child with global developmental delay, Shevell [/bib_ref] DD is evidenced as age-specific deficits in learning skills and adaptation in comparison with chronological peers. [bib_ref] Practice parameter: Evaluation of the child with global developmental delay, Shevell [/bib_ref] Because the diagnosis of MR requires accurate and valid assessments of intelligence, the term DD is generally reserved for children five years of age or younger, prior to the age at which IQ testing can be applicable. Thus, a child with DD is not necessarily destined to have MR. Several conditions, such as cerebral palsy, some neuromuscular disorders, or adverse environmental effects, may result in early childhood learning delay, though the child may test in the normal range for intelligence when he or she is old enough to be accurately assessed. Like MR, the prevalence rate of DD in the general population is estimated to be 1 to 3%. The etiology of MR/DD is complex and may include environmental factors, Mendelian disorders, and chromosomal abnormalities, presenting alone or in combination. The cause of MR/DD can be identified in 40% to 60% of cases; 1 however, the percentage of mild MR/DD cases for which a cause can be established is 24%, which is significantly lower. 11 Chromosome abnormalities are the single most common cause found in series of unselected patients with MR/DD. Rates of identifying chromosome abnormalities range from 15% to 40% in surveys of severe MR/ DD, with substantially lower rates for mild MR/DD. [bib_ref] The genetics of mental retardation, Flint [/bib_ref] Furthermore, it is estimated that approximately 5% of MR/DD can be attributed to chromosomal abnormalities in the subtelomeric regions. [bib_ref] The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation, Flint [/bib_ref] [bib_ref] Subtle chromosomal rearrangements in children with unexplained mental retardation, Knight [/bib_ref] In addition, individuals with learning disabilities and/or speech delays, with or without behavior problems, although not mentally retarded, are also more likely to have chromosome abnormalities, particularly 47,XXX, 47,XXY, or 47,XYY. Chromosome abnormalities are also found in approximately 5% of individuals with autism, usually in association with MR/DD. [bib_ref] Infantile autism and associated autosomal chromosome abnormalities: A register-based study and a..., Lauritsen [/bib_ref] Thus, cytogenetic studies can reveal the cause in a substantial proportion of cases of MR/DD. An accurate diagnosis for MR/DD is valuable for the patient and the patient's family as well as for health care providers. An early diagnosis can elucidate the recurrence risk for parents, especially those carrying chromosome rearrangements. Therapeutic strategies can be investigated more easily, appropriate counseling and intervention issues can be addressed, and important diagnostic and treatment information can be provided to schools and care providers. [bib_ref] Evaluation of mental retardation: Recommendations of a Consensus Conference: American College of..., Curry [/bib_ref] A set of guidelines for diagnosis and genetic testing would be useful, given the variety and complexity of causes of MR/DD, and the benefits of an accurate diagnosis. The following are the recommendations of the American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee, which was convened to assist health care professionals in making decisions regarding cytogenetic diagnostic testing and counseling for MR/DD. This document reviews available evidence concerning the value of conventional and molecular cytogenetic testing for the identification of chromosomal anomalies that play a role in the etiology of MR/DD, and, based on this evidence, specific recommendations for each method of testing are provided. ## Recommendations for testing # Routine chromosome analysis Historically, when investigating an individual with MR or DD, with or without dysmorphic features, the initial analysis began with routine chromosome analysis of peripheral blood. Developed in the 1970s, G-banding and other chromosome banding techniques permit the identification of the alternating light and dark staining bands comprising each chromosome, the detection of aneuploidy (extra or missing chromosomes), and the identification of microscopically apparent structural aberrations, including deletions and translocations. The routine G-banding level of blood chromosome analysis is in the range of 400-550 bands per haploid karyotype; however, for patients with MR or developmental delay, constitutional studies with banding levels of Ͻ 550 should be repeated (ACMG Standards and Guidelines for Clinical Genetics Laboratories, Section E5.1.1.4). Banding techniques are routine procedures in clinical cytogenetic laboratories and are important in the evaluation of all individuals with MR or developmental delay regardless of the presence of dysmorphic features, small stature, congenital abnormalities, or unusual or manneristic behavior. It should not be assumed that perinatal distress and delivery complications are adequate to explain subsequent developmental delay and MR, because these complications can be associated with chromosome abnormalities. Based on good and consistent evidence, the overall yield of routine cytogenetic testing is 3.7%. 6 # High-resolution chromosome analysis Because the chromosomal alterations that result in MR/DD frequently are undetectable at the level of resolution of routine chromosomal analysis, high-resolution analysis may be required to detect microdeletions, microduplications, or subtle translocations in the individual with MR/DD. Rather than using cells in mid-metaphase, which display bands that have fused during contraction, high-resolution chromosomal analysis involves the synchronization of lymphocyte cultures to achieve a population of cells in prophase or prometaphase. [bib_ref] High resolution of human chromosomes, Yunis [/bib_ref] Whereas the metaphase cells used in conventional chromosomal analysis yield approximately 400-550 bands per haploid genome, prophase or prometaphase preparations enable the visualization of up to 1000 bands. [bib_ref] Mid-prophase human chromosomes. The attainment of 2000 bands, Yunis [/bib_ref] Because of the increased number of visible bands, small structural chromosomal abnormalities such as deletions or duplications not resolvable with standard karyotypes may be detected. The ACMG Standards and Guidelines for Clinical Genetics Laboratories recommends that a focused high-resolution analysis should be reserved for cases in which a specific microabnormality syndrome is being considered, the diagnosis of which generally requires chromosomes above the 650-band stage (resolution at the 850-band level may be necessary). In addition, complete high-resolution chromosome analysis should always include a minimum of three pairs of each chromosome at a level of resolution above the 650-band stage. However, because of the increased amount of work required and the difficulty of high-resolution chromosomal analysis, routinely achieving approximately 850 bands is usually reserved for targeting specific chromosomal regions. [bib_ref] Molecular cytogenetics of contiguous gene syndromes: mechanisms and consequences of gene dosage..., Shaffer [/bib_ref] At resolutions Ͼ 650 bands, alterations as small as 3-5 Mb can be reliably detected using chromosome analysis on peripheral blood; for the detection of subtle rearrangements in patients with either abnormal or normal karyotypes, molecular cytogenetic analysis may be useful. # Molecular cytogenetic analysis For individuals with MR/DD and phenotypes suggestive of particular disorders, targeted fluorescence in situ hybridization (FISH) can be performed prior to or concurrent with routine chromosome analysis if a particular microdeletion/microduplication syndrome is under consideration. FISH involves the hybridization of fluorescently labeled DNA probes to the denatured DNA of metaphase chromosomes or interphase nuclei directly on a glass slide. Types of DNA probes include unique sequence probes such as: - bacterial artificial chromosome (BAC) clones, yeast artificial chromosome (YAC) clones, and cosmid clones that are used to interrogate a specific locus on a chromosome; - repetitive sequence probes, such as alpha-satellite sequences to identify the centromeric regions of individual chromosomes; or - whole-chromosome painting (WCP) probes, which utilize chromosomal libraries of clones for hybridization along the length of a specific chromosome. FISH is capable of detecting submicroscopic (Ͻ5 Mb) alterations that cannot be reliably observed using routine or high-resolution microscopic chromosome analysis. Resolution by FISH is dictated by the size of the probes used. For ## Cytogenetic evaluation of developmental delay or mental retardation November/December 2005 ⅐ Vol. 7 ⅐ No. 9 example, single cosmids provide a resolution of approximately 30 to 40 kb, while contigs of overlapping cosmids or BAC probes provide a resolution of 80 to 200 kb. [bib_ref] Molecular cytogenetics of contiguous gene syndromes: mechanisms and consequences of gene dosage..., Shaffer [/bib_ref] The importance of FISH is illustrated by its use in detecting submicroscopic rearrangements in numerous microdeletion syndromes, including those with a relatively high frequency in the general population (e.g., DiGeorge/velocardiofacial syndrome, approximately 1:4000 [bib_ref] The annual incidence of DiGeorge/velocardiofacial syndrome, Devriendt [/bib_ref] , and some microduplication syndromes (e.g., dup(17)(p11.2p11.2) 23 ). However, because FISH relies upon the use of locationspecific probes, it can only be used when the phenotype suggests a particular disorder so a specific probe can be requested. If locus-specific FISH analyses reveal abnormalities, FISH should also be performed on both parents to identify a carrier parent. FISH screening on patients with moderate to severe MR/DD has been shown to have a relatively high yield of 6.8%. 6 # Subtelomeric analysis Because idiopathic MR/DD accounts for a significant proportion of MR/DD cases-approximately 40% of moderate to severe MR/DD 11 and 45% to 65% of mild MR/DD 24 -and because most of these individuals do not have a specific phenotype that would indicate the use of a locus-specific probe, locus-specific FISH is not feasible for most initial attempts at diagnosis. However, evidence exists that aberrations in the terminal bands of chromosomes, the subtelomeric regions, are the cause of many cases of idiopathic MR/DD. Although reports of subtelomeric aberrations in unexplained MR/DD vary by their inclusion criteria, number and type of subjects, and testing acumen, it is estimated that approximately 5% of unexplained cases of MR/DD can be attributed to alterations of the subtelomeric regions. [bib_ref] The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation, Flint [/bib_ref] [bib_ref] Subtle chromosomal rearrangements in children with unexplained mental retardation, Knight [/bib_ref] [bib_ref] The end of the beginning of chromosome ends, Biesecker [/bib_ref] This is because the subtelomeric regions are relatively gene-rich, [bib_ref] The highest gene concentrations in the human genome are in telomeric bands..., Saccone [/bib_ref] with alterations in these regions predicted to be more likely to result in abnormal phenotypes, and are believed to be prone to rearrangement due to a number of mechanisms. [bib_ref] Translocation breakpoint mapping and sequence analysis in three monosomy 1p36 subjects with..., Ballif [/bib_ref] [bib_ref] Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating..., Ballif [/bib_ref] Because the ends of chromosomes lack distinctive G-bands, it is difficult to see small rearrangements at these regions in routine karyotype analysis and sometimes even at higher resolution (850-band). Furthermore, the presence of repetitive sequences within the telomeric regions precludes the use of chromosome-specific telomeric probes for FISH analysis due to the potential for multiple hybridization signals. However, the development of a set of 41 unique subtelomere probes (the short arms of the acrocentric chromosomes are not represented, and the X/Yp and X/Yq pseudoautosomal regions are represented by one clone each) [bib_ref] Development and clinical application of an innovative fluorescence in situ hybridization technique..., Knight [/bib_ref] has permitted analysis of the unique regions approximately 300 kb proximal to the repetitive telomere region. The degree of developmental delay/mental retardation or learning disability is a major predictor of the likelihood of finding a subtelomeric rearrangement as the cause of the individual's disorder. Those with moderate or severe MR/DD and a small chromosomal abnormality are more likely to have some combination of facial dysmorphism, minor physical abnormalities of the hands or feet, small stature, and/or microcephaly. The finding of MR/DD and an abnormal phenotype in a relative increases the chances of detecting a small chromosomal rearrangement. [bib_ref] Perfect endings: A review of subtelomeric probes and their use in clinical..., Knight [/bib_ref] Recently, a set of clinical criteria for subtelomere screening was proposed 32 that may be helpful in some cases. The authors concluded that good indicators for subtelomeric defects are positive family history, prenatal-onset growth retardation, postnatal poor growth/overgrowth, two or more facial dysmorphic features, and one or more nonfacial dysmorphic features and/or congenital abnormalities. [bib_ref] Clinical studies on submicroscopic subtelomeric rearrangements: a checklist, De Vries [/bib_ref] If subtelomere FISH analyses reveal abnormalities, FISH should also be performed on both parents to establish the parental origin of the anomaly and exclude the possibility of polymorphism. [bib_ref] The promise and pitfalls of telomere regionspecific probes, Ballif [/bib_ref] [bib_ref] Caution: Telomere crossing, Shaffer [/bib_ref] Subsequent testing after finding a structural chromosome abnormality After initial testing, if the patient's chromosomes display a structural abnormality, chromosome analysis should be performed on both parents to determine whether one of them carries a balanced rearrangement. If a carrier parent is detected, the nature of the rearrangement should become clear. If parental chromosomes are normal, several molecular cytogenetic techniques, used alone or in tandem (e.g., FISH using WCP probes or subtelomere probes) can be used to define the patient's rearrangement. In addition, techniques have been developed to differentially label each human chromosome with a unique color combination to obtain 24-color karyotypes. [bib_ref] Multicolor spectral karyotyping of human chromosomes, Schrock [/bib_ref] [bib_ref] Multiplex-FISH for pre-and postnatal diagnostic applications, Uhrig [/bib_ref] [bib_ref] Spectral karyotyping refines cytogenetic diagnostics of constitutional chromosomal abnormalities, Schrock [/bib_ref] [bib_ref] Karyotyping human chromosomes by combinatorial multi-fluor FISH, Speicher [/bib_ref] This allows the detection of structural chromosomal aberrations at a level of resolution similar to that of a routine karyotype (400 to 550 bands). However, these techniques cannot detect rearrangements involving only a single chromosome such as deletions, inversions, and intrachromosomal duplications, and the limited number of spectrally resolvable fluorochromes may prohibit accurate detection of some translocations. [bib_ref] Classifying by colors: FISH-based genome analysis, Fauth [/bib_ref] Thus, 24-color karyotyping is usually used in conjunction with other procedures (e.g., subtelomere FISH) to maximize effectiveness. ## Subsequent testing options if no chromosome abnormality is found Direct DNA analysis for the fragile X syndrome is indicated in addition to chromosome analysis for all developmentally delayed/mentally retarded individuals, both male and female, who do not have an apparent underlying cause for their clinical status such as microcephaly, craniofacial dysmorphism and multiple congenital abnormalities. [bib_ref] American College of Medical Genetics Professional Practice and Guidelines Committee, Sherman [/bib_ref] Both chromosome analysis and fragile X DNA analysis should be performed because chromosome abnormalities are as common, or more common, than fragile X mutations in mentally retarded individuals. ACMG recommendations for diagnostic testing for fragile X syndrome, a significant inherited cause of MR/DD, have been published previously. [bib_ref] American College of Medical Genetics Professional Practice and Guidelines Committee, Sherman [/bib_ref] The overall yield of abnormal results after fragile X testing is ϳ2.6%. [bib_ref] Practice parameter: Evaluation of the child with global developmental delay, Shevell [/bib_ref] If, after initial testing by karyotyping and molecular cytogenetics the patient's chromosome analysis reveals no abnormal-ity, and fragile X DNA analysis is negative, several options remain. Comparative genomic hybridization (CGH) is one possible option. In this technique, two genomes are differentially labeled and directly compared by simultaneous hybridization to normal metaphase chromosomes. It has an average resolution of approximately 10 Mb in most laboratories, [bib_ref] Minimal sizes of deletions detected by comparative genomic hybridization, Bentz [/bib_ref] [bib_ref] Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors, Kallioniemi [/bib_ref] [bib_ref] Clinical applications of comparative genomic hybridization, Levy [/bib_ref] although higher resolutions have been reported. [bib_ref] Deletions below 10 megabasepairs are detected in comparative genomic hybridization by standard..., Kirchhoff [/bib_ref] However, for most laboratories the low resolution precludes its usefulness. The future application of CGH is on microarrays (array CGH), in which the two differentially labeled genomes are compared using large-insert clones immobilized on a glass slide as the substrates for analysis. [bib_ref] High resolution analysis of DNA copy number variation using comparative genomic hybridization..., Pinkel [/bib_ref] [bib_ref] Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances, Solinas-Toldo [/bib_ref] With this technique the resolution is substantially increased over conventional cytogenetics, depending on the size and density of clones used. It is likely that for certain applications, such as the individual with nonspecific MR/DD, array CGH may be used in conjunction with routine cytogenetics to replace the locus-specific and/or subtelomere FISH in the future. 47 ## Analysis of tissues other than blood The routine and molecular cytogenetic analyses outlined thus far are usually performed on peripheral blood. However, there are some situations in which the cytogenetic analysis of a skin biopsy or other tissue may be indicated. First is the analysis of a different tissue type in T-cell deficient individuals. Because the analysis of metaphase chromosomes requires stimulation of T-cells by a mitogen (phytohemagglutinin) to enter mitosis, some individuals, such as those with DiGeorge syndrome, may not have enough normal T-cells to yield adequate metaphases for analysis. In these cases, skin fibroblast cultures, which do not depend on phytohemagglutinin stimulation, can be used to evaluate the chromosomes. A second example is the cytogenetic analysis of skin fibroblasts to detect mosaicism. Current standard methods for cytogenetic analysis of peripheral blood will identify only those chromosome aberrations that are present in the circulating T-lymphocytes. However, there are certain chromosome abnormalities that do not appear to be compatible with survival of the T-cells. [bib_ref] Unusual mosaic karyotype resulting from adjacent 1 segregation of t(11;22): Importance of..., Kulharya [/bib_ref] Therefore, only those T-cells that do not contain the aberration will be present in the circulating lymphocytes. Examples of this include mosaic tetrasomy of the short arm of chromosome 12 (Pallister-Killian syndrome [bib_ref] The characteristic physiognomy and tissue specific karyotype distribution in the Pallister-Killian syndrome, Hunter [/bib_ref] [bib_ref] Pallister-Killian syndrome: Cytogenetic and molecular studies, Peltomaki [/bib_ref] and mosaic trisomy 17. [bib_ref] A clinical and molecular study of mosaicism for trisomy 17, Shaffer [/bib_ref] Finally, the chromosomal aberration simply may not be present in the peripheral blood because of tissue-limited mosaicism. [bib_ref] A clinical and molecular study of mosaicism for trisomy 17, Shaffer [/bib_ref] In cases in which chromosomal analysis is normal but suspicion of a chromosome abnormality remains high, a skin fibroblast culture can be used to detect the aberration. Skin biopsies may be taken from individuals with asymmetry or individuals with hypo-and hyperpigmented regions. The skin should be cleansed with alcohol and not with iodine-containing compounds because these inhibit cell growth in culture. Chromosome analysis of skin biopsies has been used to study parents who have more than one child with the same chromosome aberration, e.g., trisomy 21. [bib_ref] Paternal trisomy 21 mosaicism and Down's syndrome, Hsu [/bib_ref] Case reports suggest that cytogenetic analysis of skin biopsies is a possible alter-native when chromosome analysis of blood is normal, although the yield is unknown. Studies using series of patients are needed to determine the overall yield for finding a cytogenetic diagnosis using skin biopsies. Analysis when fetal karyotype is normal following prenatal diagnosis In cases of developmental delay or MR, with or without physical anomalies, and in newborns with dysmorphic features and/or multiple malformations, a blood karyotype should be performed even when a fetal karyotype from amniocentesis or chorionic villus sampling is normal. There are several reasons to perform a blood karyotype. First, there may be mosaicism that has gone undetected in the fetal analysis. Second, the banding resolution is often higher in postnatal blood preparations than in cultured amniocytes or chorionic villi. Finally, the majority of fetal chromosome analyses are done for general reasons (e.g., advanced maternal age, abnormal triple-marker screening) and not for a specific set of dysmorphic features. After birth, the clinical features may provide clues regarding a specific chromosomal imbalance or for the use of additional techniques (e.g., FISH). ## Summary of recommendations - For any child with unexplained MR/DD, even in the absence of dysmorphic facial features, other clinical features or positive family history, routine chromosome analysis (minimum 550-band resolution) is indicated. - For children with clinical features of known chromosomal abnormality syndromes (e.g., Down syndrome), cytogenetic analysis should be performed. The identification of a translocation may affect the family's recurrence risk. - High-resolution chromosome analysis is not routinely indicated unless a specific chromosomal region is to be investigated or there is a family history of a particular abnormality. These studies should be limited in focus and used when FISH is not available. [fig] •: For children with clinical features suggestive of a particular microdeletion/microduplication syndrome, FISH or other molecular techniques should be performed prior to or concurrently with chromosome analysis. If chromosome analysis is normal at 550-band resolution, subtelomere FISH testing may be considered. ter, Ph.D. (Emory University, Atlanta, GA), Jon Zonana, M.D. (Oregon Health Sciences University, Portland, OR), Debra Driscoll, M.D. (University of Pennsylvania Medical Center, Philadelphia, PA) for their critical reviews of the manuscript; and Aaron Theisen (Washington State University, Spokane, WA) for his editorial support. [/fig]	None	https://www.nature.com/articles/gim2005124.pdf	The following are the recommendations of the American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee, which was convened to assist health care professionals in making decisions regarding cytogenetic diagnostic testing and counseling for mental retardation (MR) and developmental delay (DD). This document reviews available evidence concerning the value of conventional and molecular cytogenetic testing for the identification of chromosomal anomalies that play a role in the etiology of MR/DD, and, based on this evidence, specific recommendations for each method of testing are provided.
aae5623c4fc0d4850701cee91c9611e4f7620e38	pubmed	Chinese expert consensus on echelons treatment of thoracic injury in modern warfare	Chinese expert consensus on echelons treatment of thoracic injury in modern warfare The emergency treatment of thoracic injuries varies of general conditions and modern warfare. However, there are no unified battlefield treatment guidelines for thoracic injuries in the Chinese People's Liberation Army (PLA). An expert consensus has been reached based on the epidemiology of thoracic injuries and the concept of battlefield treatment combined with the existing levels of military medical care in modern warfare. Since there are no differences in the specialized treatment for thoracic injuries between general conditions and modern warfare, first aid, emergency treatment, and early treatment of thoracic injuries are introduced separately in three levels in this consensus. At Level I facilities, tension pneumothorax and open pneumothorax are recommended for initial assessment during the first aid stage. Re-evaluation and further treatment for hemothorax, flail chest, and pericardial tamponade are recommended at Level II facilities. At Level III facilities, simple surgical operations such as emergency thoracotomy and debridement surgery for open pneumothorax are recommended. The grading standard for evidence evaluation and recommendation was used to reach this expert consensus. In previous wars, thoracic injury accounted for approximately 4.4-33.0% of all wartime injuries. It is a major cause of injury and death in warfare and accounts for approximately 1-3% of all preventable wartime casualties [bib_ref] United States Army rangers in Somalia: an analysis of combat casualties on..., Mabry [/bib_ref] [bib_ref] Wartime thoracic injury: perspectives in modern warfare, Propper [/bib_ref] [bib_ref] The UK military experience of thoracic injury in the wars in Iraq..., Poon [/bib_ref] [bib_ref] Thoracic injuries in US combat casualties: a 10-year review of operation enduring..., Ivey [/bib_ref] [bib_ref] Thoracic trauma in Iraq and Afghanistan, Keneally [/bib_ref] [bib_ref] UK specialist cardiothoracic management of thoracic injuries in military casualties sustained in..., Senanayake [/bib_ref] [bib_ref] Epidemiology of combat wounds in operation Iraqi freedom and operation enduring freedom:..., Belmont [/bib_ref]. In the United States (US)-led Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), the epidemiological features and treatment needs for wartime thoracic injury were different than those in previous wars [bib_ref] The UK military experience of thoracic injury in the wars in Iraq..., Poon [/bib_ref] [bib_ref] Thoracic injuries in US combat casualties: a 10-year review of operation enduring..., Ivey [/bib_ref] [bib_ref] Thoracic trauma in Iraq and Afghanistan, Keneally [/bib_ref] [bib_ref] UK specialist cardiothoracic management of thoracic injuries in military casualties sustained in..., Senanayake [/bib_ref]. Currently, there are no uniform guidelines for the treatment of wartime thoracic injuries in the modern battlefield of the Chinese People's Liberation Army (PLA). Therefore, we organized experts from the Chinese PLA Thoracic and Cardiovascular Surgery Professional Committee, the Army Medical University, the Naval Medical University, and the Academy of Military Medical Sciences to compile the "Chinese expert consensus on echelons treatment of thoracic injury in modern warfare" to provide a reference for the treatment of wartime thoracic injuries in the Chinese PLA. Since the specialized treatment for wartime thoracic injury is basically the same as that for general conditions, only the guidelines of specialized treatment for wartime thoracic injury are introduced in this consensus. The guidelines contain three levels: first aid in the battlefield, emergency treatment, and early treatment, which are based on the currently used step care model in the Chinese PLA. The evidence and recommendation grades adopted in this expert consensus are mainly based on the standards recommended by the Oxford Evidence-Based Medicine Center and on the criteria commonly used in clinical studies, as we have previously described [bib_ref] Expert consensus on the evaluation and diagnosis of combat injuries of the..., Zong [/bib_ref]. ## Characteristics of epidemiological changes in thoracic injury in modern warfare The available data show that the incidence of thoracic injury in previous wars was 4.4-33.0%. During the recent OEF/OIF, the incidence of thoracic injury was 8.6-10.5%, which was lower than that in World War II. This is mainly attributed to the widespread use of body armor, which effectively reduces the incidence of thoracic injury [bib_ref] United States Army rangers in Somalia: an analysis of combat casualties on..., Mabry [/bib_ref] [bib_ref] Wartime thoracic injury: perspectives in modern warfare, Propper [/bib_ref] [bib_ref] The UK military experience of thoracic injury in the wars in Iraq..., Poon [/bib_ref] [bib_ref] Thoracic injuries in US combat casualties: a 10-year review of operation enduring..., Ivey [/bib_ref] [bib_ref] Thoracic trauma in Iraq and Afghanistan, Keneally [/bib_ref] [bib_ref] UK specialist cardiothoracic management of thoracic injuries in military casualties sustained in..., Senanayake [/bib_ref] [bib_ref] Epidemiology of combat wounds in operation Iraqi freedom and operation enduring freedom:..., Belmont [/bib_ref]. The mortality of thoracic injury has a different trend from its incidence. From the American Civil War to the Vietnam War, the mortality of thoracic injury has continued to decline. The mortality of wartime thoracic injury during the American Civil War, World War I, World War II, the Korean War, and the Vietnam War was 62.6%, 27.0%, 11.0%, 1.5%, and 2.9%, respectively [bib_ref] United States Army rangers in Somalia: an analysis of combat casualties on..., Mabry [/bib_ref] [bib_ref] Wartime thoracic injury: perspectives in modern warfare, Propper [/bib_ref] [bib_ref] The UK military experience of thoracic injury in the wars in Iraq..., Poon [/bib_ref] [bib_ref] Thoracic injuries in US combat casualties: a 10-year review of operation enduring..., Ivey [/bib_ref] [bib_ref] Thoracic trauma in Iraq and Afghanistan, Keneally [/bib_ref] [bib_ref] UK specialist cardiothoracic management of thoracic injuries in military casualties sustained in..., Senanayake [/bib_ref] [bib_ref] Epidemiology of combat wounds in operation Iraqi freedom and operation enduring freedom:..., Belmont [/bib_ref]. Interestingly, during OEF/OIF, the mortality of thoracic injury "unexpectedly" increased to 10.5%. This was mainly due to the widespread use of protective equipment, improvement of first aid in the battlefield, rapid evacuation, which allows more soldiers with severe thoracic injuries to be evacuated to treatment facilities than in previous wars, and an improved registration system for wounded soldiers. All these improvements led to more soldiers with severe thoracic injuries being included in the statistics than those for previous wars, which led to the "unexpected" increase in the mortality of wounded soldiers with wartime thoracic injury in OEF/OIF [bib_ref] The UK military experience of thoracic injury in the wars in Iraq..., Poon [/bib_ref] [bib_ref] Thoracic injuries in US combat casualties: a 10-year review of operation enduring..., Ivey [/bib_ref] [bib_ref] Thoracic trauma in Iraq and Afghanistan, Keneally [/bib_ref] [bib_ref] UK specialist cardiothoracic management of thoracic injuries in military casualties sustained in..., Senanayake [/bib_ref]. Moreover, unlike previous wars such as the Vietnam War, blast injuries surpassed gunshot injuries in OEF/OIF and became a major cause of thoracic injury. A blast injury increases the incidence of visceral injury after blunt thoracic trauma and is difficult to diagnose and treat [bib_ref] The epidemiology of blast lung injury during recent military conflicts: a retrospective..., Smith [/bib_ref] [bib_ref] Behind Armour blunt trauma--an emerging problem, Cannon [/bib_ref] [bib_ref] Value of thoracic computed tomography in the first assessment of severely injured..., Trupka [/bib_ref]. These specific changes require corresponding changes in treatment; for instance, intensive care for soldiers with severe thoracic injury is needed to reduce the mortality. ## Consensus 1 Due to changes in the injury mechanisms, the widespread use of protective equipment, and the improvement of first aid on the battlefield, thoracic injury in modern warfare is associated with an increased incidence of severe injury and organ injury caused by blunt trauma and with high mortality, which are different from the characteristics of thoracic injury observed in previous wars. Therefore, these changes require corresponding changes in treatment (Class B/Category I). Protective equipment can reduce the incidence of thoracic injury As mentioned above, there has been a downward trend in the overall incidence of thoracic injury for US forces throughout all previous wars. This change is mainly attributed to the widespread use of body armor by US forces, which increases the protection of the torso [bib_ref] United States Army rangers in Somalia: an analysis of combat casualties on..., Mabry [/bib_ref]. Data from OIF/OEF show that effective protection significantly reduces the incidence and overall mortality of thoracic injury in US forces and their allies [bib_ref] Wartime thoracic injury: perspectives in modern warfare, Propper [/bib_ref] [bib_ref] The UK military experience of thoracic injury in the wars in Iraq..., Poon [/bib_ref]. ## Consensus 2 Body armor and other protective equipment can effectively reduce the incidence, severity, and overall mortality of thoracic injury (Class B/Category I). First aid on the battlefield for current wartime thoracic injury Tension pneumothorax accounted for 3-5% of all preventable wartime injuries during the Vietnam War [bib_ref] Needle thoracostomy for tension pneumothorax: the Israeli defense forces experience, Chen [/bib_ref]. In OIF and OEF, tension pneumothorax and open pneumothorax are the third cause of preventable wartime casualties, as timely and effective treatment can save over 90% of the wounded soldiers [bib_ref] Died of wounds on the battlefield: causation and implications for improving combat..., Eastridge [/bib_ref]. Therefore, it is necessary to differentiate tension pneumothorax from open pneumothorax without an auxiliary examination at the scene of the battlefield and to start emergency treatment. In the battlefield, the following signs can be used to identify soldiers with tension pneumothorax: 1) history of chest injury; 2) progressive difficulty breathing, i.e., fast breathing and labored respiration; 3) attenuated or absent breath sound on the side of the injury; 4) elevated chest wall on the side of the injury compared with the contralateral side, subcutaneous emphysema, and jugular vein distension; and 5) hypotension and shock induced by tachycardia and shortness of breath, which can be worsened by the increased intrathoracic pressure. Chen et al. [bib_ref] Needle thoracostomy for tension pneumothorax: the Israeli defense forces experience, Chen [/bib_ref] analyzed the symptoms and signs of 111 cases of tension pneumothorax in the trauma database of the Israel Defense Forces from 2007 to 2012 and found that the most common clinical manifestations were attenuated breath sound on the side of the injury and shortness of breath. Loss of consciousness and absence of radial artery pulse are also common symptoms and are associated with high mortality. No tracheal deviation was observed in any cases in the database with tension pneumothorax. Moreover, it is very difficult to identify attenuated breath sound through a physical examination on the battlefield due to environmental noise. In OIF and OEF, US forces discovered that hand-held, miniaturized B-mode ultrasound instruments were helpful in the diagnosis of tension pneumothorax in the battlefield, and medics were able to use this technique after a short training session. Studies have shown that the sensitivity and specificity of ultrasound in the diagnosis of tension pneumothorax is 92.0% and 99.4%, respectively, which are higher than those of X-ray and similar to those of computed tomography (CT) scan [bib_ref] Rapid detection of pneumothorax by ultrasonography in patients with multiple trauma, Zhang [/bib_ref] [bib_ref] A prospective comparison of supine chest radiography and bedside ultrasound for the..., Blaivas [/bib_ref] [bib_ref] In-flight thoracic ultrasound detection of pneumothorax in combat, Madill [/bib_ref]. Needle thoracentesis is required for wounded soldiers diagnosed with tension pneumothorax. The Advanced Trauma Life Support (ATLS) recommends the use of a 5-cm-long puncture needle to perform thoracentesis for the treatment of tension pneumothorax at the second intercostal space in the midclavicular line. After comparative measurements and clinical observations, studies revealed that the thickness of the chest wall of individual US soldiers was often more than 5 cm at the second intercostal space. Therefore, a 3.25-in.-long (8.25 cm) puncture needle (No. 14) is recommended by the Committee for Tactical Emergency Casualty Care (C-TECC) [bib_ref] Proper catheter selection for needle thoracostomy: a height and weight-based criteria, Powers [/bib_ref] [bib_ref] Chest wall thickness and decompression failure: a systematic review and metaanalysis comparing..., Laan [/bib_ref]. The recommended site for needle thoracentesis is still at the second intercostal space in the midclavicular line [bib_ref] Needle thoracostomy for tension pneumothorax: the Israeli defense forces experience, Chen [/bib_ref] [bib_ref] Needle decompression for tension pneumothorax in tactical combat casualty care: do catheters..., Beckett [/bib_ref] [bib_ref] Needle thoracotomy in trauma, Rottenstreich [/bib_ref]. After needle thoracentesis, it is still controversial whether or not to make a valve in the drainage tube in the battlefield. Some researchers argue that the diameter of the drainage tube is much smaller than that of the airway. Air circulation through the drainage tube could not significantly affect respiration. Without a valve, the thoracentesis can still convert tension pneumothorax into open pneumothorax, which is less severe. We support the idea of using a glove to make a one-way valve to increase the effectiveness of decompression if the battlefield conditions allow, especially when the estimated evacuation time is long or the evacuation may be delayed. The drainage tube can be placed in the puncture site and flushed with saline every 2 hours to ensure its patency. If conditions allow, the drainage tube can be removed, and the soldier should be monitored closely. If signs of tension pneumothorax are present, needle thoracentesis should be repeated. If necessary, tube thoracostomy should be performed. A study by Chen et al. [bib_ref] Needle thoracostomy for tension pneumothorax: the Israeli defense forces experience, Chen [/bib_ref] showed that 32% of wounded soldiers undergoing needle thoracentesis underwent tube thoracotomy in battlefield hospitals. The main signs for the diagnosis of open pneumothorax include the following: 1) history of thoracic injury and presence of chest wall wounds; 2) sucking or hissing sounds in the chest wall and foamed blood in the wound; 3) difficulty breathing; and 4) chest wall unable to rise normally during inhalation. In 2013, the US C-TECC updated the treatment guidelines for open pneumothorax. Once open pneumothorax is confirmed, a breathable chest pad must be used immediately to close the wound. If a breathable chest pad is not available, a conventional chest pad can be used to close the wound, and then the soldier should be monitored closely for symptoms of tension pneumothorax. If the wounded soldiers suffer from persistently progressive hypoxia, respiratory distress, or hypotension, the occurrence of tension pneumothorax should be considered and the chest pad should be removed or needle thoracentesis should be performed for decompression [bib_ref] Management of open chest wounds in tactical emergency casualty care: application of..., Margolis [/bib_ref] [bib_ref] Management of open pneumothorax in tactical combat casualty care: TCCC guidelines change..., Butler [/bib_ref]. ## Consensus 3 Wounded soldiers with a history of thoracic injury may be diagnosed with tension pneumothorax when they have symptoms of progressive dyspnea and attenuated breath sound on the side of the injury. Portable B-mode ultrasound instruments may help with the diagnosis when effective physical examinations cannot be performed on the battlefield due to environmental noise (Class B/Category IIb). ## Consensus 4 Once tension pneumothorax is confirmed, it is recommended to use a No. 14 puncture needle (8.25 cm in length) for needle thoracentesis at the second intercostal space in the midclavicular line. If conditions allow, a valve can be added at the end of the puncture needle. After needle thoracentesis, the wounded soldier should be closely monitored. When the symptoms of tension pneumothorax reoccur, needle thoracentesis should be repeated, or tube thoracostomy should be performed (Class B/Category IIa). ## Consensus 5 Wounded soldiers with a history of thoracic injury may be diagnosed with open pneumothorax if they have progressive dyspnea, sucking or hissing sounds in the chest wall, and foamed blood in the wound (Class B/Category IIb). ## Consensus 6 Once open pneumothorax is confirmed, a breathable chest pad can be used immediately to close the wound. If a breathable chest pad is not available, a conventional chest pad can be used to close the wound. The soldier should then be closely monitored for symptoms of tension pneumothorax. If the wounded soldiers suffer from persistently progressive hypoxia, respiratory distress, or hypotension, the occurrence of tension pneumothorax should be considered, and the chest pad should be removed or needle thoracentesis should be performed for decompression (Class B/Category IIa). ## Emergency treatment for wartime thoracic injury in modern warfare During the level of emergency treatment, tension pneumothorax, open pneumothorax, massive hemothorax, flail chest, and pericardial tamponade need to be further observed and treated, and painkillers and tetanus antitoxin may be used. ## Identification and treatment of massive hemothorax Chest pain and shortness of breath are two major symptoms of massive hemothorax, and some of the wounded soldiers may be accompanied by shock. Attenuated or absent breath sound can be noted on the side of the injury, and percussion dullness can be noted. In emergency treatment facilities, B-mode ultrasound instruments can be used in the diagnosis of hemothorax. When soldiers with thoracic injury suffer shortness of breath and no remission after needle thoracentesis, massive hemothorax should be considered. For soldiers considered to have massive hemothorax, tube thoracostomy should be performed, and in general, the drainage tube should be placed in the fourth/fifth intercostal space in the midaxillary line [bib_ref] Straightening out chest tubes: what size, what type, and when, Mahmood [/bib_ref]. ## Identification and emergency treatment of flail chest In the emergency facilities of the Chinese PLA, X-ray and CT scan are not available, therefore the diagnosis of flail chest depends mainly on the clinical manifestations and signs. For soldiers with a thoracic injury with multiple rib fractures, rapid breathing, and shock, flail chest combined with lung injury (mainly pulmonary contusion) should be considered first. The presence of paradoxical movement of the chest wall is of great significance in the diagnosis of flail chest. In emergency treatment facilities, paradoxical movement of the chest wall should be controlled as soon as possible, airway patency and adequate oxygen supply should be maintained, respiratory and circulatory dysfunction should be corrected, and shock should be prevented. When the softening chest wall is limited or located on the back, a local pad can be used as a pressure dressing. A paradoxical movement of the chest wall of 3-5 cm can cause severe respiratory and circulatory disorders and can quickly lead to death. Thus, emergency treatment must be applied. A pressure dressing with pads should be temporarily applied, and then the chest is fixed with a multi-head chest strap. For soldiers with flail chest and pulmonary contusion, adequate tissue perfusion should be ensured without limitation. Once wounded soldiers are fully resuscitated, unnecessary fluid should be avoided. The appropriate methods should be selected to control the pain of the wounded soldiers to reduce the possibility of respiratory failure [bib_ref] Management of pulmonary contusion and flail chest: an eastern Association for the..., Simon [/bib_ref]. ## Identification and emergency treatment of pericardial tamponade For soldiers with penetrating chest injuries, medics should be aware of the possibility of pericardial tamponade. Blunt trauma located in the area, which is bordered by the horizontal line at the level of the clavicle, the vertical lines to the costal margin via the bilateral nipples, and the connecting line between the crossing points of the bilateral vertical lines to the costal margin line, may cause pericardial tamponade. The presence of Beck's triad (distant and muffled heart sounds, distended jugular vein, and low arterial blood pressure) is the indication of pericardial tamponade in wounded soldiers. However, it is extremely difficult to find these phenomena in emergency treatment facilities, especially the muffled heart sounds. Therefore, medics in the battlefield should pay attention to the location of the injury and the sign of low blood pressure and give wounded soldiers the appropriate treatment. In this case, the use of B-mode ultrasound instruments can effectively improve the success rate of the diagnosis of pericardial tamponade, whereas electrocardiography (ECG) examination can only show low QRS voltage [bib_ref] ESC guidelines for the diagnosis and management of pericardial diseases: the task..., Adler [/bib_ref] [bib_ref] Triage strategy for urgent management of cardiac tamponade: a position statement of..., Ristic [/bib_ref]. Pericardiocentesis is an effective and common treatment for pericardial tamponade that works by draining fluid from the pericardial sac. Two specific puncture locations are described as follows: 1) Puncture under the xiphoid process, at the junction of the xiphoid process and the left costal margin. The puncture needle can be advanced toward the left side into the posterior-inferior part of the pericardial cavity at a 30-45°angle to the abdominal wall. 2) Puncture in the apex of the heart, with the puncture site located 2 cm within the border of cardiac dullness in the left fifth intercostal space or the sixth intercostal space. The needle is inserted at the upper edge of the rib and advanced slightly toward the midline into the pericardial cavity. Ultrasound can be used to guide the pericardiocentesis to reduce complications when the conditions allow. Wounded soldiers undergoing pericardiocentesis have priority to be evacuated to an early care facility for further assessment of injuries and auxiliary examinations, in order to clarify the condition of the heart injury and receive effective treatment. ## Further observation and treatment of pneumothorax Tube thoracostomy should be performed if the symptoms are not obviously relieved or even progressively worsening in soldiers with tension pneumothorax undergoing needle thoracentesis in the battlefield. If there is no accompanying hemothorax, the drainage tube can be inserted into the second and third intercostal space. It should be noted that wounded soldiers with a drainage tube are still at great risk to develop tension pneumothorax during evacuation, especially if they are under positive pressure ventilation. If signs of tension pneumothorax begin to appear, kinking in the chest tube or connecting tube should be excluded first; then, the connection from the connecting tube to the liquid seal and drainage equipment should be secured. Even if there are no severe symptoms of tension pneumothorax, soldiers who have gradually developed symptoms of tension pneumothorax may need needle thoracentesis. ## Consensus 7 When symptoms such as chest pain, shortness of breath, signs of shock, and attenuated breath sound on the side of the injury appear in wounded soldiers with a history of thoracic injury, massive hemothorax should be considered. In this case, it is recommended to insert the drainage tube in the fourth/fifth intercostal space for closed thoracic drainage (Class B/Category IIa). ## Consensus 8 If the symptoms of rapid breathing and shock appear in soldiers with thoracic injury and multiple rib fractures, flail chest accompanied by pulmonary contusion should be considered first. In emergency treatment facilities, paradoxical movement of the chest wall should be controlled as soon as possible. The patency of the airway should be maintained and tissue perfusion should be ensured under limited fluid resuscitation. Pain should also be controlled (Class A/Category I). ## Consensus 9 Wartime blunt and penetrating injury may lead to pericardial tamponade, and adequate alertness is an important factor for its identification. Beck's triad, low QRS voltage from the ECG examination, and echocardiography can be used to support the diagnosis of pericardial tamponade. Pericardiocentesis is required in wounded soldiers with possible pericardial tamponade. The pericardiocentesis should be performed at the site under the xiphoid process or the apex of the heart. Ultrasound can be used to guide the operation to improve safety (Class B/Category IIa). ## Early treatments for wartime thoracic injury in modern warfare At present, relatively simple surgical procedures such as emergency thoracotomy, debridement, and suturing of open pneumothorax can be performed in early treatment facilities in the Chinese PLA. As mentioned above, during modern warfare, soldiers with thoracic injury who are evacuated to Level III treatment facilities are usually in critical condition. If they are not treated in time, mortality is extremely high. The US forces' experience in OIF and OEF shows that penetrating cardiac injuries, thoracoabdominal injuries, and diaphragm ruptures can be treated by cardiac repairs, removal of injured lung tissue, hemostasis, and diaphragm repairs in Level III facilities to save more lives [bib_ref] Multidisciplinary trauma team care in Kandahar, Afghanistan: current injury patterns and care..., Beckett [/bib_ref] [bib_ref] Surgical challenges in a new theater of modern warfare: the French role..., Malgras [/bib_ref] [bib_ref] Lessons learned from the experience of visceral military surgeons in the French..., Bonnet [/bib_ref]. ## Resuscitative emergency thoracotomy Indications for resuscitative emergency thoracotomy include short-term (usually no more than 15 min) cardiac arrest or impending cardiac arrest caused by penetrating and blunt trauma. The success rate of resuscitation emergency thoracotomy is 7-21%. However, the success rate is generally higher for some soldiers, particularly those who lose their life signs for less than 45 min and those who are evacuated to Level III facilities alive but experience cardiac arrest later and were treated by closed chest cardiopulmonary resuscitation (CC-CPR) for less than 15 min. Resuscitative emergency thoracotomy should be performed on the basis of effective blood transfusions, fluid infusions, and other anti-shock treatments. The leftsided incision or clamshell approach is usually used to open the chest. The pleura and pericardium are opened, the injured aorta is clamped, and intrathoracic CPR is performed. If the heart resuscitation is successful, emergency procedures should be prepared immediately, and the wounded soldier should be transferred to the operating room for further surgical treatment [bib_ref] Emergency department resuscitative thoracotomy for nontorso injuries, Sheppard [/bib_ref] [bib_ref] Defining the limits of resuscitative emergency department thoracotomy: a contemporary Western trauma..., Moore [/bib_ref] [bib_ref] Longterm outcomes after combat casualty emergency department thoracotomy, Edens [/bib_ref] [bib_ref] Challenges in war-related thoracic injury faced by French military surgeons in Afghanistan, De Lesquen [/bib_ref]. ## Damage control thoracotomy The indications for damage control thoracotomy (DCT) in the battlefield include the following: 1) Wounded soldiers with massive and progressive hemorrhages in the chest cavity, including soldiers who have not improved after anti-shock treatment or improved temporarily and then deteriorated rapidly, whose initial drainage volume after closed thoracic drainage is more than 1000 ml or the drainage volume exceeds 200 ml per hour for more than 3 h. Severe lung lacerations and large intrathoracic blood vessel ruptures are the major causes of intra-thoracic hemorrhage during wartime. 2) Wounded soldiers with severe heart contusion. 3) Wounded soldiers with severe tracheal and bronchial injuries [bib_ref] Challenges in war-related thoracic injury faced by French military surgeons in Afghanistan, De Lesquen [/bib_ref] [bib_ref] Damage-control thoracic surgery: management and outcomes, O'connor [/bib_ref] [bib_ref] Damage-control techniques in the management of severe lung trauma, Garcia [/bib_ref] [bib_ref] Temporarily pulmonary hilum clamping as a thoracic damage-control procedure for lung trauma..., Liu [/bib_ref]. After DCT is confirmed, the left-sided anterolateral thoracotomy approach is generally used as an initial incision to expose the pericardium, descending aorta, proximal left subclavian arteries, and left hilum. If necessary, the clamshell approach can be used to improve the exposure of the pericardium, heart, and anatomical structure of the thoracic inlet. The main drawback of this approach is the insufficient exposure of the esophagus and trachea. After weighing the advantages and disadvantages of different approaches, the anterolateral incision is the best for exposure and control of urgent, fatal injuries. The median sternotomy is the most practical incision that can reach the heart and great vessels. It is can also be used to access the hilar structure and a small part of the lungs. The use of this incision is very common, and it can be extended through the "roof window" to the neck and adjacent upper extremity. This window provides access to the subclavian artery and its branches (including the proximal vertebral artery, internal mammary artery, and axillary artery). However, the disadvantages of the median sternotomy are as follows: the access to the lungs is not optimal, especially to the left lower lobe, and it fails to expose the posterior mediastinum structure, especially the descending aorta; sternum saws or a Lebsche knife are required for sternotomy in an adult, but on the battlefield, these power tools may not be available. A combined thoracoabdominal incision is an option for obtaining access to the lower chest and upper abdomen, but it is rarely used for emergency treatment. After full exposure of the chest, appropriate treatment is performed based on the findings (see below for details). In terms of uncontrollable bleeding, gauze packs are recommended to control bleeding [bib_ref] Gauze packing as damage control for uncontrollable haemorrhage in severe thoracic trauma, Moriwaki [/bib_ref] , and wounded soldiers should be given priority to be evacuated to specialist hospitals for treatment. ## Diagnosis and early treatment of severe lung laceration Both penetrating and blunt trauma can cause lung lacerations. A large lung laceration can cause difficulty breathing, cyanosis, and rapid pulse. If the blood loss is considerable, blood pressure may drop, and shock may even occur. Most soldiers with lung lacerations can be cured by closed thoracic drainage. For soldiers with no obvious improvement in dyspnea and progressive hemothorax after closed thoracic drainage, thoracotomy is needed to find the sites of hemorrhage or leakage in order to suture them. If the laceration is too severe to be repaired, lobectomy or segmentectomy may be an option. Pneumonectomy is the last option for soldiers with lung or hilar tissue damage. The mortality of soldiers with unilateral pneumonectomy is greater than 50%. Large air leaks in the trachea or severe pulmonary hemorrhage can be temporarily controlled by cutting the inferior pulmonary ligament, clamping the hilum, or twisting the lung by 180°around the hilum. During pneumonectomy, the hilum should be clamped slowly to allow the other lung to adapt. The amount of fluid during resuscitation should be minimized to avoid the occurrence of acute right heart failure [bib_ref] Damage-control techniques in the management of severe lung trauma, Garcia [/bib_ref] [bib_ref] Temporarily pulmonary hilum clamping as a thoracic damage-control procedure for lung trauma..., Liu [/bib_ref]. Suture and ligation of hilar vessels and bronchial tubes should be performed individually with the support of pleura or other flexible soft tissue such as the internal jugular muscle. ## Diagnosis and early treatment of severe tracheal and bronchial injuries Both penetrating and blunt trauma can cause the rupture of the trachea and bronchus, which leads to pneumothorax, airway obstruction by hemorrhage, and pulmonary contusion, resulting in dyspnea. After the rupture of the trachea, the typical manifestations of tracheal injury, such as mediastinal emphysema and subcutaneous emphysema in the suprasternal fossa, may quickly occur and spread to the neck, face, and chest. X-ray should show a collection of gas along the anterior edge of the spine, followed by signs of severe gas accumulation in the mediastinum. If there are mediastinal pleura ruptures, signs of pneumothorax or hydropneumothorax in the chest should be found. Conservative treatment can be used for small ruptures of the intrathoracic trachea and bronchi. For soldiers with a large rupture, if a tracheotomy and closed thoracic drainage do not alleviate the dyspnea, surgical repair should be performed in an early treatment facility. The advantages of surgical treatment include early pulmonary re-expansion, prevention of stricture of the injury site, clear exposure of the rupture sites, and simplicity in operation [bib_ref] Delayed presentation and treatment of tracheobronchial injuries due to blunt trauma, Glazer [/bib_ref] [bib_ref] Update on the diagnosis and treatment of tracheal and bronchial injury, Zhao [/bib_ref]. A thoracic surgeon should be available for the repair of the damaged trachea and bronchi in battlefield hospitals; if one is not available, the wounded soldiers should be given priority to be evacuated with tracheal intubation and ventilatory support. ## Early treatment of heart injury More than 80% of soldiers with penetrating heart injuries die at the time of injury. Early diagnosis and surgery are the key factors for survival for wounded soldiers who are still alive when arriving at battlefield hospitals. The diagnosis of penetrating heart injury is usually confirmed by reliable clinical symptoms and ultrasound examination of pericardial trauma. Chest radiography may help in the diagnosis of penetrating heart injury and the valuable signs include enlarged heart shadow, widened superior mediastinum, and gas accumulation in the pericardial sac. Approximately 30% cases of penetrating heart injury could be diagnosed by ECG with the presence of the following signs: low QRS voltage, ST-segment elevation, inverted T waves, etc. [bib_ref] High-velocity penetrating thoracic trauma with suspected cardiac involvement in a combat support..., Dominguez [/bib_ref] [bib_ref] Complete heart block following penetrating chest trauma in operation Iraqi freedom, Eckart [/bib_ref]. The diagnosis of blunt heart injury is challenging. Some of the wounded soldiers may experience tachycardia, arrhythmia, or cardiogenic shock. Laboratory tests may reveal elevated troponin levels and an abnormal ECG. Sufficient awareness is the key to improving the success rate of the diagnosis. Trauma ultrasound examination, ECG, and measurement of troponin levels should be performed on suspected wounded soldiers. If these examinations are normal, no further investigation is required; if the ECG is abnormal or the troponin levels are elevated, the soldier should be closely monitored by ECG [bib_ref] Screening for blunt cardiac injury: an eastern Association for the Surgery of..., Clancy [/bib_ref]. For soldiers with penetrating and blunt heart injuries, early diagnosis is required, and surgical repair may provide a certain chance of survival. ## Early treatment of injury of the thoracic great vessels Soldiers with penetrating trauma of the thoracic great vessels often die at the scene on the battlefield and do not have the chance to be evacuated to an early treatment facility. However, soldiers with blunt trauma of the great vessels may suffer from pain in the retrosternal or scapular area. Since the all-layer aortic wall rupture is covered by the mediastinal pleura, a hematoma may form and extend along the gap of the loose tissue to the chest and neck, resulting in pleural effusion, thickening of the neck, pulsatile masses, or compression to the jugular veins and descending aorta. If the hematoma tension is too great and the mediastinal pleura suddenly ruptures, the soldier may die because of the delayed massive bleeding. Physical examination should reveal a rough, blowing, systolic murmur in the precordial area and the interscapular area. X-rays can show signs of widening of the mediastinum and blurring or irregular outline of the thoracic aorta. CT angiography can improve the success rate of the diagnosis of great vascular injury [bib_ref] Evaluation and management of blunt traumatic aortic injury: a practice management guideline..., Fox [/bib_ref] [bib_ref] The utility of chest X-ray as a screening tool for blunt thoracic..., Gutierrez [/bib_ref]. However, CT scanners are not available in Level III treatment facilities in the Chinese PLA. Soldiers with an injury of the great vessels who do not suffer massive hemorrhage or shock should be quickly evacuated for specialist treatment under close monitoring. In the event of a progressive chest hemorrhage, thoracotomy should be performed urgently to repair damaged blood vessels, or vascular bypass surgery should be performed. In OIF and OEF, US forces reported successful stenting of the thoracic vessel in battlefield hospitals after blunt trauma [bib_ref] Endovascular treatment of a blunt aortic injury in Iraq: extension of innovative..., Propper [/bib_ref] [bib_ref] Management of blunt traumatic thoracic aorta injuries with endovascular stent-grafts in a..., Leong Tan [/bib_ref] , but we do not recommend performing this procedure in battlefield hospitals under the existing technical and equipment conditions of the Chinese PLA. ## Early treatment of esophageal injuries The incidence of wartime esophageal injuries is low. This type of injury is a result of a penetrating injury caused by a gunshot wound. Therefore, penetrating injuries near the esophagus usually lead to esophageal injury. Severe posterior sternal and epigastric pain, dyspnea, and cyanosis, as well as mediastinal and subcutaneous emphysema, are common symptoms and signs. Severe infections may cause sepsis and even shock [bib_ref] Western trauma association critical decisions in trauma: diagnosis and management of esophageal..., Biffl [/bib_ref]. Subcutaneous emphysema in the mediastinum or neck, which can be revealed by chest radiographs, is important for the diagnosis of esophageal injury [bib_ref] Western trauma association critical decisions in trauma: diagnosis and management of esophageal..., Biffl [/bib_ref]. The US forces, which are equipped with esophagoscopes in battlefield hospitals and trained to perform an esophagoscopy, can make a much more accurate diagnosis and assessment of esophageal injury. Soldiers with esophageal rupture should be fasted. If wounded soldiers can be evacuated to a specialist hospital within 12 h after the injury, they should be given the priority. If skilled surgeons are available in the early treatment facility and the evacuation time is estimated to be long, repairs should be performed because delayed repair could lead to a high risk of sepsis and high mortality. Conventional procedures of transthoracic esophageal repair are described as follows: rupture of the middle or upper esophagus is most likely in the right chest, therefore, a right thoracotomy should be performed; rupture of the lower esophagus is most likely in the left chest, and thus a left thoracotomy is appropriate. Necrotic and inflammatory tissue should be removed, and accidental damage of the surrounding vital tissues and organs should be avoided. After trimming the edges of the esophageal rupture, a small rupture can be closed with two layers of intermittent sutures and covered by the surrounding pleura or tissue. A larger rupture can be closed with sutures and covered by an intercostal muscle flap or diaphragmatic muscle flap. If the evacuation of the wounded soldiers is delayed and infection has already occurred in the early treatment facility, a mediastinal or chest drainage tube should be placed. If the infection is confined to the upper mediastinum, it can be drained through a cervical incision; if it is in the middle or inferior mediastinum, posterior mediastinal drainage can be performed. For posterior mediastinal drainage, 1-2 corresponding posterior segments of the ribs are removed to expose the posterior mediastinum by retracting the pleura. No damage to the pleura is required in order to avoid infection of the thoracic cavity. ## Diagnosis and early treatment of penetrating thoracoabdominal injury A combined thoracoabdominal wound refers to the same injury mechanism causing simultaneous damages to the chest, abdominal organs, and diaphragmatic muscle, resulting in an extremely high mortality rate. The incidence of a combined thoracoabdominal wound is not high during peacetime but is higher in wartime. In World War II, the incidence of a combined thoracoabdominal wound was 10-28%, and in the Vietnam and Korean Wars, it was 27-35%. During OEF/OIF, the incidence of a combined thoracoabdominal wound was 4.4% in the British forces [bib_ref] Ballistic thoracoabdominal injury: analysis of recent military experience in Afghanistan, Morrison [/bib_ref]. The clinical manifestations of a penetrating combined thoracoabdominal wound are complex and include clinical manifestations of both chest and abdominal injuries. Rapid pulse, lower blood pressure, and other shock symptoms are common. The thoracic injury is mainly manifested as hemopneumothorax. Wounded soldiers have chest pain, dyspnea, and cyanosis. The abdominal injury may be manifested as abdominal pain, abdominal muscle tension, tenderness, and rebound tenderness as well as other peritonitis symptoms. Chest and abdomen X-ray examinations can determine the degree of pneumothorax, hemothorax, and lung collapse, and can observe whether there is free air in the abdominal cavity or abdominal content in the chest. X-ray examinations should be carried out at the bedside for soldiers with severe injuries. The findings of non-coagulating blood or air by thoracentesis indicate a blood vessel injury in the chest or lungs. Abdominocentesis or peritoneal lavage is helpful for the diagnosis of intraabdominal organ injuries [bib_ref] Ballistic thoracoabdominal injury: analysis of recent military experience in Afghanistan, Morrison [/bib_ref] [bib_ref] The routine use of sonography in penetrating torso injury is beneficial, Boulanger [/bib_ref] [bib_ref] Penetrating thoracoabdominal injuries: ongoing dilemma-which cavity and when, Asensio [/bib_ref] [bib_ref] Is non-operative approach applicable for penetrating injuries of the left thoraco-abdominal region?, Kones [/bib_ref]. The treatment principles for a combined thoracoabdominal wound include adequate respiratory support, maintenance of the water-acid-base balance, infection control, and early surgical treatment. Damage control resuscitation strategies can be used when necessary. Penetrating thoracoabdominal injuries require a laparotomy in most cases, but the decision of whether to open the chest is based on the intraoperative findings. In general, thoracic injury should be treated with closed thoracic drainage. However, if there is progressive hemothorax or continuous massive air leakage, chest exploration should be performed. The procedure sequence between laparotomy and thoracotomy should be determined by the wounded soldiers' condition. If necessary, two groups of surgeons can perform surgery at the same time. However, rapid hemostasis is the focus of surgical treatment and a thoracoabdominal combined incision should be avoided [bib_ref] Ballistic thoracoabdominal injury: analysis of recent military experience in Afghanistan, Morrison [/bib_ref] [bib_ref] Penetrating thoracoabdominal injuries: ongoing dilemma-which cavity and when, Asensio [/bib_ref]. ## Early treatment of flail chest The main treatment of the early stage of flail chest is to control and relieve pain. Based on emergency treatment, treating flail chest with towel clip traction is recommended. With advances in treatment, mandatory mechanical ventilation is generally not recommended for fixation of the flail chest wall if the soldier has no signs of respiratory failure in an early treatment facility. When wounded soldiers have signs of respiratory failure, mechanical ventilation can be used, but early weaning of the ventilation should be considered. Positive end-expiratory pressure or continuous positive pressure ventilation are generally recommended [bib_ref] Management of pulmonary contusion and flail chest: an eastern Association for the..., Simon [/bib_ref] [bib_ref] A comparative study of continuous positive airway pressure (CPAP) and intermittent positive..., Gunduz [/bib_ref]. In terms of soldiers with severe flail chest, surgical fixation of the affected ribs is recommended to facilitate early weaning of the ventilation. The affected ribs can be fixated during thoracic surgery when it is required for other reasons. There is no clinical evidence to support which type of fixation is more advantageous. In vitro experiments have shown that the mechanical effects of plate fixation are better than those of intramedullary screw fixation and wire fixation [bib_ref] Management of pulmonary contusion and flail chest: an eastern Association for the..., Simon [/bib_ref] [bib_ref] Operative fixation of rib fractures after blunt trauma: a practice management guideline..., Kasotakis [/bib_ref]. ## Behind armor blunt trauma In modern warfare, the weapons are more effective than those in previous wars. Even with significant protection from body armor, some mechanical energy can still be transferred to the body. If the bullet fails to penetrate the body armor or the helmet, the mechanism of the body injury changes to behind armor blunt trauma (BABT) [bib_ref] Behind Armour blunt trauma--an emerging problem, Cannon [/bib_ref]. The role of all types of body armor and helmets is to prevent bullets from penetrating the body and to absorb the mechanical energy of the bullet. The severity of the injury depends on the speed of the bullet, the effectiveness of the body armor, and the body contact site and area. Deformation of the body wall and the conduction of energy to internal organs can cause severe injuries and even death. BABT is a common consequence of blunt injury in the battlefield during OIF and OEF. In this case, a systematic assessment should be conducted based on the ATLS. Soldiers with the aforementioned massive thoracic hemorrhage and heart injury should be treated in early treatment facilities [bib_ref] Behind Armour blunt trauma--an emerging problem, Cannon [/bib_ref]. ## Consensus 10 Resuscitative emergency thoracotomy should be recommended for wounded soldiers with cardiac arrest and impending cardiac arrest. The left-sided incision or clamshell approach is usually used to open the chest. Then, the pleura and pericardium are opened, the injured aorta is clamped, and intrathoracic CPR is performed. If the heart resuscitation is successful, emergency procedures should be immediately prepared, and the wounded soldier should be transferred to the operating room for further surgical treatment (Class B/Category IIa). ## Consensus 11 Damage control thoracotomy should be performed in soldiers with a progressively massive hemorrhage, severe heart contusions, and severe tracheal and bronchial injuries. The anterolateral left thoracotomy approach is generally used as an initial incision. If necessary, it can be extended to become the clamshell approach. Chest injuries should be treated on a case-by-case basis (Class B/Category IIa). ## Consensus 12 Damage control thoracotomy should be performed for severe pulmonary lacerations in which thoracic closed drainage cannot relieve dyspnea or leads to continuous hemorrhage in the thorax. The surgical methods can be used according to different injury conditions, including repair, lobectomy, segmentectomy, unilateral lung resection, and hilar torsion (Class B/Category IIb). ## Consensus 13 For soldiers with a large rupture of the trachea and bronchus, if tracheotomy and closed thoracic drainage are not able to alleviate the dyspnea, surgical repair should be performed in early treatment facilities. However, if skilled thoracic surgeons are not available, wounded soldiers should be given priority to be evacuated with tracheal intubation and ventilatory support (Class C/Category IIb). ## Consensus 14 For soldiers with penetrating and blunt heart injuries, early diagnosis is required and surgical repair may provide a certain chance of survival. A history of injury in the precordial area, symptoms of tachycardia, signs of enlarged heart shadows on the chest radiograph, and ST-segment elevation in the ECG indicate the possibility of cardiac injury. Ultrasound examination of pericardial trauma can confirm the diagnosis of penetrating cardiac injury, and close monitoring of troponin levels as well as ultrasound should be helpful in improving the diagnostic success rate of blunt heart injury (Class B/Category IIb). ## Consensus 15 In the event of progressive chest hemorrhage caused by penetrating trauma of the thoracic great vessels, thoracotomy should be performed urgently to repair damaged blood vessels or vascular bypass surgery should be performed. Otherwise, wounded soldiers should be quickly evacuated for specialist treatment under close monitoring (Class C/Category IIb). ## Consensus 16 Penetrating injury near the esophagus can cause severe posterior sternal and epigastric pain, dyspnea, and cyanosis, as well as mediastinal and subcutaneous emphysema. The possibility of esophageal injury should be highly considered for wounded soldiers with these symptoms, and mediastinal or subcutaneous emphysema from the chest radiograph can assist in the diagnosis. These soldiers should be given priority for evacuation. If the estimated evacuation time is too long, the repair surgery should be performed in battlefield hospitals (Class C/Category IIb). ## Consensus 17 A combined thoracoabdominal wound is complex and has high mortality. For wounded soldiers who have a definite abdominal organ injury, abdominal damage control surgery should be performed, and the results of closed thoracic drainage can be a reference to determine whether open chest surgery is necessary (Class B/Category IIa). ## Consensus 18 In early treatment facilities, for soldiers with flail chest who have signs of respiratory failure, mechanical ventilation should be used with positive end-expiratory pressure or continuous positive pressure. For soldiers with severe flail chest, surgical fixation of the ribs is recommended to facilitate early weaning of the mechanical ventilation, and the ribs can be fixated during thoracic surgery when it is required for other reasons (Class B/ Category IIa). ## Consensus 19 With the increase in the killing effect of weapons, the incidence of BABT is increasing and may lead to serious chest injuries. Corresponding measures should be taken in the early treatment facilities according to different injury conditions (Class B/Category IIa).	None	https://mmrjournal.biomedcentral.com/track/pdf/10.1186/s40779-018-0181-6	None
feb6d84b37bbd67e59cc6eb5a70370167cdb00b4	pubmed	Chinese guidelines on management of hepatic encephalopathy in cirrhosis	Chinese guidelines on management of hepatic encephalopathy in cirrhosis ## Epidemiology At present, the main causes of liver cirrhosis in China are chronic hepatitis B and chronic hepatitis C, followed by alcohol-or drug-induced liver disease. Autoimmune liver disease, especially primary biliary cirrhosis, is gradually increasing in clinical practice. In the Yangtze River basin, schistosomiasis is also an important cause of cirrhosis. There is no marked correlation between the occurrence of MHE and the etiology, but the incidence increases with the degree of cirrhosis decompensation. Even in patients with Child-Pugh grade A cirrhosis, the incidence of MHE can be as high as 24.8%. Reports of HE associated with cirrhosis in China and other countries are not uniform, likely because clinicians use different diagnostic criteria for HE and have different perceptions of MHE. Among symptoms of decompensated cirrhosis, HE developed at an annual rate of 8% in one Japanese cohort. Most patients with cirrhosis develop a certain degree of MHE during a certain period of the disease, and MHE has an incidence of 30% to 84% over the course of cirrhosis. In recent years, Chinese researchers have conducted a multicenter study on the epidemiology of HE, including MHE. They found that approximately 40% of hospitalized cirrhosis patients have MHE. Moreover, 30% to 45% of cirrhosis patients and 10% to 50% of posttransjugular intrahepatic portosystemic shunt (TIPS) patients presented with overt hepatic encephalopathy (OHE). According to data from other countries, the HE incidence in cirrhosis patients is 30% to 45%, and the incidence may be higher during the progression of the disease. The North American Consortium for the Study of End-stage Liver Disease confirmed that HE has an independent correlation with death in cirrhosis patients . ## Pathogenesis and pathophysiology ## Pathogenesis and pathophysiology In cirrhotic portal hypertension, hepatocyte dysfunction and portosystemic shunt (i.e., the formation of collateral circulation between the portal vein and the vena cava) reduce the detoxification function, which causes the intestinal tract to absorb large amounts of toxic substances such as ammonia. Toxic substances bypassing the liver via the portal vein and directly entering systemic circulation and brain tissue are the main pathophysiological features of HE associated with cirrhosis. The pathogenesis of HE has not yet been fully elucidated. Currently, the ammonia poisoning theory is still the core; however, the roles of inflammatory mediators and other toxic substances are receiving increasing attention. Hyperammonemia: Ammonia poisoning theory is an important explanation for HE pathogenesis. Protein in the diet is decomposed by intestinal bacteria, producing ammonia, and increased permeability of the intestinal wall can lead to increased ammonia in the portal vein. Liver dysfunction prevents effective detoxification of blood ammonia through the ornithine cycle; at the same time, the portosystemic shunt causes blood containing ammonia to directly enter systemic circulation. The entry of blood ammonia into the brain tissue increases the synthesis of glutamine by astrocytes, leading to cellular degeneration, edema, and tissue degeneration that result in acute neurocognitive dysfunction. Ammonia can also directly lead to an imbalance in the ratio of excitatory and inhibitory neurotransmitters, produce clinical symptoms, and impair the autoregulation of intracranial blood flow. Neuroinflammation: It is currently believed that hyperammonemia interacts with inflammatory mediators to promote HE development. Inflammation can lead to the destruction of the blood-brain barrier, which causes toxic substances such as ammonia and inflammatory cytokines to enter the brain tissue, resulting in brain parenchymal change and brain dysfunction. At the same time, high blood ammonia can induce neutrophil dysfunction, release reactive oxygen species, and promote bodily oxidative stress production and inflammatory response, resulting in a vicious circle. Moreover, cytokines produced by the inflammatory process aggravate liver damage and increase HE incidence. In addition, HE is related to the presence of infection in the body. Studies have shown that peritonitis, urinary tract infections, pneumonia, etc. are the most common infections in cirrhosis patients . Other theories: Neurotransmitter dysfunction: When cirrhotic liver dysfunction occurs, the ability to degrade aromatic amino acids is reduced, and blood phenylalanine and tyrosine increase, thereby inhibiting normal neurotransmitter production. Increased phenylalanine and tyrosine produce the false transmitters phenylethanolamine and hydroxyphenylethanolamine, and a large number of false neurotransmitters replace normal neurotransmitters, resulting in HE. γ-aminobutyric acid is a unique neurotransmitter that is the most important inhibitory neurotransmitter in the central nervous system. It exists in the brain in the form of a complex receptor with benzodiazepine receptors. The γ-aminobutyric acid content in the blood increases in HE, as does the amount that passes the blood-brain barrier, resulting in an increase in the endogenous benzodiazepine level in the brain. Experimental studies have confirmed that drugs that activate γ-aminobutyric acid/benzodiazepine complex receptors, such as phenobarbital and diazepam, can induce or aggravate HE in cirrhotic animals and that benzodiazepine receptor antagonists such as flumazenil can be administered to reduce the onset of HE . Manganese toxicity: Some studies have found that the blood or brain manganese content of some cirrhosis patients is two to seven times higher than that of healthy people. When manganese enters human nerve cells, low-value manganese ions are oxidized into high-value manganese ions, which accumulate in the mitochondria due to the unique affinity of the mitochondria for manganese. At the same time, manganese ions can produce a large number of free radicals during valence transition, which leads to a further decrease in key enzyme activity in the mitochondrial respiratory chain of the brain cells in the substantia nigra and striatum, thus affecting the function of these brain cells . Brainstem reticular system dysfunction: The brainstem reticular systems and their substantia nigra-striatum system neuronal activity are damaged to varying degrees in severe cirrhosis patients, resulting in HE, asterixis production, and muscle tone change. The degree of brainstem reticular system damage corresponds to HE severity. ## Predisposing factors The most common predisposing factor for HE is infection (especially abdominal infections, including those of the intestines, urinary tract, and respiratory tract). The next most common factors are gastrointestinal bleeding, electrolyte and acid-base balance disorders, large amounts of ascites, high-protein diets, hypovolemia, diuresis, diarrhea, vomiting, constipation, and the use of benzodiazepine drugs and anesthetics. HE incidence is increased after TIPS in association with preoperative liver function reserve status, the presence or absence of HE history, and stent type and diameter. Studies have found that proton pump inhibitors (PPIs) may cause excessive growth of intestinal bacteria, thereby increasing the risk of HE in cirrhosis patients; this risk increases with increased drug dose and treatment course . In the presence of high blood ammonia in patients with cirrhosis, the above factors may further aggravate brain edema and oxidative stress, leading to the rapid deterioration of cognitive function. ## Clinical manifestations and diagnosis ## Clinical symptoms and signs HE manifests as a continuum from unimpaired cognitive function with intact consciousness through coma. Presently, the West-Haven criteria, which grade HE on a scale from 0 to 4, are still the most widely used standard for grading HE in China and other countries . The main drawback of the West-Haven criteria is that grading is very subjective for discriminating grade 0 (probably MHE) and grade 1. MHE is an abnormal change that is not detectable based on personality or behavior; it is characterized by normal nervous system signs but abnormal neuropsychological test results. In the clinical manifestations of grade 1 HE, signs such as euphoria, depression, or a reduced attention span are difficult to identify. Only close relatives familiar with a patient's personality notice mild abnormal changes in cognitive function, and repeatability in clinical practice and multicenter studies is poor. Recently, the ISHEN proposed the Spectrum of Neurocognitive Impairment in Cirrhosis (SONIC) grading standard, in which MHE and West-Haven grade 0 or 1 HE are labeled covert hepatic encephalopathy. If there are abnormalities falling under West-Haven classifications of HE grades 2 to 4, such as personality or behavior changes, mental abnormalities, coma, and other neurological abnormalities, the disorder is labeled OHE. It should be noted that HE grade 1 patients will have mild cognitive dysfunction and that a small number of patients who are positive for asterixis are classified as having OHE under the SONIC standard. In the past, cirrhosis patients with grade 0 HE were described as having "subclinical hepatic encephalopathy" or "early hepatic encephalopathy" or simply as patients without mental and neurological abnormalities. In 1998, the 11th World Congress of Gastroenterology unanimously adopted the term MHE. MHE is an insidious stage in the pathogenesis of HE and is defined as neuropsychological/neurophysiological abnormalities in cirrhosis patients without directional dysfunction or asterixis, in other words, with normal cognitive function . The incidence is as high as 25% to 39.9% and is unrelated to age, gender, tobacco use, or education level but has a clear relationship with the Child-Pugh grade. Although MHE has no marked clinical symptoms or signs, the clinical prognosis and quality of life are worse than those of cirrhosis patients with normal neuropsychological test results . During clinical follow-up, 56% of MHE patients develop OHE within three years, and other complications and mortality also increase markedly. After recovery from OHE, MHE may persist . Furthermore, these patients' general health-related quality of life, driving safety, work efficiency, and socioeconomic status are all significantly reduced. Some patients' MHE may progress to OHE if they are not treated effectively. Therefore, the clinical focus is on screening patients with end-stage liver diseases, such as cirrhosis, for MHE. Consequently, these guidelines use the revised grading standards for MHE and HE grades 1 to 4. Patients with marked changes in consciousness can be further evaluated and classified using the Glasgow Coma Scale score (Supplementary Annex 1). ## Blood tests Biochemical indicators: Patients' liver biochemical indicators, such as bilirubin, alanine aminotransferase, aspartate aminotransferase, albumin, prothrombin time activity, and the like should be tested for marked abnormalities. Renal function and routine blood tests are used as routine tests for suspected HE. Blood ammonia: Elevated blood ammonia has relatively high value for HE diagnosis. Multiple studies have shown that HE patients, especially those with portosystemic HE, often have elevated blood ammonia, but the level of elevation does not completely correlate with disease severity . The presence of normal blood ammonia cannot exclude HE. If a tourniquet is maintained in place for too long, if testing is carried out too long after blood collection, or if blood is transported at high temperatures, a false elevation in blood ammonia may result. Venous blood should be collected at room temperature and immediately sent for testing, and the blood should be kept at low temperatures. Testing should be completed within 30 minutes, or if blood is kept at 4 °C after centrifuging, testing should be completed within two hours. Other: Chitinase-3-like protein 1 (CHI3L1) is a member of the glycosyl hydrolase family. It can bind to chitin, but without the activity of chitinase. It plays an important role in inflammation and tissue remodeling. It is a protein secreted by the liver to the extracellular matrix. It is significantly increased in liver cirrhosis and liver fibrosis. The expression level of CHI3L1 reflects the degree of cirrhosis and liver fibrosis . Golgi protein 73 (GP73) is a type of transmembrane glycoprotein located in the Golgi apparatus. GP73 is primarily expressed in biliary epithelial cells and is rarely expressed in hepatocytes. However, in various types of advanced liver disease due to various causes, the GP73 expression level in hepatocytes is increased . Recent studies have found that elevated levels of GP73 in patients with hepatocellular carcinoma (HCC) are primarily associated with cirrhosis but not with HCC itself. ## Neuropsychological testing Neuropsychological testing is the easiest method for clinical screening and early diagnosis of MHE and grade 1 HE. Neuropsychological testing methods are recommended in many national HE guidelines as an important method for MHE screening or early diagnosis. Each test needs to be combined with other tests. Traditional pen-and-paper neuropsychological tests: The Psychometric Hepatic Encephalopathy Score (PHES) includes five subtests, namely, number connection tests (NCTs) A and B, a digit symbol test (DST), a line tracing test, and a serial dotting test (Annex 2). At present, if both the NCT-A and DST are positive or there are abnormalities in any two of the five subtests, an MHE diagnosis can be made. Although the sensitivity and specificity of the PHES are high, the results can be affected by various factors, such as age, education level, cooperation level, and the patient's learning effectiveness. Some scholars in China have adopted age-and education-corrected NCT and DST tests, which show higher accuracy and applicability . In short, the NCT and DST are simple and easily carried out and have high operability and suitability for epidemiological investigations of MHE. In recent years, computer software-assisted tools such as the electronic number connection test (eNCT) have been developed to monitor and screen for cognitive dysfunction in cirrhosis patients; these tools offer enhanced repeatability and reliability . Repeatable battery for the assessment of neuropsychological status: The repeatable battery for the assessment of neuropsychological status is one of two neuropsychological testing tools recommended by the ISHEN guidelines. Its content examines immediate memory; delayed memory; attention; and visual, spatial, and linguistic abilities. It has been used in Alzheimer's disease, schizophrenia, and traumatic brain injury and in some research on patients waiting for liver transplants, but not specifically as an HE detection tool. speed and cognitive flexibility by recording the interference response time between color fields and written color names and is considered the most effective and direct tool for examining cognitive regulation and interference control. Recently, EncephalApp, a mobile application software tool based on this test, was developed. It has better discrimination ability, is better in distinguishing known cirrhosis-related cognitive dysfunctions, and has great prospects for applicability . It should be noted that this test tool is not available for patients with color blindness. ## Stroop and encephalapp tests: the stroop test (annex 3) evaluates mental activity ## Inhibitory control test: Among cirrhosis-related neurological dysfunctions, low-level cognitive dysfunctions, such as changes in vigilance and attention, are the most sensitive indicators. The inhibitory control test (ICT) uses computer technology to display letters over a 50-ms period to test patient response inhibition, attention, and working memory, which can be useful for MHE detection. Studies have shown that the ICT's sensitivity for diagnosing MHE is as high as 88%. It is an easy way to diagnose MHE. ## Critical flicker frequency (cff) test: This test detects the minimum stimulation frequency that can cause a flicker fusion sensation. The CFF can assess cerebral nerve conduction dysfunction. The findings of this test are sensitive and specific for MHE diagnosis and easily interpreted, making it useful as an auxiliary testing method . When the threshold is 39 Hz, there is no difference between MHE patients and healthy individuals, but the difference between grade 2 HE and grade 1 is larger, making it more suitable for distinguishing grade 2 HE . Cirrhosis patients with a CFF threshold < 39 Hz have a five-year survival rate that is significantly lower than that of patients with CFF ≥ 39 Hz. Older age, CFF < 39 Hz, and Model for End-stage Liver Disease (MELD) scores are independently associated with survival during follow-up . Scan test: This is a computerized test that measures speed and accuracy when performing increasingly complex digital recognition memory tasks. The scan test was found to have predictive value for prognosis, but its clinical application is heavily influenced by educational background. New neuropsychological testing methods: This category of tools includes the animal naming test , the posture control and stability test , and multisensory integration testing . ## Neurophysiological testing Electroencephalography (EEG): EEG can show cerebral cortex function without patient cooperation and without learning effects risks. Although EEG has been widely studied and applied in clinical practice, typical EEG changes can only be detected in patients with severe HE. Therefore, this tool is not clinically useful for early HE diagnosis and is only used for auxiliary HE diagnosis. The primary EEG abnormality is a slowing rhythm, but this change is not specific to HE and is also observed in other metabolic brain diseases, such as hyponatremia and uremic encephalopathy . Evoked potential detection: Evoked potentials include visual evoked potentials, auditory evoked potentials, and somatosensory evoked potentials. Of the endogenous time-related evoked potentials, P300 has the best diagnostic sensitivity. Patients with MHE can show an increase in latency and a decrease in amplitude. The advantages of neurophysiological testing are that the results are relatively specific and have no learning effects, but the disadvantages are poor sensitivity, the need for specialized equipment and personnel, and poor consistency of results. ## Radiology evaluation Liver and brain CT: Liver-enhanced CT revascularization can indicate whether there is obvious portosystemic shunt. CT scans of the brain itself cannot be used for the diagnosis or grading of HE, but they can determine the presence of cerebral edema and exclude cerebrovascular accidents and intracranial tumors. Magnetic resonance imaging (MRI): (1) Damage or alteration of brain structure: Diffusion tensor imaging (DTI) is a new method for describing brain structure. It can show the degree and scope of damage to the white matter structure. Research shows that cirrhosis and HE patients have normal MRI findings in the white matter area, but mean diffusivity (MD) can still show a marked increase related to HE stage, blood ammonia levels, neurophysiological status, and neuropsychological changes . (2) Blood perfusion changes: Arterial spin labeling (ASL) using magnetically labeled water protons as a tracer allows the noninvasive detection of cerebral blood perfusion changes through the acquisition of cerebral blood volume, cerebral blood flow, oxygen metabolism rate, and other perfusion parameters. Studies have shown that MHE patients have a greater increase in cerebral blood flow perfusion than non-MHE patients, and this change is associated with neuropsychological scores . However, large-scale clinical verification is necessary to determine whether blood perfusion changes can be used as an MHE diagnostic marker. ## Functional mri (fmri): In recent years, great progress has been made in the use of fMRI technology to study the functional localization and pathophysiological mechanisms of brain functions, such as cognition and sensory perception. A number of scholars using resting-state fMRI studies have shown that basal-thalamocortical loops in HE patients are impaired and that changes in functional connectivity are associated with altered cognitive function in HE patients. Resting state fMRI using ReHo analysis can be used as a noninvasive method for detecting cognitive changes in patients with cirrhosis. Due to the poor prognosis of patients with MHE as well as the risk of OHE, safety risks, and high risks for other complications of cirrhotic portal hypertension, clinicians should make appropriate use of current detection techniques and methods and attach great importance to MHE screening and early diagnosis. ## Diagnosis and differential diagnosis OHE: OHE diagnosis based on clinical manifestations and signs in accordance with the West-Haven criteria is not difficult . Neuropsychological, neurophysiological, and radiological evaluations are generally unnecessary. The diagnostic points are: (1) Underlying diseases are present that cause HE, severe liver disease, and/or extensive portosystemic shunt; (2) Clinically identifiable neuropsychiatric symptoms and signs are present; (3) Other diseases that cause neuropsychiatric disorders, such as metabolic encephalopathy, toxic encephalopathy, neurological diseases (such as intracranial hemorrhage, intracranial infection and intracranial space occupation), and mental illness, are excluded; (4) Special attention should be paid to determining the cause of HE (type C or type B), such as infection, upper gastrointestinal bleeding, or a large amount of ascites; and (5) Blood ammonia is elevated. ## Mhe: Patients have no obvious manifestations of cognitive dysfunction, so it is often necessary to use special examinations to confirm this diagnosis; these special examinations are the focus of clinical attention . MHE can be diagnosed based on any one or more of the following primary diagnostic points: (1), (2), or (3) through (6). These primary diagnostic points are as follows: (1) Underlying disease causing HE, severe liver disease and/or extensive portosystemic shunt; (2) At least two abnormal traditional neuropsychological test indicators; (3) At least one abnormal result of new neuropsychological test methods (ANT, posture control and stability test, and multisensory integration test); (4) Abnormal CFF; (5) Abnormal EEG, visual evoked potential (VEP), or brainstem auditory evoked potential (BAEP); and (6) Abnormal fMRI. Differential diagnosis points: HE needs to be differentiated from the following diseases: (1) Mental disorders: When the only prominent manifestations of HE are mental symptoms, such as personality changes, abnormal behavior, or insomnia, it is easily misdiagnosed as a mental disorder. Therefore, when patients with severe liver disease or a history of portosystemic shunt present with neurological and mental abnormalities, physicians should be alert to the possibility of HE; (2) Intracranial lesions: Subarachnoid, epidural, or intracerebral hemorrhage, cerebral infarction, brain tumors, intracranial infections, epilepsy, and the like should be diagnosed using testing such as physical examinations of the nervous system or meningeal stimulation combined with CT, lumbar puncture, angiography, EEG, virological detection, and the like; (3) Other metabolic encephalopathy: Ketoacidosis, hypoglycemia, hyponatremia, renal encephalopathy, and pulmonary encephalopathy can be differentially diagnosed by performing blood biochemical analyses for characteristics corresponding to the underlying disease; (4) Wernicke encephalopathy: Patients with severe alcoholic liver disease often suffer from vitamin B 1 deficiency, and symptoms can be significantly improved after vitamin B 1 supplementation ; (5) Toxic encephalopathy: Alcoholic encephalopathy, acute poisoning, withdrawal syndrome, heavy metal (mercury, manganese, etc.) encephalopathy, and psychotropic or salicylate drug toxicity can be differentially diagnosed by reviewing the corresponding medical history and/or corresponding toxicology tests; (6) Liver cirrhosis associated with Parkinson's disease;Hepatic myelopathy: This disorder often occurs due to cirrhosis. Sympathetic pathological changes are characterized by laterally symmetrical demyelination of the cortical spinal cord. The clinical manifestation is slow, progressive, symmetrical paralysis of the limbs, including decreased muscle strength, increased muscle tone, spasticity, hyperreflexia, often pathological positive reflexes, and, in some patients, elevated blood ammonia; and (8) Acquired hepatic degeneration: This diagnosis is a rare but generally irreversible extrapyramidal syndrome caused by chronic liver disease. The manifestations include Parkinson's syndrome, ataxia, intentional tremor, chorea, dyskinesia, other mental and behavioral disorders, impaired intellect, and neuropsychological changes. fMRI has good discriminating value. Recommendation 1: HE comprises neuropsychiatric abnormalities with a wide range and scope. Using a combination of clinical manifestations, neuropsychological testing methods, and differential diagnosis, HE can be divided into MHE and HE grades 1 through 4 (C1). Recommendation 2: HE is a continuous clinical process. Based on the presence of severe liver disease, HE grades 1 through 4 can be diagnosed based on clinical manifestations. Neuropsychology, neurophysiology, and radiology evaluations are not recommended (B1). Recommendation 3: MHE is an undetectable cognitive dysfunction with normal neurological signs but abnormal neuropsychological test results. The diagnosis of MHE requires specialized neuropsychological tests or brain function imaging (B1). Recommendation 4: Currently, the traditional pen-and-paper PHES and computeraided PHES are widely used for MHE screening and diagnosis (A1). Correcting the PHES for age and education level can improve the accuracy of the MHE diagnosis (B1). Recommendation 5: MHE is common in patients with cirrhosis, especially those with Child-Pugh grade C cirrhosis and TIPS, which may affect the prognosis of patients; thus, these patients require focused screening (A1). Cirrhosis patients with high safety requirements, such as those who must drive, should be routinely screened for MHE (B1). Recommendation 6: Attention must be paid to quality control in blood ammonia testing. If a tourniquet is maintained for too long, if testing is carried out too long after blood collection, or if blood is transported at high temperatures, a false elevation in blood ammonia may result. Venous blood should be collected at room temperature and immediately sent for testing. Testing should be completed within 30 min, or if blood is kept at 4°C after centrifuging, testing should be completed within two hours (B1). Recommendation 7: Elevated blood ammonia is not an indicator of HE severity, prognosis, or grade (C1). ## He treatment HE is one of the primary causes of death in end-stage liver disease patients. Early HE identification and timely treatment are keys to improving prognosis. The treatment of HE relies on the hierarchical management of its severity. Treatment principles include the timely elimination of risk factors, recovery of acute neuropsychiatric abnormalities to baseline status, primary prevention, and secondary prevention as soon as possible . ## Eliminating mhe/he predisposing factors Clinically, more than 90% of MHE/HE cases have predisposing factors, and the elimination of MHE/HE predisposing factors is an important treatment measure. For HE patients with cirrhosis, infection is the most common predisposing factor. Actively searching for the source of infection is necessary. Even if there is no obvious infection, there is potential for an inflammatory state due to increased intestinal bacterial translocation and endotoxin levels. Antibiotic treatment can reduce this inflammatory state. Therefore, empirical antibiotic treatment should be started as soon as possible. Gastrointestinal hemorrhage is also a common predisposing factor for HE. HE is easily induced on the day of or the day after bleeding. Moreover, occult gastrointestinal hemorrhage can also induce HE. Bleeding should be stopped as soon as possible, and blood should be removed from the gastrointestinal tract. Insufficient alkalosis and electrolyte disturbances caused by excessive diuresis induce HE. When this occurs, diuretics use should be suspended, fluids and albumin should be replenished, and electrolyte imbalances (hypokalemia or hyperkalemia, hyponatremia or hypernatremia) should be corrected. For hypovolemic hyponatremia (especially in cases of blood sodium less than 110 mmol/L), intravenous saline should be administered. For patients with hypervolemic or isovolumic hyponatremia, a selective vasopressin type 2 receptor (V2) antagonist can be administered. For patients with HE grades 3 to 4, the active control of cerebral edema with 20% mannitol (250 to 1000 mL/d, 2 to 6 times/d) alone or combined with compound furosemide (40 to 80 mg/d) is recommended . ## Drug therapy Ammonia reduction treatment: High blood ammonia is an important factor in HE; therefore, it is very important to reduce ammonia production and absorption. The primary drugs for lowering blood ammonia are as follows: Lactulose: Lactulose is a disaccharide composed of galactose and fructose that does not exist in nature. It has few adverse reactions and can be administered to patients with diabetes or lactose intolerance. Lactulose is converted into a low molecular weight organic acid by the digestive flora in the colon, which causes the intestinal pH to decrease. Lactulose also increases stool volume by retaining water, which stimulates colonic peristalsis, keeping the stool smooth, relieving constipation, and exerting a cathartic effect that restores the circadian rhythm of the colon. In HE, lactulose promotes the growth of intestinal acidophilic bacteria (such as lactobacilli), inhibits proteolytic bacteria, and converts ammonia into an ionic state. Lactulose also reduces intestinal bacterial translocation and prevents spontaneous bacterial peritonitis. A number of randomized controlled clinical trials have shown that lactulose not only can improve the neuropsychological test results of MHE patients but can also improve their quality of life, prevent MHE progression, and prevent HE recurrence. The usual dose is 15 to 30 mL per oral administration, 2 to 3 times/d (dose adjusted according to patient response), and two to three soft stools per day are considered appropriate. If necessary, lactulose can be combined with retention enema treatment. Lactitol or other antihypertensive drugs can be used in lactulose intolerant patients. The effects of lactitol and lactulose with enema are similar . Lactitol: Lactitol is a disaccharide that is not absorbed by the intestines and that can cleanse and acidify the intestinal tract, reduce ammonia absorption, regulate intestinal microecology, and effectively reduce endotoxins. The efficacy of lactitol for treating HE is similar to that of lactulose. It has a rapid onset, a low incidence of abdominal distension, and low sweetness. It can be administered normally in diabetic patients. A randomized controlled clinical trial of cirrhosis patients who underwent TIPS found no statistically significant difference between the lactitol group and the lactulose group in terms of the incidence of HE and related parameters (mental state, EEG, asterixis, number connection test results, and blood ammonia) during treatment, suggesting that lactitol can effectively prevent HE onset over the long term in TIPS cirrhosis patients. The recommended initial dose is 0.6 g/kg, divided into three administrations and taken with meals. The dose can be increased or decreased to achieve the standard of two soft stools per day. L-ornithine L-aspartate (LOLA): LOLA can be administered as an alternative treatment or given to patients who do not respond to conventional therapy. The dose is 10 to 40 g/d intravenous infusion. LOLA has a therapeutic effect on OHE and MHE; it can be administered alone or combined with lactulose, and oral preparations are available. LOLA can reduce the level of ammonia by promoting the liver ornithine cycle and glutamine synthesis, which can markedly reduce fasting blood ammonia and postprandial blood ammonia, improve the HE grade and neuropsychological test results, shorten hospital stays, and improve quality of life. Rifaximin-α: Rifaximin-α is a synthetic derivative of rifamycin with a low absorption rate. In theory, orally administered antibiotics that are not absorbed by the intestinal tract can inhibit intestinal bacterial overgrowth, reduce the number of ammonia-producing bacteria, reduce the production and absorption of intestinal NH 3 , and thereby reduce HE symptoms and prevent HE occurrence. In fact, however, they have no marked effect on type B HE. Routine dose is 800 to 1200 mg/d, divided into three to four oral doses. The course of treatment is still under investigation. Other antibacterial drugs: Neomycin, metronidazole, vancomycin, paromomycin, and the like have been administered in the past but are rarely used due to side effects and poor efficacy. Microbial ecological agents: This category includes probiotics, prebiotics, and synbiotics, which can promote the growth of bacterial strains beneficial to the host and inhibit the reproduction of harmful bacteria (such as urease-producing bacteria). Moreover, these preparations can improve the nutritional status of intestinal epithelial cells and reduce intestinal mucosal permeability, thereby reducing bacterial translocation and endotoxemia and improving hyperdynamic circulation. They can also reduce hepatocyte inflammation and oxidative stress, thereby increasing ammonia clearance in the liver. A number of randomized controlled clinical trials have shown that probiotics and lactulose have similar efficacy for improving MHE test results . Other therapeutic drugs: (1) Arginine: Arginine hydrochloride contains hydrochloric acid and is acidic; consequently, it can be used to treat metabolic alkalosis with HE. During the administration process, it is important to carefully monitor blood gas testing and analysis and be alert to excessive acidosis. The efficacy of arginine hydrochloride in HE treatment is limited, and clinically, it is seldom used; (2) Glutamine: Recently, we have come to believe that glutamate can only temporarily reduce blood ammonia; it cannot pass the blood-brain barrier or reduce ammonia in brain tissue. Moreover, it can induce metabolic alkalosis and even aggravate HE. Furthermore, excessive brain glutamine produces a hyperosmotic effect and contributes to the formation of cerebral edema, which is not conducive to HE recovery. Currently, it is seldom used clinically; (3) Acarbose: Originally used to treat diabetes, the exact mechanism of acarbose in HE is unknown, but it may be related to the inhibition of α-glucosidase in the small intestine brush border. Acarbose 300 mg/d can reduce the clinical symptoms of type 2 diabetes and grades 1 to 2 HE. Side effects include abdominal pain, flatulence, and diarrhea; and (4) Elimination of Helicobacter pylori (Hp): Research shows that the incidence of Hp infection is statistically significantly higher for patients with HE or MHE than for cirrhosis patients without HE. There may be a relationship between Hp infection and HE in cirrhosis. Eradicating Hp may be beneficial for the clinical prevention and treatment of HE in liver cirrhosis . Sedative drugs: HE is associated with the upregulation of gamma-aminobutyric acid neuroinhibitory receptors and N-methyl-D-aspartate-glutamate excitatory receptors, causing imbalances between inhibitory and excitatory signals. Theoretically, the use of flumazenil, bromocriptine, levodopa, and acetylcholine esterase inhibitors is feasible. For comatose HE patients taking benzodiazepines or opioid factors, flumazenil or naloxone can be tried. There is less evidence for the efficacy of bromocriptine or levodopa in HE treatment. A recent double-blind randomized controlled trial showed that bromocriptine is effective in the treatment of cirrhosis with mild to moderate Parkinson's syndrome and is safe. However, it lacks evidence and experience in evidence-based medicine for patients in China. It is recommended to carefully evaluate before use . Naloxone: Plasma β-endorphin (β-EP) is closely related to HE occurrence. On the one hand, β-EP interferes with the ATP metabolic process in brain cells, resulting in decreased cell membrane stability and dysfunction. β-EP binds to the opioid receptors in the brain and inhibits blood circulation in the cerebral cortex; the resulting insufficient blood supply to brain tissues further aggravates brain cell dysfunction. A meta-analysis found that after HE patients were treated with LOLA combined with naloxone, their blood ammonia and total bilirubin levels were lower than those of the control group; additionally, their time to awareness upon awakening was shortened, and their NCT and DST test results improved markedly with no obvious adverse reactions. Some research shows that naloxone alone or in combination with drugs such as lactulose promotes patient awakening, but these studies had small sample sizes and some design defects . Propofol: A study comparing the clinical efficacy and adverse reactions of propofol with those of diazepam in 40 HE patients who had manic episodes showed that propofol was safer and more effective for controlling HE symptoms. Compared with midazolam, the propofol group had a shorter recovery time and faster recovery of cognitive function. Benzodiazepine sedatives: Due to high incidences of anxiety, depression, pain, and sleep cycle disturbance in cirrhosis patients, these patients often have a history of sedative-hypnotic drug or pain killer use, and these drugs can induce HE. Flumazenil is a benzodiazepine antagonist. A randomized, double-blind, controlled trial showed that flumazenil was superior to placebo, and no subjects who used flumazenil died. Serious mental disorders, such as mania, endanger the safety of others and make patients unable to cooperate with doctors. Benzodiazepine sedatives can be used, after informing patients' families of the risks, to gain initial symptomatic control. These drugs should be administered intravenously at reduced doses. Traditional Chinese medicine: Chinese medicine holds that HE is caused by liver and kidney deficiency, unhealthy influences of damp heat and pestilent toxin, combined with factors such as internal injuries, eating disorders, and alcoholism; these factors result in illness from blazing heat toxin, pericardium heat attack, excessive phlegm turbidity, and phlegm confounding the heart orifices. The urgent need is to cure the symptoms, and treatment entails refreshing the brain and clearing the phlegm. Chinese patent medicines or decoctions, such as the Angong Niuhuang pills, can be used to clear phlegm, refresh the brain, remove heat, and detoxify. Moreover, in the prevention and treatment of HE, the traditional Chinese medicine theory of "orifice opening" is widely used in accordance with the ammonia poisoning theory and the endogenous endotoxin theory of HE. The most representative treatment is a retention enema using traditional Chinese medicine decoctions such as Chengqi soup, rhubarb decoctions, rehmannia preparations, and the like. A number of clinical studies have shown that the use of rhubarb decoction retention enemas to treat HE achieves good results; they act as a laxative to promote the excretion of toxic substances from the intestines, reduce blood ammonia levels, and shorten coma time. Radical treatment of chronic disease: Fuzheng Huayu tablets (capsules), Anluo Huaxian pills and compound Biejia soft liver tablets are tonics with actions that activate the blood and reduce stasis; they have an anti-hepatic fibrosis and cirrhosis effect, improve liver function and immune function, reduce liver blood circulation disorders, and attenuate portal vein hypertension . Consequently, they may have certain value in the prevention of cirrhosis HE. Traditional Chinese medicine has certain preventive measures for HE/MHE. Many studies have shown that Chinese herbal formula has a higher effect on the cognitive and neurophysiological functions of cirrhosis patients with MHE compared with single lactulose alone. When used together, synergistic effects have been shown, but the mechanism of action of the drug is still unclear and under investigation. Some experts believe that metabolomics may help explain the mechanism of Chinese medicine for the treatment of HE patients. ## Nutritional support treatment The traditional view is that protein should be strictly limited in the diets of HE patients. In recent years, however, it has been found that 80.3% of cirrhosis patients are enterally malnourished; additionally, diets that excessively restrict protein for a long time can cause muscle group reduction, which makes HE more likely to occur. Correct assessment of the patient's nutritional status and early nutritional interventions can improve quality of life, reduce the incidence of complications, and prolong patient survival. Energy intake and pattern: Reduced liver glycogen synthesis and storage leads to increased resting energy expenditure, causing the body to produce a fasting response similar to that of a healthy body experiencing extreme hunger. Currently, the ideal daily energy intake is believed to be 35 to 40 kcal/kg . Patients should be encouraged to eat more frequent, smaller meals; distribute these small meals evenly throughout each day; and add a meal before bedtime that includes at least 50 g of complex carbohydrates so that fasting time does not exceed 3 to 6 h during the day. Chronic hyperammonemia may negatively affect attention. Cirrhotic patients had significantly lower total scores and significantly lower subscores in 4 of 7 cognitive categories, which is indicative of MHE. Patients' scores improved after breakfast consumption. Therefore, experts believe that eating breakfast can improve MHE patients' attention and function . ## Protein: The European Society of Parenteral and Enteral Nutrition's recommended daily protein intake is 1.2-1.5 g/kg to maintain nitrogen balance. The daily dietary protein intake for obese or overweight cirrhosis patients should be maintained at 2 g/kg, which is safe for HE patients. Because vegetable proteins contain less methionine and cysteine, they do not easily induce HE; additionally, vegetable proteins contain more ornithine and arginine, which can promote ammonia removal through the urea cycle. Therefore, patients with recurrent or persistent HE can consume 30 to 40 g of plant protein each day. The following principles should be applied when supplementing protein in HE patients: Patients with grade 3-4 HE should be prevented from supplementing protein intestinally. Grade 1 to 2 MHE patients and HE patients should limit protein for several days, control it at 20 g/d, and then increase it by 10-20 g every two to three days as symptoms. Plant protein is better than animal protein; intravenous albumin supplementation is safe. For chronic HE patients, measures including less food spread over more meals, gradually increasing the total protein, and individualizing the protein intake to the patient should be adopted. ## Branched chain amino acids (bcaa): Patients with grade 3-4 HE can be provided with parenteral nutrition supplements rich in BCAA (valine, leucine, and isoleucine). Although several studies have shown that BCAA do not reduce mortality in HE patients, those who can tolerate normal protein diets or long-term BCAA supplementation can benefit from long-term improvement in nutritional status. Moreover, in addition to supporting glutamine synthesis in the brain and muscles, BCAA also promote ammonia detoxification and reduce the entry of excessive aromatic amino acids into the brain . Other micronutrients: Mental symptoms caused by HE may be related to insufficient trace elements and water-soluble vitamins, especially thiamine, which can lead to elevated ammonia levels. Patients with decompensated cirrhosis or malnutrition risk can be treated with multivitamins or zinc supplements . ## Artificial liver treatment When liver failure is complicated with HE, some artificial liver models can be used to improve HE, depending on the medical treatment, and some inflammatory factors, endotoxins, blood ammonia, bilirubin, etc. can be eliminated to an extent. The artificial liver models commonly used to improve HE include blood perfusion, hemofiltration, plasma filtration dialysis, the molecular adsorbents recirculating system (MARS), the dual plasma molecular adsorption system (DPMAS), and plasma exchange combined with blood perfusion . ## Liver transplantation The therapeutic efficacy of internal medicine treatment is not ideal, and recurrent refractory HE accompanied by liver failure is an indication for liver transplantation. ## He nursing care A system of three preventions and three guards should be implemented. The "three preventions" are preventing the patient from wandering and getting lost, preventing injuries, and preventing self-harm. The "three guards" refers to bed guard rails, restraint belts (after family members sign informed consent), and table tennis gloves. It is important to closely observe HE patients' personality and behavior, mental state and awareness, and neuropsychiatric symptoms and signs for changes; monitor patients' diets, especially their daily protein intake, and carefully record their intake and excretion; observe the color, characteristics, and frequency of urine and stools; monitor vital signs, changes in coma patients' pupil size and light reflex, and sputum condition; and ensure that the intravenous infusion channel is unobstructed, and check surrounding skin conditions for extravasation, puncture points, etc. Recommendation 8: HE factors (such as infection, gastrointestinal bleeding, and electrolyte imbalance) should be actively identified and eliminated (A1). Recommendation 9: Lactulose can effectively improve the quality of life and survival rate of cirrhosis patients with HE/MHE. The recommended dose is 15 to 30 mL, 2 to 3 times/d, and two to three soft stools per day is considered appropriate (A1). Recommendation 10: Lactitol can acidify the intestinal tract, regulate intestinal microecology, reduce ammonia absorption, effectively reduce endotoxins, and improve HE/MHE clinical symptoms/indicators. The recommended initial dose is 0.6 g/kg, divided into three administrations and taken with meals (B1). Recommendation 11: Aspartate ornithine can reduce HE patients' blood ammonia levels, shorten hospital stays, and have a therapeutic effect on HE (B1). Recommendation 12: BCAA can be used as an alternative treatment or a long-term nutritional intervention (B2). Routine dose is 800 to 1200 mg/d taken orally two to four times a day (B2). Rifaximin is not recommended for type B HE (A1). Recommendation 13: Serious mental disorders, such as mania, endanger the safety of others and make patients unable to cooperate with doctors. Benzodiazepine sedatives can be used for symptom control after patients' families are informed of the risks; these sedatives should be administered intravenously at a slow rate (B1). Recommendation 14: HE patients with liver cirrhosis complicated by metabolic alkalosis can be treated with arginine hydrochloride, glutamine, and other drugs (C2). Recommendation 15: A reasonable diet and nutritional supplements (daily breakfast and moderate amounts of protein) can help improve patient quality of life and prevent MHE/HE recurrence (B1). Recommendation 16: Blood perfusion, hemofiltration, MARS, etc. can reduce blood ammonia, inflammatory factors, bilirubin, and other factors and improve clinical HE symptoms in liver failure patients (B1). Recommendation 17: Patients with recalcitrant, recurrent HE accompanied by liver failure should be prioritized for liver transplantation (B1). Recommendation 18: Chinese medicine has certain preventive actions for HE/MHE (B2). ## Prevention ## Primary prevention HE primary prevention refers to reducing the risk of developing HE when HE has not yet occurred. The goal is to prevent MHE/OHE, reduce OHE-related hospitalization, improve quality of life, and improve survival rates. In addition to closely observing the conditions of liver cirrhosis, liver failure, and post-TIPS patients for changes, regular screening for MHE should be performed using neurophysiology and neuropsychology tests, radiology evaluation, etc. Once MHE is diagnosed, immediate treatment is necessary to avoid progression to OHE. The focus of primary prevention is primary liver disease treatment and nutritional intervention. Etiological treatment can reduce liver inflammation and liver fibrosis, reduce portal vein blood pressure, and prevent or reverse cirrhosis progression, all of which are important for the prevention and control of HE and other complications. Infection, gastrointestinal bleeding, electrolyte imbalance, acid-base balance disorders, constipation, and other HE predisposing factors should be actively treated and prevented. Additional recommendations for patients include avoiding excessive ascites or diuresis, eating less and spreading energy intake over more meals, and avoiding the excessive intake of high amounts of protein. ## Secondary prevention After the first OHE episode, patients have a high risk of HE recurrence, and secondary prevention is recommended to improve quality of life and survival rates. The focus of secondary prevention is health education for patients and their families, control of elevated blood ammonia, and regulation of intestinal microecology. It is important to strengthen health education for patients and their families; inform them of the potential hazards of HE, especially MHE; and make them aware of the causes of HE. Under the guidance of a doctor, patients should rationally adjust their diet according to their degree of liver function damage and avoid high-protein diets and large one-time intakes of protein while suffering from HE. Lactulose, lactitol, and the like can be used as prophylactic drugs. Patients should be gradually guided toward self-managing their health, and family members should be instructed to carefully monitor the patients' behavior and personality for changes. Patients should be checked for declines in attention, memory, and orientation, and efforts should be made to detect HE as soon as possible to ensure early diagnosis and treatment. Recommendation 19: If there is a high risk of MHE or OHE, primary prevention is required (B1). The focus of primary prevention is targeting disease-causing factors and providing nutritional intervention (C1). Recommendation 20: After OHE is controlled, secondary prevention must be carried out (A1), and lactulose and lactitol can be used as first-line drugs (A1). Recommendation 21: The focus of secondary prevention is to provide relevant health education to patients and their families and to strengthen appropriate nutritional support, which can markedly reduce the recurrence of OHE episodes (B1). Sleep disorders and decreased attention are the earliest manifestations of OHE. Instruct family members to watch for them closely (C1). ## Problems that need to be resolved The problems that need to be resolved include use of neuroimaging, genomics biomarkers, and fMRI in HE diagnosis research and application; the study and application of serum biomarkers and new neuropsychological testing methods for the early diagnosis of MHE; and research into new HE treatment methods, including fecal transplantation for HE prevention and treatment, HE stem cell therapy, and new HE therapeutic targets.	None	None	The Chinese Society of Hepatology developed the current guidelines on the management of hepatic encephalopathy in cirrhosis based on the published evidence and the panelists’ consensus. The guidelines provided recommendations for the diagnosis and management of hepatic encephalopathy (HE) including minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy, emphasizing the importance on screening MHE in patients with end-stage liver diseases. The guidelines emphasized that early identification and timely treatment are the key to improve the prognosis of HE. The principles of treatment include prompt removal of the cause, recovery of acute neuropsychiatric abnormalities to baseline status, primary prevention, and secondary prevention as soon as possible.
6cba6c2c72f8b50113d9767bf11b83671b334160	pubmed	Inflammatory bowel disease management during the COVID-19 outbreak: The 10 do's and don'ts from the ECCO-COVID Taskforce	Inflammatory bowel disease management during the COVID-19 outbreak: The 10 do's and don'ts from the ECCO-COVID Taskforce Conflict of InterestECCO has diligently maintained a disclosure policy of potential conflicts of interests. The conflict of interest declaration is based on a form used by the International Committee of Medical Journal Editors. The conflict of interest statement is not only stored at the ECCO Office and the editorial office of Journal of Crohn's and Colitis, but also open to public scrutiny on the ECCO website [https://www.ecco-ibd.eu/about-ecco/eccodisclosures.html] providing a comprehensive overview of potential conflicts of interest of authors.AbstractOur knowledge on COVID-19 is changing and evolving rapidly, with novel insights and recommendations, almost on a daily basis. It behooves the medical community to provide updated information on a regular basis, on best practice to facilitate optimal care of infected patients and appropriate advice for the general population. This is particularly important in the case of patients with chronic conditions, such as Inflammatory Bowel Disease (IBD).In this paper, we compiled the existing evidence on the impact of COVID-19 in IBD patients and provide guidance and on the most appropriate care to adopt during the pandemic. Our review highlighted that IBD, per se, is not a risk factor for COVID-19.However, all IBD patients with symptoms should be tested for SARS-CoV-2 and the procedures for disease management shall be carefully adapted: i) in SARS-CoV-2 positive IBD patients, medical treatments should be re-evaluated (with particular focus on corticosteroids) always with the purpose of treating active disease and maintaining remission; ii) non-urgent surgeries and endoscopic procedures should be postponed for all patients; iii) online consultancy should be implemented; and iv) hospitalization and surgery should be limited to life threatening situations. # Introduction At the end of 2019, a cluster of patients with pneumonia emerged in Wuhan, Hubei Province, China, with possible zoonotic origin. [bib_ref] Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia, Li [/bib_ref] This unidentified pneumonia was later found to be related to a novel coronavirus (CoV) 2 named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), by the International Committee on Taxonomy of Viruses (ICTV).To prevent the use of inaccurate or stigmatizing names, the World Health Organization (WHO) proposed a standard format for the disease nomenclature: COronaVIrus Disease-2019 .SARS-CoV-2 is a single positive-stranded RNA virus enveloped in a lipid bilayer. The virus sneaks into the human body via the mucous membranes (mouth, nasal, ocular) and enters host cells through the binding of viral spike proteins (S-protein) to the human protein receptor angiotensin converting enzyme-2 (ACE2). [bib_ref] A novel coronavirus outbreak of global health concern, Wang [/bib_ref] This receptor is abundant in lung, heart, kidney, adipose tissue, esophagus, stomach, bladder, ileum, and colon. [bib_ref] ACE2: from vasopeptidase to SARS virus receptor, Turner [/bib_ref] [bib_ref] Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential..., Zou [/bib_ref] Transmission of COVID-19 is efficient. Aerosol and fomite transmission of SARS-CoV-2 is plausible, since the virus can remain viable and infectious in aerosols for hours, and on surfaces up to days (depending on the inoculum shed). In fact, the concentration of viral RNA in airborne samples is minimal or close to zero, but it can be detected on fomites including plastic. [bib_ref] Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1, Van Doremalen [/bib_ref] Transmission occurs from close contact and respiratory droplets, without evidence of airborne transfer [bib_ref] Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1, Van Doremalen [/bib_ref]. Thus, people who are in close contact with patients, their family members or healthcare workers are part of the high-risk population. [bib_ref] Pathogenesis, and Control of COVID-19, Jin [/bib_ref] The spread of SARS-CoV-2 identifed two important modes of disease transmission: i) local transmission, at each local epicenter; and ii) transmission via international travelers which favored the global spread of the infection, fueling COVID-19 pandemic. Large outbreaks were reported in closed communities and hospitals, raising the possibility of 'superspreading' events, as reported before in previous CoV outbreaks. [bib_ref] The daily impact of COVID-19 in gastroenterology, Magro [/bib_ref] By May 2020, M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa160 the pandemic had affected almost 2 million people, worldwide, accounting for over 125,000 deaths, with the numbers rising sharply (Worldometer's COVID-19 data).SARS-CoV-2 infection is associated with five different clinical courses: asymptomatic infection, mild to medium cases, severe cases, critical cases and death. [bib_ref] Pathogenesis, and Control of COVID-19, Jin [/bib_ref] While highly transmissible, more than 80% of the patients have mild disease. [bib_ref] Management of IBD during the COVID-19 outbreak: resetting clinical priorities, Danese [/bib_ref] In the face of these challenging circumstances, gastroenterologists need to adapt priorities, reset standards of quality of care, and guide patients by providing relevant information. In this context, the European Crohn's and Colitis Organization (ECCO) gathered a group of gastroenterologists, with particular interest in opportunistic infections, and infectious disease experts, to deliver guidance to physicians in the setting of gastrointestinal (GI) diseases during COVID-19 pandemic. The aim of the current paper is to provide health care professionals with understanding and knowledge of the optimal care we can provide to our patients, including those taking immunomodulatory treatment. According to and to the European Centre for Disease Prevention and Control (ECDC), social distancing, hand hygiene and respiratory etiquette should be adopted by all the population to prevent the spread of the infection. Hand hygiene is considered to be ## 1-general measures Do's  Do avoid contact with infected people  Do avoid touching eyes, nose or mouth with unwashed hands  Do clean hands using soap and water or an alcohol-based solution  Do avoid crowded places  Do use face masks according to local policies  Do ensure flu vaccine for all non-vaccinated IBD patients  Do ensure pneumococcal vaccination for all non-vaccinated IBD patients  Do discourage travelling M a n u s c r i p t Such measures include routine cleaning of frequently used surfaces and objects (phones, tablets, keyboards), and minimizing the sharing of objects 17 (ECDC). Surgical masks may be used as an infection control measure or as a mitigation measure, in community settings, when used by individuals with respiratory symptoms but that did not seek medical attention yet. People at high risk of exposure include care providers with extensive face-to-face contact. A recent meta-analysis on influenza prevention suggested that N95 respirators should not be recommended to general public and low risk medical staff. [bib_ref] Effectiveness of N95 respirators versus surgical masks against influenza: A systematic review..., Long [/bib_ref] Travelling should be limited, for everyone, as much as possible, with the aim of reducing: i) acquisition of infection by travelers to areas or countries where community transmission is ongoing; ii) importation of cases from affected countries; and iii) transmission among travelers. Patients with IBD, taking immunomodulatory therapy, have increased risk of influenza and pneumococcal disease. [bib_ref] Increased Risk of Influenza and Influenza-Related Complications Among 140,480 Patients With Inflammatory..., Tinsley [/bib_ref] [bib_ref] Inflammatory Bowel Disease Patients Are at Increased Risk of Invasive Pneumococcal Disease:..., Kantsø [/bib_ref] To avoid pulmonary comorbidities with influenza and pneumococcal disease during this outbreak, and next winter, all IBD patients should be vaccinated. Influenza and pneumococcal vaccination are recommended for the majority of patients with immune mediated disorders, including IBD. [bib_ref] Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic..., Rahier [/bib_ref] Since influenza infection rates can be reduced by annual vaccination, flu vaccine is recommended in all non-vaccinated IBD patients, and especially during COVID-19 pandemic. Although not numerous, some cases of influenza coinfection with SARS-CoV-2 have been described. [bib_ref] The clinical characteristics of pneumonia patients coinfected with 2019 novel coronavirus and..., Ding [/bib_ref] [bib_ref] Paniz Mondolfi AE. Co-infection in SARS-CoV-2 infected Patients: Where Are Influenza Virus..., Nowak [/bib_ref] During the next seasonal outbreak, SARS-CoV-2 and influenza are likely to occur simultaneously. Patients who have not been previously vaccinated for Streptococcus pneumoniae, should receive a dose of PCV13 followed by a dose of PPSV23, at least 8 weeks later. [bib_ref] Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among..., Matanock [/bib_ref] So far, IBD patients have not shown increased susceptibility to COVID-19 [bib_ref] Incidence and patterns of COVID-19 among inflammatory bowel disease patients from the..., Allocca [/bib_ref] [bib_ref] Prevention of COVID-19 in patients with inflammatory bowel disease in Wuhan, China, An [/bib_ref]. This is clearly evidenced in very recent studies, in Spanish, French and Italian IBD cohorts studied, in which the risk of infection, associated mortality and incidence of COVID-19 were similar to those reported for the general population. [bib_ref] Incidence and patterns of COVID-19 among inflammatory bowel disease patients from the..., Allocca [/bib_ref] A recent study from Wuhan, performed during the local outbreak of the disease, including 318 patients with IBD, did not report a single COVID-19 case. [bib_ref] Prevention of COVID-19 in patients with inflammatory bowel disease in Wuhan, China, An [/bib_ref] However, all biological and immunomodulatory treatments were discontinued rendering interpretation difficult. [bib_ref] Inflammatory bowel diseases and COVID-19: the invisible enemy, D'amico [/bib_ref] The therapeutic approach for these patients should instead consider the risk of viral infection weighed against the risk 2-Should we stop drugs in patients without symptoms suggestive of COVID-19 (not tested or tested negative)? Do's  Do continue immunomodulators  Do continue biologics  Do continue JAK inhibitors  Do reduce corticosteroids whenever possible  Do keep infusions in an infusion center whenever possible Don'ts  Don't reduce the dose of immunomodulators or biologics to prevent SARS-CoV-2 infection  Don't switch infliximab to adalimumab in a stable patient, unless it is not possible to provide intravenous infusions  Don´t assume that IBD patients are at increased risk of being infected Don't Know  Patients with IBD, who are exposed to SARS-CoV-2, have a higher risk of developing symptomatic or severe COVID-19 M a n u s c r i p t immunomodulators, anti-TNF therapy, anti-integrins and anti-Il12/23 were not associated with increased mortality.Therefore, in balance, we believe that immunomodulatory drugs should be maintained in IBD patients without COVID-19 infection. There are biological reasons to support why COVID-19 may not pose increased risk to IBD patients on immunomodulatory therapy. First, it has been suggested that the soluble form of ACE2 acts as a competitive binding partner for SARS-CoV-2 sequestring the virus, hindering binding to the virus's cell surface receptor, the full-length ACE2 protein. [bib_ref] COVID-19 spike-host cell receptor GRP78 binding site prediction, Ibrahim [/bib_ref] [bib_ref] Covid-19 and immunomodulation in IBD, Neurath [/bib_ref] Elevated levels of ACE2 were measured in the plasma from patients with IBD 36 with evidence of limited infection progression and low susceptibility to infection. [bib_ref] Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy?, Batlle [/bib_ref] The role of A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa160 ACE2 was also evidenced through the use of a chemical inhibitor of ACE2 (GL1001), that was able to reduce dextran sulfate sodium (DSS) colitis severity, in the mouse model, suggesting that ACE2 plays a pathogenic role in colitis. [bib_ref] Covid-19 and immunomodulation in IBD, Neurath [/bib_ref] Second, tumor necrosis factor (TNF) inhibitors might be effective in reducing organ damage.This effect is achieved through the decreased shedding of the ACE2 ectodomain (mediated by TNF-α-converting enzyme) which is essential for the penetration of SARS-CoV-2 into the cell. Third, as IFNγ and TNF production has been associated with severe SARS-CoV infection, inhibition of TNF has been proposed as a treatment for the cytokine release syndrome that can occur in some of these patients. [bib_ref] Cell Responses to Whole SARS Coronavirus in Humans, Li [/bib_ref] Fourth, mercaptopurine and 6-thioguanine have potential antiviral activity against MERS and SARS, at least in vitro. [bib_ref] Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle..., Cheng [/bib_ref] Fifth, tacrolimus is a potent in vitro antiviral for human coronaviruses. [bib_ref] Human coronavirus NL63 replication is cyclophilin A-dependent and inhibited by non-immunosuppressive cyclosporine..., Carbajo-Lozoya [/bib_ref] Sixth, most of the drugs used in IBD have a long elimination half-life and keep some activity even after treatment cessation. [bib_ref] Management of Patients with Crohn's Disease and Ulcerative Colitis During the COVID-19..., Rubin [/bib_ref] Seventh, viral infections did not increase among IBD patients receiving ustekinumab and vedolizumab therapy. In addition, in a phase I clinical trial, the viral load of HIV patients on vedolizumab did not change significantly. In conclusion, the available data suggest that immunosuppressed patients are not at increased risk for severe disease and complications, compared with the general population. In circumstances where it is not possible to safely run an infusion service, it may be reasonable to consider switching to sub-cutaneous alternatives. However, this practice must be used judiciously since elective switching from infliximab to adalimumab is associated with a loss of tolerance and efficacy within 1 year. [bib_ref] Switch to adalimumab in patients with Crohn's disease controlled by maintenance infliximab:..., Van Assche [/bib_ref] A c c e p t e d M a n u s c r i p t M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa160 admission (19%) and death (11%); although this data is currently unadjusted for age or comorbidity.Concerning SARS-CoV-2 infection, steroids were not effective for the treatment of lung injury or shock. [bib_ref] Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury, Russell [/bib_ref] However, short-term steroids (≤ 0.5-1 mg/kg for 7 days) may be beneficial to control overwhelming inflammation and cytokine-related lung injury, particularly in severe forms of ARDS. [bib_ref] Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia, Zhou [/bib_ref] [bib_ref] On the use of corticosteroids for 2019-nCoV pneumonia, Shang [/bib_ref] [bib_ref] Surviving Sepsis Campaign: guidelines on the management of critically ill adults with..., Alhazzani [/bib_ref] Data on low-dose and short-term steroids, budesonide and beclomethasone therapy are not currently available. The first analysis of the SECURE-IBD data also identified 5-ASAs as a risk for severe VZV, HSV), mostly in patients exposed to thiopurines.This can be related to the ability of azathioprine/6-mercaptopurine and tofacitinib to reduce the number of activated T cells and affect T-cell activation and effector function. [bib_ref] Covid-19 and immunomodulation in IBD, Neurath [/bib_ref] Tofacitinib has also been associated with viral infections (VZV) [bib_ref] A Phase 2 Study of Tofacitinib, an Oral Janus Kinase Inhibitor, in..., Sandborn [/bib_ref] and demonstrated inhibition of interferon-α production in vitro. [bib_ref] JAK-inhibitor tofacitinib suppresses interferon alfa production by plasmacytoid dendritic cells and inhibits..., Boor [/bib_ref] The decision to pharmacologically immunosuppress a patient with COVID-19 remains difficult. The possible beneficial effects in reducing inflammation should be carefully weighed against the potential deleterious impairment of anti-microbial immunity. A c c e p t e d M a n u s c r i p t The maximal viral shedding of SARS-CoV-2 occurs in the early stages of infection, meaning that spreading from asymptomatic patients is a reality. In hospitals and clinics caring for a large number of COVID-19 patients, the rate of infection is high among health ## 5-how can we continue iv infusion clinics? Do's  Do implement screening procedures for suspected COVID-19 in all patients  Do implement measures to minimize crowding  Do implement at least 2m distance between chairs  Do impose the use of surgical face masks in all patients  Do continue biologics at regular intervals and doses Don'ts  Don't switch infliximab to adalimumab in stable patients unless it is not possible to provide intravenous infusions  Don't allow accompanying persons inside the hospital workers. [bib_ref] Clinical characteristics of 80 hospitalized frontline medical workers infected with COVID-19 in..., Wang [/bib_ref] In IV infusion clinics, the first measure is to identify the patients who are possibly infected, since the approach and safety requirements will be different. Thus, symptomatic (fever, cough, fatigue, myalgia, expectoration, diarrhea, and loss of sense of smell or taste) or suspected (contact with a positive person) patients should be promptly tested and submitted to protective measures. The use of masks, in patients attending hospitals, is highly recommended, even in those without symptoms.populations. In fact, faecal calprotectin levels showed a significant correlation with endoscopic extent, mucosal healing, and histological activity. [bib_ref] Review article: faecal calprotectin and histologic remission in ulcerative colitis, D'amico [/bib_ref] [bib_ref] Accuracy of Faecal Calprotectin and Neutrophil Gelatinase B-associated Lipocalin in Evaluating Subclinical..., Magro [/bib_ref] Moreover, non-invasive imaging, such as ultrasonography, is essential for diagnosis and monitoring because it is a low risk procedure with the advantage of providing a rapid assessment of disease activity (location, extension, inflammation, and presence of complications like fistula, strictures or intrabdominal abscesses). [bib_ref] Endoscopy in inflammatory bowel diseases during the COVID-19 pandemic and post-pandemic period, Iacucci [/bib_ref] A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa160 In the case of patients enrolled in clinical trials before the outbreak, the sponsors can be asked to: i) postpone non-necessary follow-up visits or to replace them by virtual clinics; ii) identify local labs that can guarantee the regular lab tests required by the protocol; iii) manage home delivery of study drugs, mainly those of oral and subcutaneous administration. In this scenario, patients would go to the hospital only for key visits (end of induction, re-randomization, end of study) and to receive intravenous drugs, when these cannot be suspended. The administration of intravenous drugs can also be adapted, mainly regarding dose intervals. For instance, infliximab administration can be postponed to every 10 weeks. [bib_ref] De-escalation of Infliximab Maintenance Therapy from 8-to 10-week Dosing Interval Based on..., Papamichael [/bib_ref] Regarding vedolizumab, the GEMINI trial showed that patients randomized to placebo can maintain remission up to week 24. Therefore, postponing vedolizumab 4-8 weeks may be reasonable. However, maintaining the original schedule remains the best strategy in most cases. IBD patients on immunomodulators do not seem to have a higher risk of infection than the rest of the population. However, due to disease specificities and possible side effects of the treatment, avoidance of SARS-CoV-2 requires an additional set of precautions. Thus, patients should take extra protective measures, over and above those of the general population. Some societies use the concept of "stringent social distancing" and "shielding", with measures ranging from avoidance of crowded places to advice to not leave the house Endoscopy should be performed in a negative-pressure room, if possible, in accordance with the guidelines for infection control in endoscopy. [bib_ref] Reprocessing of flexible endoscopes and endoscopic accessories used in gastrointestinal endoscopy: Position..., Beilenhoff [/bib_ref] [bib_ref] ASGE guideline for infection control during GI endoscopy, Calderwood [/bib_ref] In addition, the staff of the endoscopy department should follow standardized precautions. 12 SARS-CoV-2 is easily inactivated by many common disinfectants and no additional approach should be implemented to clean and disinfect the endoscope. [bib_ref] Human Coronaviruses: Insights into Environmental Resistance and Its Influence on the Development..., Geller [/bib_ref] Even so, due to the risk of aerosolization, the room should be kept empty for at least for 1 hour before the next procedure in the absence of negative pressure, and for 30 minutes in the case of a negative-pressure room. [bib_ref] COVID-19) outbreak: what the department of endoscopy should know, Repici [/bib_ref] The basic protection requirements of the medical staff, in the endoscopy centre, should reach Biosafety level 2 (wearing of disposable gowns, N95 A c c e p t e d M a n u s c r i p t Emergency surgery is required in life-threatening situations, such as bowel perforation, closed loop, or medically refractory acute severe colitis. Conversely, non-urgent surgery should be postponed to protect patients and healthcare workers, and facilitate the management of healthcare resources, in times of scarcity of staff and material. [bib_ref] Global guidance for surgical care during the COVID-19 pandemic, Covids [/bib_ref] [bib_ref] Managing COVID-19 in Surgical Systems, Brindle [/bib_ref] Non-elective surgery is indicated for invasive colorectal cancer/high-grade dysplasia, intractable stenosis, and abdominal/perianal abscesses not amenable to medical/interventional management. [bib_ref] International Organization for the Study of Inflammatory Bowel Disease Recommendations for Surgery..., Remzi [/bib_ref] Perioperative complexity should be minimized, including liberal use of terminal ostomy instead of a high-risk anastomosis, and drainage procedures, with or without antibiotics, instead of complex surgery. [bib_ref] International Organization for the Study of Inflammatory Bowel Disease Recommendations for Surgery..., Remzi [/bib_ref] Keeping track of deferred surgeries is the key to provide responsible surgical care after the pandemic. Owing to the paucity of symptoms in the majority of COVID-19-positive patients and to the surgical morbidity reported during viral incubation (mortality 20.5%, ICU requirement ## 10-can we still perform ibd surgery? Do's  Do emergency surgery in life-threatening situations  free bowel perforation  closed loop obstruction  acute severe colitis refractory to medical treatment  active bleeding not amenable to interventional therapy  Do non-elective surgery as soon as possible  invasive colorectal cancer, high-grade dysplasia  intractable stenosis failing medical management  penetrating luminal disease resistant to medical therapy  perianal abscesses  Do postpone surgery in uncomplicated IBD  Do test all IBD patients with SARS-CoV-2-PCR before any surgery  Do use N95 respirators as a minimal requirement for surgery Don'ts  Don't perform non-urgent IBD surgery A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjaa160 44.1%), it is mandatory to test all patients for SARS-CoV-2 before surgery. [bib_ref] COVID-19 Outbreak and Surgical Practice, Aminian [/bib_ref] When rapid PCR tests are unavailable, chest CT can be the diagnostic. If neither testing nor imaging is available, all patients must be considered positive. [bib_ref] International Organization for the Study of Inflammatory Bowel Disease Recommendations for Surgery..., Remzi [/bib_ref] At surgery, the risk of aerosolization is high and contamination with body fluids is a concern. 93 To date, infectious virus was found in airway, blood, and feces.Aerosol formation is potentiated by tissue dissection with energy devices, while concentration of abdominal aerosol is inherent to laparoscopy. [bib_ref] Protecting Surgical Teams During the COVID-19 Outbreak, Brat [/bib_ref] [bib_ref] COVID-19 & the General Surgical Department -Measures to Reduce Spread of SARS-COV-2..., Yeo [/bib_ref] [bib_ref] Minimally Invasive Surgery and the Novel Coronavirus Outbreak: Lessons Learned in China..., Zheng [/bib_ref] Consequent use of PPE is mandatory, including face shield/googles, N95 mask, and proper donning and doffing. [bib_ref] Protecting Surgical Teams During the COVID-19 Outbreak, Brat [/bib_ref] The number of staff should be minimized and negative pressure operating rooms should be preferred. Scientific societies have issued conflicting statements regarding the use of laparoscopy, with no firm contraindication in the COVID-19 era. Avoidance of laparoscopy is thus debatable, as open surgery will translate in additional morbidity and resource utilization. Low energy setting and pneumoperitoneum pressure, avoidance of 2-way insufflators, closed circulation with efficient filtration of pneumoperitoneum, and gentle desufflation are advised. [bib_ref] What Is the Appropriate Use of Laparoscopy over Open Procedures in the..., Vigneswaran [/bib_ref] # Conclusions In conclusion, the existing evidence shows that IBD is not a risk factor for COVID-19. However, medical treatments should be re-evaluated in SARS-CoV-2 positive IBD patients and corticosteroid therapy should be re-evaluated regardless of symptoms. A goal should be to treat active disease and maintain remission, while adopting the same protective measures as the general population. In addition, non-urgent surgeries and endoscopic procedures should be postponed. A c c e p t e d M a n u s c r i p t [fig] 6 -: Do patients need specific protective equipment? Do physicians need specific equipment when seeing IBD patients? Do's  Do avoid close contact with people and wash hands frequently  Do use face masks (patient and physician) Don'ts  Don't see patients with accompanying persons unless strictly necessary7-How to manage outpatient IBD clinics?Do's  Do implement telemedicine  Do monitor at distance  Do web report outcomes  Do promote local labs with e-mail reports  Do implement point-of-care biomarkers  Do implement calprotectin measurement at home  Do implement measure of drug levels (TDM) with rapid tests  Do cross sectional imaging, including intestinal ultrasound instead of invasive procedures Don'ts  Don't hospitalize patients unless strictly necessary  Don't schedule unnecessary appointments, limit to what is strictly decision-making [/fig] [fig] 8 -: Can IBD patients on immunomodulator/biological treatment continue working? What about Health Care professionals with IBD? Do's  Do avoid contact with infected patients  Do use masks when working  Do redirect towards the lowest risk zones  Favor teleworking when possible not rare to find IBD patients working in health care systems. Considering that this population experiences higher rates of infections than general population, it may be necessary to introduce extra precautions in health care workers with IBD. If possible, these professionals should be redirected from high risk areas (like emergency departments, infectious disease units, and intensive care units) to low risk areas and, when possible, working from home should be implemented. Protective Personal Equipment (PPE) should be used according to international guidelines, when homeworking is not viable. 9-Can we perform non-urgent endoscopy? If not, what is non-urgent endoscopy? Do's  Do perform endoscopy as priority 3 months after the infection rates decrease  IBD patients with mild-moderate flare-up confirmed by biomarkers, to exclude CMV infection  Longstanding IBD in surveillance for CRC, if prior dysplasia  Endoscopic resection in IBD patients known to have LGD/HGD colonic lesions already detected  Do perform endoscopy within 3-6 months after the infection rates decrease  Pouchitis  IBD patients with flare-up not confirmed by biomarkers  Longstanding IBD in surveillance for CRC Dont's  Don't perform non-urgent endoscopy  Don't use surgical masks in the endoscopy room [/fig]	None	https://academic.oup.com/ecco-jcc/article-pdf/14/Supplement_3/S798/36940671/jjaa160.pdf	Abstract Our knowledge on COVID-19 is changing and evolving rapidly, with novel insights and recommendations, almost on a daily basis. It behooves the medical community to provide updated information on a regular basis, on best practice to facilitate optimal care of infected patients and appropriate advice for the general population. This is particularly important in the case of patients with chronic conditions, such as Inflammatory Bowel Disease (IBD). In this paper, we compiled the existing evidence on the impact of COVID-19 in IBD patients and provide guidance and on the most appropriate care to adopt during the pandemic. Our review highlighted that IBD, per se, is not a risk factor for COVID-19. However, all IBD patients with symptoms should be tested for SARS-CoV-2 and the procedures for disease management shall be carefully adapted: i) in SARS-CoV-2 positive IBD patients, medical treatments should be re-evaluated (with particular focus on corticosteroids) always with the purpose of treating active disease and maintaining remission; ii) non-urgent surgeries and endoscopic procedures should be postponed for all patients; iii) online consultancy should be implemented; and iv) hospitalization and surgery should be limited to life threatening situations
db3328aa604d8a327a2eaa41fbb0797e6151127a	pubmed	SEOM clinical guideline in ovarian cancer (2020)	SEOM clinical guideline in ovarian cancer (2020) Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinumbased chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice. # Introduction Epithelial ovarian cancer (OC) remains the 5th cause of death in women and the first cause of death due to gynecological cancer. In the last two decades, we have assisted to achievements in the knowledge of molecular biology, surgical outcome, chemotherapy administration, and 1 3 implementation of antiangiogenic therapy that have translated into clinically significant improvements in the time of disease control and overall survival in some cases. More recently, the incorporation of Poly ADP Ribose Polymerase (PARP) inhibitors as maintenance after response to platinum-based chemotherapy seems to start changing the natural history of the disease and the aim of decreasing the mortality is becoming a reality. This SEOM guideline is providing updated evidence-based recommendation for the current treatment of ovarian, primary peritoneal and fallopian tube cancer, globally considered as OC along the guideline. # Methodology This guideline has been developed with the consensus of ten oncologists, with high expertise in OC treatment, from the cooperative group GEICO (Spanish Group for Investigation in Ovarian Cancer) and SEOM (Spanish Society of Medical Oncology). To assign a level and quality of evidence and a grade of recommendation to the different statements of this treatment guideline, the Infectious Diseases Society of America-US Public Health Service Grading System for Ranking Recommendations in Clinical Guidelines was used. ## Diagnosis and staging Early-stage OC is frequently associated to non-specific symptoms, but in late-stages ascites, abdominal disorders and/or pleural effusion are common. In women with symptoms suggestive of OC, physical examination, laboratory testing with CA 125 and pelvic ultrasonography are recommended at a first level [II, A]. High levels of HE4 identify malignancy with a similar sensitivity than CA 125, but with higher specificity. Both CA 125 and HE4 are included in the Risk Ovarian Malignancy Algorithm (ROMA), used for calculating the risk of malignancy of adnexal masses. In patients with presumed OC, computed tomography (CT) imaging of the thorax, abdomen and pelvis will define the extent of the disease and provide information to plan treatment options [II, A]. Magnetic resonance imaging (MRI) and Positron Emission Tomography (PET)-CT are not included in the routine preoperative staging but could improve the accuracy of the evaluation of the advanced disease . Laparoscopic surgery is a mainstay not only in staging of OC but also in pathological diagnosis . FIGO 2014 is the staging system currently recommended [bib_ref] Staging classification for cancer of the ovary, fallopian tube, and peritoneum, Prat [/bib_ref] [fig_ref] Table 1 2014: FIGO staging system for ovarian, fallopian tube, and peritoneal cancer 1 [/fig_ref]. Tumour limited to one or both ovaries or fallopian tubes, with capsule ruptured before surgery or tumour on ovarian or fallopian tube surface IC3 Tumour limited to one or both ovaries or fallopian tubes, with malignant cells in the ascites or peritoneal washings Stage II Tumour involves one or both ovaries or fallopian tubes with pelvic extension or primary peritoneal cancer IIA Extension and/or implants on uterus and/or fallopian tubes and/or ovaries IIB Extension to other pelvic intraperitoneal tissues Stage III Tumour involves one or both ovaries or fallopian tubes, or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes IIIA1 Positive retroperitoneal lymph nodes only (cytologically or histologically proven) IIIA1(i) Metastasis up to 10 mm IIIA1(ii) Metastasis more than 10 mm IIIA2 Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes IIIB Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes IIIC Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumour to capsule of liver and spleen without parenchymal involvement of either organ) Stage IV Distant metastasis excluding peritoneal metastases IVA Pleural effusion with positive cytology IVB Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity) ## Pathology and biomarkers According to the WHO classification, there are five major subtypes of epithelial ovarian carcinoma: high-grade serous (HGSC), low-grade serous (LGSC), clear cell (CCC), endometrioid (EC), and mucinous (MC). The use of an immunohistochemical (IHC) panel including Wilms Tumor 1 (WT1), p53, progesterone receptor (PR), and Napsin A (NAPSA) has been suggested to assist in the diagnosis of cases in which the histological type is difficult to establish [bib_ref] An immunohistochemical algorithm for ovarian carcinoma typing, Kobel [/bib_ref] [II, A]. The OC subtypes differ not only in IHC expression but also in molecular features ( ## Early stages ## Surgery The treatment for early-stage OC (stages I-II) consists of a staging surgery that includes hysterectomy with bilateral salpingo-oophorectomy, bilateral pelvic and para-aortic lymphadenectomy, omentectomy, random peritoneal biopsies, peritoneal washing, and careful inspection and palpation of all peritoneal surfaces, the serosa of the entire digestive tract and the bowel mesentery ## Adjuvant treatment Adjuvant platinum-based chemotherapy after staging surgery is indicated in high-risk early stages (IA/B high grade, IC-IIA) [I, A]. The benefit is uncertain and should be discussed on individually in: Grade 1-2 EC stage IB/IC, MC with expansile invasion stage IB/IC, MC with infiltrative invasion stage IA, LGSC stage IB/IC, and CCC stage IA-IC1 [bib_ref] ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early..., Colombo [/bib_ref]. The recommended regimen is paclitaxel-carboplatin, but single-agent carboplatin is also considered a reasonable option [I, A]. 6-cycle regimen is recommended in HGSC, but the optimal duration remains controversial in the rest of histologic subtypes, in which three cycles can be accepted [bib_ref] ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early..., Colombo [/bib_ref] [I, A]. ## Advanced disease: front-line treatment ## Cytoreductive surgery Cytoreductive surgery plays a crucial role in the treatment of advanced OC (stages III and IV). The presence of visible residual disease after cytoreduction is a major prognostic factor with an important negative impact on survival. Thus, the goal must be to obtain a complete cytoreduction [II, A]. In this context surgical effort must be maximal and may include histerectomy, double anexectomy, omentectomy, extensive peritonectomy, bowel resection or excision of any enlarge nodes. Due to the recent results of Lion trial lymphadenectomy in primary completely debulked advanced OC with clinically negative lymph nodes is not further recommended [bib_ref] A randomized trial of lymphadenectomy in patients with advanced ovarian neoplasms, Harter [/bib_ref] [I, A]. Several studies and meta-analysis suggest that the expertise of the surgeon is of utmost importance in the outcomes and thus the recommendation is that patients should be operated in highly experienced centers [bib_ref] Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian..., Bois [/bib_ref] [II, A]. ## Neoadjuvant chemotherapy The EORTC55971 trial and the CHORUS trial showed a similar progression-free survival (PFS) and overall survival (OS) for patients with stage IIIC or IV disease receiving neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) compared with primary debulking surgery (PDS). In spite of these non-inferiority results, these aforementioned trials have been criticized because of the median OS, mean operative time and low rates of optimal cytoreduction. Therefore, both approaches (PDS or NACT followed by IDS) can be considered valid, although PDS remains as the preferred primary treatment when complete cytoreduction is feasible and patient is operable [bib_ref] ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early..., Colombo [/bib_ref] [I, A]. Incorporation of weekly chemotherapy into first-line treatment does not improve PFS or OS in the population of western countries [bib_ref] Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal..., Clamp [/bib_ref]. Moreover, single agent carboplatin or weekly chemotherapy could have even worse outcomes in vulnerable elderly patients, as shown by EWOC-1 trial, so that 3-weekly regimen remains the standard for all OC populations [I, A]. ## Chemotherapy regimen and route of administration Three large randomized studies (GOG 104, GOG 114, and GOG 172) and one meta-analysis have found clinically significant improvements in PFS and OS with intraperitoneal (IP) chemotherapy [bib_ref] Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer, Jaaback [/bib_ref]. However, in the GOG 252 trial the duration of PFS was not significantly increased with either IP regimen when bevacizumab was incorporated in all arms, and IP cisplatin arm was associated to higher toxicity [bib_ref] Randomized trial of intravenous versus intraperitoneal chemotherapy plus bevacizumab in advanced ovarian..., Walker [/bib_ref]. Therefore, and according to last ESMO-ESGO consensus, currently IP chemotherapy is not a standard of care [bib_ref] ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early..., Colombo [/bib_ref] [III, A]. Nevertheless, it could still be considered in selected patients (stage III, < 1 cm residual disease) as long as bevacizumab is not used [I, B]. A randomized phase III trial evaluating hyperthermic intraperitoneal chemotherapy (HIPEC) after IDS showed a better OS for HIPEC arm. However, this trial has received significant methodological criticisms, so HIPEC cannot be considered a standard treatment and should not be offered out of clinical trials [bib_ref] ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early..., Colombo [/bib_ref] [I, C]. ## Bevacizumab Two large randomized studies (GOG 218 and ICON 7) have reported that bevacizumab added to the initial chemotherapy followed by a maintenance period improves PFS in comparison with standard chemotherapy alone [bib_ref] Incorporation of bevacizu-mab in the primary treatment of ovarian cancer, Burger [/bib_ref] [bib_ref] A phase 3 trial of bevacizumab in ovarian cancer, Perren [/bib_ref]. None of these trials showed an OS benefit in the overall study populations but post hoc subgroup analysis indicated statistically significant OS benefit in patients with stage IV disease in GOG 218 [bib_ref] Randomized phase III study to evaluate the impact of secondary cytoreductive surgery..., Bois [/bib_ref] and patients at high risk of progression (defined as FIGO stage III with > 1 cm residual disease after PDS or stage IV) in the ICON7 trial. Bevacizumab (15 mg/kg or 7.5 mg/kg every 3 weeks for a maximum of 15 months) should be considered in addition to carboplatin and paclitaxel, and it is especially recommended in patients with stage III and residual disease or stage IV [I, A]. ## Maintenance treatment with parp inhibitors Four randomized phase III trials (SOLO-1, PRIMA, PAOLA-1 and VELIA) have shown that maintenance treatment with PARP inhibitors (PARPi) after response to frontline platinum-containing regimens increased significantly the median PFS in HGSOC [bib_ref] Maintenance Olaparib in patients with newly diagnosed advanced ovarian cancer, Moore [/bib_ref] [bib_ref] Olaparib plus bevacizumab as firstline maintenance in ovarian cancer, Coquard [/bib_ref] [bib_ref] Niraparib in patients with newly diagnosed advanced ovarian cancer, Gonzalez-Martín [/bib_ref] [bib_ref] Veliparib with first line chemotherapy and as maintenance therapy in ovarian cancer, Coleman [/bib_ref]. [fig_ref] Table 3: Characteristics of patients and outcomes of phase III clinical trials with PARP... [/fig_ref] summarizes differences in the design between these trials and the results in the ITT and the different biomarker subgroup populations. All trials have shown a remarkable and unprecedented benefit in BRCAmut. In addition, PAOLA-1 and PRIMA demonstrated also a significant benefit in HR deficient (HRD) population. Finally, only PRIMA showed a benefit in the HR proficient (HRP) subgroup although of lesser magnitude. The benefit observed with PARPi is sustained along the follow-up as demonstrated by the impact on PFS2, as well as by the results after a 5-year follow-up of the SOLO-1 showing that almost 50% of patients remain progression-free in contrast to 21% in the control arm. Based on these results, olaparib (with or without bevacizumab) or niraparib after partial or complete response to first-line platinum-based chemotherapy are highly effective in BRCA -mutated patients and strongly recommended [I, A]. According to PAOLA-1 and PRIMA results, niraparib or olaparib-bevacizumab are also highly recommended for patients with HRD tumors [I, A]. In the HRP subgroup maintenance with niraparib can also be considered although bevacizumab remains as a reasonable alternative [I, B]. ## Recurrent disease Approximately, 80-85% of patients with advanced OC will relapse in the first 10 years after the diagnosis [bib_ref] Can advanced-stage ovarian cancer be cured?, Narod [/bib_ref]. When planning treatment for recurrent disease, first considerations must be willingness of the patient to receive further therapy and performance status (PS). Next step is to decide if platinum might be the best option taking into account the following factors. Conversely, the traditional and arbitrary classification as platinum-sensitive and platinumresistance has been abandoned during the Fifth Ovarian ## 3 Cancer Consensus Conference (OCCC) of the GCIG and the ESMO-ESGO consensus [bib_ref] ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early..., Colombo [/bib_ref] [bib_ref] Fifth ovarian cancer consensus conference of the gynecologic cancer intergroup: recurrent disease, Wilson [/bib_ref]. ## Factors to consider when selecting therapy Depending on the tumour: Site and extension of the disease, histological subtype, BRCA mutation status. Depending on the patient: Treatment-free interval. Platinum-free interval (TFIp) has classically been considered a predictive factor of response to platinum-rechallenge. Also TFInp (non-platinum) or TFIb (biological) should be considered as well as number of previous therapies, residual toxicity, patient preferences and comorbidities with special attention to geriatric population [bib_ref] Fifth ovarian cancer consensus conference of the gynecologic cancer intergroup: recurrent disease, Wilson [/bib_ref]. ## Surgery for relapsed ovarian cancer The randomized Desktop III trial has shown a significant OS benefit of surgery at relapse among patients accomplishing AGO score. Therefore, surgery should be recommended for patients with TFIp > 6 months, no residual disease after first surgery, good PS (0-1), and absence or less than 500 ml of ascites [bib_ref] Randomized phase III study to evaluate the impact of secondary cytoreductive surgery..., Bois [/bib_ref] [I, A]. In addition, PET-CT could improve the selection of candidates for secondary cytoreduction [bib_ref] Clinically occult recurrent ovarian cancer: patient selection for secondary cytoreductive surgery using..., Bristow [/bib_ref] [II, B]. ## Systemic treatment when platinum might be the best option A platinum-based combination (with paclitaxel, gemcitabine or pegylated liposomal doxorubicin -PLD-) is associated with a longer PFS and OS compared to single-agent platinum. None of these combinations can be considered superior in terms of efficacy; the doublet selection should be based on the toxicity profile. A randomized phase III trial of bevacizumab combined with carboplatin-gemcitabine, in patients in first relapse who have not been treated with antiangiogenic therapy, has shown a benefit in response rate (RR) and PFS [bib_ref] OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or..., Aghajanian [/bib_ref]. The combination of bevacizumab with carboplatin and paclitaxel in this setting has also shown improvement in PFS [bib_ref] Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoredutcion in recurrent, platinum-sensitive ovarian cancer..., Coleman [/bib_ref]. Recently, the combination carboplatin-PLD and bevacizumab have shown benefit in PFS and OS over carboplatingemcitabine and bevacizumab [bib_ref] AGO-OVAR 2.21/ENGOTov 18 Investigators, et al. Bevacizumab and platinum-based combinations for recurrent..., Pfisterer [/bib_ref]. Three PARP inhibitors (olaparib [bib_ref] Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer..., Pujade-Lauraine [/bib_ref] niraparib [bib_ref] Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer, Mirza [/bib_ref] and rucaparib [bib_ref] Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy..., Coleman [/bib_ref] have shown benefit in PFS as maintenance treatment after response to platinum based therapy in relapsed ovarian cancer. The magnitude of benefit is greater, but not limited, to patients with BRCA mutation. For BRCA -mutated patients maintenance treatment with olaparib improves PFS (HR 0.30) and OS (HR 0.74) with an improvement of 12.9 months in median OS vs placebo. Niraparib and rucaparib have also shown positive results in phase III ## 3 trials, not only in BRCA -mutated patients but also in BRCA wild type (wt), regardless the status of HR. Therefore, when platinum might be the best option both platinum-based combination with bevacizumab and platinum-based combination followed by PARPi are optimal options [I, A]. Based on the higher RR with the addition of bevacizumab, this option would be indicated for symptomatic patients, without BRCA mutation, who did not receive bevacizumab at first line. For the rest of patients, platinumbased combination followed by PARPi would be the preferred option [III, A]. For BRCA -mutated patients olaparib, niraparib or rucaparib can be used, and for BRCA wt patients niraparib or rucaparib are the available options [I, A]. If BRCA is mutated, monotherapy with rucaparib (not as maintenance) is also an alternative for patients with no previous PARPi treatment, who have been treated with two or more prior lines of platinum-based chemotherapy, and who are unable to tolerate further platinum-based chemotherapy . In patients with TFIp > 6 months who cannot receive platinum-based therapy, or after previous use of PARPi and at least two platinum regimens, the combination trabectedin plus PLD could be an option [I, B]. ## Systemic treatment when platinum might not be the best option Patients progressing on platinum-based therapy or after a short treatment-free interval of platinum are not considered eligible for re-challenge with platinum. This is an unmet medical need and when possible, patients should be included in clinical trials. Cytotoxic agents, such as weekly paclitaxel, PLD, gemcitabine and topotecan, have shown modest activity in phase III randomized trials, with an average RR of 10-15% and median OS in the range of 9-12 months. Accordingly, sequential cytotoxic single-agent therapy is the best palliative option and quality of life is the most important endpoint. Nevertheless, patients with poor PS could be considered only for best supportive care. For patients who have not received prior bevacizumab, the addition of the latter to weekly paclitaxel, PLD, or topotecan has shown to improve PFS. The combination weekly paclitaxel and bevacizumab was especially active in Aurelia trial, being the preferred option when possible [bib_ref] Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label..., Pujade-Lauraine [/bib_ref]. In summary, when platinum might not be not the best option single-drug therapy, or in combination with bevacizumab if not previously received, is recommended [I, A]. [fig_ref] Table 4: Ovarian cancer follow-up recommendations In early-stage ovarian cancer these procedures could be... [/fig_ref] summarized our recommendations for follow-up. Although performing a routine imaging is controversial we recommended to do it at least every 6 months. It is important to review any new symptom reported by the patient and to perform a physical examination in each visit. ## Follow-up [table] Table 1 2014: FIGO staging system for ovarian, fallopian tube, and peritoneal cancer 1 [/table] [table] Table 2: Immunohistochemical panel for diagnosis of the subtypes of ovarian cancer HGSC high-grade serous carcinoma, LGSC low-grade serous carcinoma, CCC clear cell carcinoma, EC endometrioid carcinoma, MC mucinous carcinoma, WT1 Wilms Tumour 1, ER estrogen receptor, NAPSA naspin A, N/A not applicable [/table] [table] Table 3: Characteristics of patients and outcomes of phase III clinical trials with PARP inhibitors in first line NACT neoadjuvant chemotherapy, HR hazard ratio, BRCA m BRCA mutated; BRCA wt BRCA wild type, HRD homologous recombination deficiency, HRP homologous recombination proficiency, PDS primary debulking surgery, NA not Applicable, n.s. not significant [/table] [table] Table 4: Ovarian cancer follow-up recommendations In early-stage ovarian cancer these procedures could be performed every 6 months from the beginning [/table]	None	https://link.springer.com/content/pdf/10.1007/s12094-020-02545-x.pdf	None
3ab91a53bf46e806b0a4c1ee1889d9e5fb5f7e94	pubmed	Preferred practice guidelines for glaucoma management during COVID-19 pandemic	Preferred practice guidelines for glaucoma management during COVID-19 pandemic [bib_ref] All India Ophthalmology Society-Indian Journal of Ophthalmology consensus statement on preferred practice..., Sengupta [/bib_ref] ## Guidelines for glaucoma practice To resume elective procedure and medically necessary procedures, following prerequisites need to be kept in mind as per World Health Organization (WHO) guidelinesand are common for all ophthalmology patients. 1. Authorization for resumption of elective procedures by state govt. guidelines 2. Hospital's preparedness for resuming facilities and updating infection control protocols and staff training in general and for COVID-19 in specific. 3. Arrangements for COVID-19 screening prior to surgery, social distancing, regular disinfection. 4. Patients coming for an appointment should be asked prior to entering the waiting room about respiratory illness/Fever and whether they or a family member reside or have travelled to the containment zone area in the past 14 days. If they answer yes to either question, they should be sent to COVID-19 care center or dedicated COVID-19 hospitals.5. Patients & attendant need to wear a three ply/ cotton mask throughout their stay in the eye care facility 6. All the instruments are well functioning and systems in place for sanitizing them in between the patients. 7. Doctors, optometrist, and para medical staff have adequate Personal Protective Equipment (PPE): like N95 or equivalent masks, Face/ Eye shields and gloves etc. 8. Availability of slit lamp breath shields and explaining patient about minimum talking during examination 9. To plan much lower patient load than pre-COVID-19 times to avoid crowding of waiting rooms. 10. Preferable to give appointments with staggered timings to patients to avoid crowding and prevent long queues and inconvenience to patients. To allow only one attendant per patient inside the premises However, these can be adapted according to the requirement of the clinic/hospital/institution and state authority guidelines. Prioritizing the care for outpatients is important to reduce the load on the clinics 1. Clinical prioritization into high risk, medium risk, and low risk using tele-triage, medical records, performa, etc., and then give appointments accordingly 2. Tele consult, virtual/video consultation, network of local ophthalmologist, opticians or optometrist's services can be used for low-risk patients to avoid crowding in the hospital/clinics. 3. Based on treating hospitals ability to deal with the number of patients and treating physician's discretion, the priorities for medical treatment and frequency of follow-up can be decided. Prioritization plan for surgery is based on the discretion of the treating Ophthalmologist. As we are slowly resuming our normal practice, we should prioritize scheduling surgeries that require immediate attention, and then shift to urgent, semi-urgent, and routine surgeries based on health care facility situation and also state government guidelines.However, the surgeries to be avoided in containment zones.Guidelines for glaucoma management are in many ways similar to the general guidelines for ophthalmology patients. The guidelines as regards specifics to glaucoma are mentioned below ## A. clinical examination when and how, this includes General guidelines: - Keep patient in the clinic for as minimal time as possible. Let the attendant into the examination or diagnostic area only if there is a need. - Perform only one test in the diagnostic lab at a time. - Receive the patient records with gloved hands and give them back after reviewing, do not place them on your tables. - If you are using electronic medical records, ensure hand sanitization or sanitizing the gloves before touching the keyboard or mouse. - Use gloved hands for cleaning of all the surfaces and equipments. - Avoid bandage contact lens insertion or removal, suture removal if possible. If necessary to use, then avoid placing forceps on table and take necessary precautions. ## Iop measurement - Goldman applanation tonometer (GAT): Use of single-use, disposable tonometer tips if available to prevent cross contamination; however, that is not cost effective. [bib_ref] Use of disposable prism tonometry in routine clinical practice, Salvi [/bib_ref] For disinfecting the GAT prism, the prism is to be kept in 0.5% bleach/sodium hypochlorite (1 Part of 5% Sodium hypochloride: 9 Parts distilled water) or 3% hydrogen peroxide for 5 min, then washed with distilled water, dried, and and then mounted on the slit lamp. This should be done at the beginning and at the end of the clinic on daily basis. However, bleach is available in various concentrations ranging from 2 to 10%; hence, dilution can be done accordingly to make it a 0.5% solution. The wipes dipped in 70% of the isopropyl alcohol (IPA) solution or alcohol wipes commercially available (with 70% IPA) can be used to clean the tips in between the patients. Since alcohol will not effectively sterilize the tip against adenoviruses and herpes simplex virus (HSV), additional use of sodium hypochlorite at the start and end of the day will help effective disinfection against adenovirus, HSV, coronavirus and other viruses commonly associated with nosocomial outbreaks in eye care. [bib_ref] Disinfection of tonometers: A report by the American Academy of Ophthalmology, Junk [/bib_ref] However, according to Finnish Centre for Occupational Health Guideline for cleaning surfaces 0.1% sodium hypochloride is also effective against coronavirus.The chlorine solutions that are 0.25% and above have to be rinsed after the contact period for disinfection; otherwise, they can be detrimental for the instruments or surfaces. Hence, regular use of these disinfectants should be avoided for sensitive instruments. - Noncontact tonometers should be avoided as they create micro aerosols that can disperse the virus and hence increase chances of spread of the virus. [bib_ref] Microaerosol formation in noncontact 'air-puff' tonometry, Britt [/bib_ref] - Icare: For screening with disposable probe and use a fresh probe for each patient. - Tonopen: Fresh sleeve to be used for each patient as it comes with a disposable sleeve. - Perkins: To be used in pediatric patients, if tonopen and I-care are not available and should be used with adequate precautions and tip should be cleaned similar to the GAT. - The Schiotz tonometer should be dipped in a 1:1000 merthiolate solution and rinsed in saline/distilled water prior to use. [bib_ref] Sterilisation of tonometers and gonioscopes, Sood [/bib_ref] Heating the base of the instrument with the flame of a spirit lamp for 10 seconds and allowing sufficient time for cooling before use. [bib_ref] Sterilisation of tonometers and gonioscopes, Sood [/bib_ref] Either of these procedures is followed at the beginning and the end of the clinic on a daily basis. Cleaning the foot plate and test cornea with alcohol swab (70% IPA allowing sufficient time for drying of chemicals) between the patients is recommended. ## Gonioscopy - To be done for patients as per discretion of ophthalmologist with appropriate precautions. Gonioscopes can be cleaned (Volk guidelines) in running water with soap solution, dried, and wiped with wipes or cotton or gauze soaked in 70% IPA, and dried after every use before placing them in the boxes. - Use 70% IPA to wipe all patient and technician interface surfaces, e.g., eyepatch, chinrest, headrest, trial lens holder, trial lens, patient response button. - To clean the bowl of perimeter, please follow manufacturer's guidelines as they vary with different companies (Quick-start guide from Zeiss and Octopus). - Chin rest and forehead rests can also have paper cover, which can be discarded after each patient However, the manufacturer's guidelines should be followed for each perimeter. Also, three-layered masks to be worn by the patient and can be sealed by micropore/tape above the nose to prevent spread of aerosols from the patient's breath into the perimeter bowl. 2. Imaging and fundus photography: Imaging is preferable over visual fields for suspects and glaucoma patients, as it has lesser chances of cross contamination, sanitization is easier, and the test is faster. The patient should be wearing a three-layered mask with a tape while performing the test Disinfection of optical coherence tomography, fundus photography machine, and other imaging machines: Use 70% IPA to wipe all patient and technician interface surfaces, e.g. eyepatch, chinrest, headrest. The lens is to be wiped with soft cloth, nonfiber, using ethanol (according to manufacturer's advice in manuals) between patients to avoid contamination. ## Ultrasound biomicroscopy (ubm): to be used only if mandatory and required to decide the management of a condition that is vision threatening. Always use gloves while performing the UBM. Best is to use disposable tips where possible and dispose after every use. Otherwise, the UBM cups can be sterilized by ETO and should be changed after every patient. The probe can be cleaned with 70% IPA, or covered with a disposable glove that can be discarded after each use. ## C. lasers Indications for laser to be decided by the treating ophthalmologist. While performing lasers, use of gloves, three-layered masks with a tape on the nasal side, slit lamp breath shield, appropriate disinfection of Abraham lens (similar to gonio lenses), and laser console with slit lamp need to be kept in mind. ## D. surgical procedures Level of urgency can be decided as per discretion of the treating surgeon/hospital/state authorities guidelines. It is preferable to operate under local anesthesia with day care and avoid general anesthesia. Further the procedures that require lesser postoperative follow up can be chosen based on the treating physician's discretion. General guidelines for operating room (OR) are similar to any ophthalmology OR for all glaucoma procedures. # Conclusion The amount of damage the COVID-19 pandemic has done all across the world is insurmountable. There are mandatory life style changes that need to be acquired to protect oneself as an individual and the community as a whole. The impact on the health care systems is huge and definitely requires a change in the way we examine and treat our patients. There have been reports of presence of the virus in conjunctival secretions. [bib_ref] There may be virus in conjunctival secretion of patients with COVID-19, Liang [/bib_ref] Therefore, in ophthalmology practice, the chances of infectivity due to close contact with the patient and aerosol generating procedures are significantly high. However, the reports of infectivity through tears and spread across the individuals show conflicting results. [bib_ref] Assessing viral shedding and infectivity of tears in coronavirus disease 2019 (COVID-19)..., Seah [/bib_ref] Nonetheless, it is important to use the preferred guidelines so as to protect ourselves as well as provide optimal care to patients without increasing the risk of virus transmission. Also, it is imperative that the barrier and disinfection systems to be kept in mind at each step. ## Disclaimer The expert panel would like to declare that this document contains guidelines based on the information issued by various relevant organizations across the globe, existing literature, ICMR directives, state and central governments orders as on the date. The current outbreak is unpredictable and adherence to any recommendations included in this document may not ensure a successful outcome in every situation and may not have included every aspect. If community transmission occurs, the capacity and priorities of healthcare systems change due to changing situation and then these may not remain relevant or sufficient. These recommendations will be regularly updated to account for the changing epidemiology and new information regarding treatment and testing. These guidelines are the suggestions for preferred practices and do not replace or override existing national/regional/local statutory requirements. The ultimate judgment regarding the management must be made by the treating physician and the patient considering all the circumstances presented by the individual patient, and the variability of the medical condition. This expert panel does not claim for the accuracy or completeness of the guidance and assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this guidance or for any errors or omissions. No suit or legal proceedings shall lie against any person for anything done or intended to be done in good faith based on these guidelines. ## Financial support and sponsorship Nil. ## Conflicts of interest There are no conflicts of interest.	None	None	The COVID-19 pandemic has threatened the humanity at a global level to a large extent by the burden of the disease with significant mortality and to a certain extent as a byproduct of the necessary efforts to contain the same. There is a significant impact on the health care system, as we not only have to contain pandemic, but continue to treat our non-COVID-19 patients in a safe and responsible manner. Ophthalmology practice in general and glaucoma in particular needs certain modifications and additional precautions while examining as well as managing these patients keeping their and our safety in mind. As the lockdown relaxations are in vogue we need to learn how to deal with our regular patients as well in addition to emergency care. This paper presents the consensus-based guidelines by an expert panel on how to restart glaucoma practice during this COVID-19 time. These guidelines will be applicable across the country and should help ophthalmologists and glaucoma specialist to restart their practices while safeguarding the patients and their own selves from getting infected.
974d6d37c017833d5a119413f7e8a05ce5be01c9	pubmed	Obstetrical brachial plexus injury (OBPI): Canada's national clinical practice guideline	Obstetrical brachial plexus injury (OBPI): Canada's national clinical practice guideline Objective: The objective of this study was to establish an evidence-based clinical practice guideline for the primary management of obstetrical brachial plexus injury (OBPI). This clinical practice guideline addresses 4 existing gaps: (1) historic poor use of evidence, (2) timing of referral to multidisciplinary care, (3) Indications and timing of operative nerve repair and (4) distribution of expertise.Setting: The guideline is intended for all healthcare providers treating infants and children, and all specialists treating upper extremity injuries.Participants: The evidence interpretation and recommendation consensus team (Canadian OBPI Working Group) was composed of clinicians representing each of Canada's 10 multidisciplinary centres.Outcome measures: An electronic modified Delphi approach was used for consensus, with agreement criteria defined a priori. Quality indicators for referral to a multidisciplinary centre were established by consensus. An original meta-analysis of primary nerve repair and review of Canadian epidemiology and burden were previously completed.Results: 7 recommendations address clinical gapsand guide identification, referral, treatment and outcome assessment: (1) physically examine for OBPI in newborns with arm asymmetry or risk factors; (2) refer newborns with OBPI to a multidisciplinary centre by 1 month; (3) provide pregnancy/birth history and physical examination findings at birth; (4) multidisciplinary centres should include a therapist and peripheral nerve surgeon experienced with OBPI; (5) physical therapy should be advised by a multidisciplinary team; (6) microsurgical nerve repair is indicated in root avulsion and other OBPI meeting centre operative criteria; (7) the common data set includes the Narakas classification, limb length, Active Movement Scale (AMS) and Brachial Plexus Outcome Measure (BPOM) 2 years after birth/surgery.Conclusions:The process established a new network of opinion leaders and researchers for further guideline development and multicentre research. A structured referral form is available for primary care, including referral recommendations. # Introduction The brachial plexus is a network of peripheral nerves providing innervation to the upper extremity. Obstetrical brachial plexus injury (OBPI) is an injury in newborns, thought to be sustained during labour and delivery. [bib_ref] Brachial palsy, Tan [/bib_ref] Incidence is estimated to be between 1.6 and 2.6 in 1000 births, 2 equivalent to autism 3 and congenital deafness. [bib_ref] Universal newborn hearing screening, Patel [/bib_ref] It is greater than for type 1 diabetes mellitus [bib_ref] Recent incidence of type 1 diabetes mellitus in children 0-14 years in..., Newhook [/bib_ref] and cystic fibrosis. [bib_ref] Diagnosis of cystic fibrosis in the Republic of Ireland: epidemiology and costs, Farrell [/bib_ref] Shoulder dystocia is the main risk factor; others are related to fetal size and presence of comorbid birth trauma. [bib_ref] The epidemiology of neonatal brachial plexus palsy in the United States, Foad [/bib_ref] Clinical presentation immediately following delivery is consistent regardless of injury severity; newborns demonstrate unilateral flaccid paralysis of the involved upper limb. [bib_ref] Obstetrical lesion of the brachial plexus, Gjorup [/bib_ref] Given the absence of an effective baseline investigation (as with other mechanisms of nerve injury), [bib_ref] Electromyography, nerve action potential, and compound motor action potentials in obstetric brachial..., Malessy [/bib_ref] serial examinations are required to determine severity and recovery potential. Recovery of upper extremity function is the outcome guiding management. Most cases of OBPI are transient, [bib_ref] Natural history of obstetric brachial plexus palsy: a systematic review, Pondaag [/bib_ref] with complete spontaneous recovery expected. However, children with incomplete recovery experience lifelong functional impairment; long-term sequelae Strengths and limitations of this study ▪ The methodology for the first obstetrical brachial plexus injury guideline was rigorous, following an established framework. ▪ Recommendations provide clinical guidance on the divergence of opinion and practice between primary care and specialists. ▪ A baseline for system performance and quality indicators for referral are established. ▪ In selecting the working group, the positional approach identified only surgeons ( plastic and orthopaedic). ▪ The working group did not formally solicit guardian preferences. include weakness, joint deformity and limb length discrepancy. Beyond physical impairment, OBPI impacts the family dynamic [bib_ref] Psychological adjustment, maternal distress, and family functioning in children with obstetrical brachial..., Alyanak [/bib_ref] and the child's global development. [bib_ref] Limb length differences after obstetrical brachial plexus injury: a growing concern, Bain [/bib_ref] For all injury severities, assessment [bib_ref] Obstetrical brachial plexus palsy, Borschel [/bib_ref] and nonoperative (occupational and physical) therapy [bib_ref] Rehabilitation of brachial plexus injuries in adults and children, Smania [/bib_ref] are provided at specialised multidisciplinary centres. [bib_ref] Obstetrical brachial plexus palsy: results following neurolysis of conducting neuromas-in-continuity, Clarke [/bib_ref] [bib_ref] Neurosurgical intervention for birth-related brachial plexus injuries, Laurent [/bib_ref] [bib_ref] Neonatal brachial plexus injury: obstetrical factors and neonatal management, Mehta [/bib_ref] [bib_ref] Obstetrical brachial plexus palsy, Zafeiriou [/bib_ref] For infants with residual deficits, numerous operative algorithms, repair techniques [bib_ref] Different methods and results in the treatment of obstetrical brachial plexus palsy, Xu [/bib_ref] [bib_ref] Outcomes with suprascapular nerve reconstruction in obstetrical brachial plexus patients, Terzis [/bib_ref] [bib_ref] Results of end-to-side nerve coaptation in severe obstetric brachial plexus lesions, Pondaag [/bib_ref] [bib_ref] Recovery of hand function following nerve grafting and transfer in obstetric brachial..., Pondaag [/bib_ref] [bib_ref] External rotation as a result of suprascapular nerve neurotization in obstetric brachial..., Pondaag [/bib_ref] [bib_ref] Accessory nerve neurotization in infants with brachial plexus birth palsy, Kawabata [/bib_ref] [bib_ref] Contralateral C7 transfer for the treatment of upper obstetrical brachial plexus palsy, Lin [/bib_ref] [bib_ref] Final results of grafting versus neurolysis in obstetrical brachial plexus palsy, Lin [/bib_ref] [bib_ref] Results of intercostal nerve transfer to the musculocutaneous nerve in brachial plexus..., Luo [/bib_ref] and evaluation methods [bib_ref] A systematic review of evaluation methods for neonatal brachial plexus palsy, Chang [/bib_ref] are available. Authors have expressed the need for guidelines for OBPI management addressing clinical gaps. Gap 1: historic poor use of evidence Residual deficits with non-operative therapy are underestimated, and surgical outcomes are evaluated inconsistently. [bib_ref] Accessory nerve neurotization in infants with brachial plexus birth palsy, Kawabata [/bib_ref] Nerve repair has not been analysed with a high-quality study, [bib_ref] Neonatal brachial plexus palsy. Outcome of absent biceps function at three months..., Smith [/bib_ref] despite acknowledgment of its need. [bib_ref] Brachial plexus birth palsy: rationale for a multicenter prospective study, Waters [/bib_ref] [bib_ref] Early infantile surgery for birth-related brachial plexus injuries: justification requires a prospective..., Bodensteiner [/bib_ref] The existing literature is not optimised; no synthesis has addressed existing cohort studies of nerve repair versus non-operative therapy. Gap 2: timing of referral to multidisciplinary care While a proportion of injuries spontaneously recover, 10 they are not discernible at baseline from those that require repair. [bib_ref] Severe obstetric brachial plexus palsies can be identified at one month of..., Malessy [/bib_ref] Primary care providers may overestimate recovery, causing guardian distress and delayed multidisciplinary referral. Ideal referral timing is not established. Early referral to a multidisciplinary centre is important; it allows guardian education, 42 treatment by specialised therapists, and serial assessment for recovery and operative planning if necessary. [bib_ref] Severe obstetric brachial plexus palsies can be identified at one month of..., Malessy [/bib_ref] Peripheral nerve injuries require timely repair. The optimal age for nerve repair is 3 months for the most severe injuries. 14 However, up to 12% of referrals to multidisciplinary clinics are 3 years or older with longstanding functional impairment. [bib_ref] Navigating the gray zone: a guideline for surgical decision making in obstetrical..., Bain [/bib_ref] Gap 3: indications and timing of operative nerve repair Mild injuries with significant recovery by 1 month do not require repair. [bib_ref] Navigating the gray zone: a guideline for surgical decision making in obstetrical..., Bain [/bib_ref] Total plexus injuries require early repair to preserve function. However, 50-90% of referrals to specialty centres have injuries between these extremes, with surgical indications and timing varying between centres. [bib_ref] Comparison of the natural history, the outcome of microsurgical repair, and the..., Waters [/bib_ref] Gap 4: distribution of expertise in Canada OBPI expertise is not evenly distributed across the country, with 10 multidisciplinary centres in Canada located at academic institutions in large cities. Unified recommendations from OBPI specialists do not exist to guide practice or inform the public. There is a clear opportunity to improve the quality of OBPI care,and the clinical conditions are appropriate for guideline development. [bib_ref] Improving patient care: the implementation of change in health care, Burgers [/bib_ref] A rigorous review of current literature would address an evidence base insufficient to support decisions of clinicians.Improving the knowledge and intent of behaviours [bib_ref] What is the best way to produce consensus and buy in to..., Wong [/bib_ref] would minimise unwanted practice variation, as well as the divergence of opinion between primary care and OBPI specialists. A consistent national message would inform guardians. Establishing quality indicators would inform policy, access to care and funding.Ultimately, implementation would result in improved outcomes. [bib_ref] Toward evidence-based quality improvement. Evidence (and its limitations) of the effectiveness of..., Grimshaw [/bib_ref] The process of guideline development itself can also foster collaboration and cohesion among national specialists, [bib_ref] What is the best way to produce consensus and buy in to..., Wong [/bib_ref] providing a platform for a national research programme.Currently, no comprehensive guideline exists in Canada, or elsewhere, to guide the management of OBPI. This guideline examines the evidence for: (1) primary management of OBPI, including treatment with nerve repair and physical/occupational therapy, (2) timing of referral to a multidisciplinary centre and (3) standardised outcome measurement. Intended users are those delivering care to infants in the first year of life, and peripheral nerve surgeons, therapists and other specialists treating OBPI impairment. # Methods The development of guideline recommendations followed Cancer Care Ontario's Program in Evidence-Based Care framework, the Guideline Development Cycle. Governance A small group consisting of a plastic surgeon with expertise in management of OBPI ( JRB), a health services researcher with expertise in the science and practice of clinical practice guidelines (MCB), and a trainee in both plastic surgery and health research methodology (CJC) provided oversight to the project. Recruitment for the OBPI Working Group 49 followed a positional approach. [bib_ref] Identifying opinion leaders to promote behavior change, Valente [/bib_ref] Lead physicians at each Canadian OBPI multidisciplinary centre of excellence were invited to be members of this team. Twelve physicians agreed to participate in guideline development, with representation from every Canadian multidisciplinary centre . This established the Canadian OBPI Working Group. The group's tasks included: providing feedback on the systematic review of primary management, approving quality indicators for referral timing analysis, collecting and providing volume and timing of referrals at their centres, participating in the formal consensus process to craft, refine and agree on recommendations for the clinical practice guideline, and establishing a common data set for future OBPI research. Recommendations were developed through two in-person meetings, and electronic correspondence from June 2013 to June 2015. The guideline was further reviewed for methodology (AT, SHV), and clinical sensibility to plastic surgery (AT, SHV) and obstetrics and gynaecology (MKC). ## Recommendation development The working group generated a preliminary topic list reflecting opportunities for quality improvement, and assigned evidence to each topic (box 1). For primary management (nerve repair, physical/occupational therapy), functional impairment was considered the primary outcome; pooled adverse events were the secondary outcome. For referral to a multidisciplinary centre, the working group identified importance of conservative timing among guardians. [bib_ref] Medical decision-making among adolescents with neonatal brachial plexus palsy and their families:..., Squitieri [/bib_ref] The consensus group concurred early referral was favoured, in order to maximise education and therapy, and capture patients for operative planning. Outcome measures addressed each domain of the WHO's International Classification of Function, Disability and Health (ICF).Quality of evidence, bias and uncertainty were considered in all outcomes.Recommendations were based on best available evidence and focused exclusively on the clinical perspective. While implementation will ultimately necessitate consideration of resources, this will be tailored to each jurisdiction.Sources of evidence Identification of existing guidelines Recognised databases were searched for existing clinical practice guidelines. OBPI is referred to by many terms, [bib_ref] Is the term "obstetrical brachial plexus palsy" obsolete? An international survey to..., Phua [/bib_ref] with specific variation in the leading (eg, neonatal or paediatric instead of obstetrical) and end (eg, palsy instead of injury) terms. For sensitivity, only the term 'brachial plexus' was used in searches. ## Systematic review and meta-analysis of primary management A new systematic review and meta-analysis was designed investigating the effect of primary nerve repair versus non-operative management on physical function. [bib_ref] Primary nerve repair for obstetrical brachial plexus injury: a meta-analysis, Coroneos [/bib_ref] Review of Canadian epidemiology and burden of disease A new analysis of Canadian epidemiology and burden was designed establishing quality indicators for referral, and investigating volume and timing of referral to multidisciplinary centres, incidence and risk factors. [bib_ref] Obstetrical brachial plexus injury: burden in a publicly funded, universal healthcare system, Coroneos [/bib_ref] Systematic review of outcome assessment To inform the selection of outcome measures for multicentre research, a focused search for systematic reviews investigating OBPI outcome measures was performed. Records meeting each of the following criteria were included: systematic review, published in peer-reviewed journals as full reports, reviewed outcome measures, included patients with OBPI, English language and published since 2009. The same electronic search strategy from the systematic review and meta-analysis was used [bib_ref] Primary nerve repair for obstetrical brachial plexus injury: a meta-analysis, Coroneos [/bib_ref] Quality assessment was performed using the AMSTAR tool. [bib_ref] Development of AMSTAR: a measurement tool to assess the methodological quality of..., Shea [/bib_ref] Environmental scan A search was performed to provide an estimate of referral processes in other jurisdictions, and inform recommendations.Relevant professional organisations were searched for applicable documents (as in identification of existing guidelines). An untargeted web search was completed on 1 November 2012 and updated on 15 February 2014. The following terms were queried: 'brachial plexus', referral and guidelines. Multidisciplinary clinic websites were reviewed for the referral process from primary care, timing and specific criteria. ## Formal consensus A formal consensus process was selected. All members participated in consensus to improve ownership and consistency in national recommendations. An electronic modified Delphi approach 64 was selected for its transparent, explicit and structured methodology. Recommendations and key evidence summaries were distributed to the consensus group. Members rated agreement for each recommendation using a nine-point Likert scale (1='strongly disagree', 9='strongly agree'),and had the ability to provide Box 1 Preliminary topic list to be addressed by recommendations ▸ Recommendation topics; ▸ Identification of obstetrical brachial plexus injury by primary care; ▸ Timing of referral to a multidisciplinary centre; ▸ Information to communicate between primary care (diagnosis), multidisciplinary care (specialised therapy) and primary care (follow-up); ▸ Personnel at multidisciplinary centres; ▸ Timing of operative therapy; ▸ Common data set elements for national multicentre research. written feedback. Thresholds for consensus to 'support' or 'reject' recommendations were conservative and defined a priori.Consensus was defined based on a group size of 12.A median of 7-9 with 3 or fewer ratings outside of the 7-9 range was defined as consensus to support the recommendation. A median of 1-3 and 3 or fewer ratings outside of the 1-3 range was defined as consensus to reject the recommendation. Further, four or more members rating in the 1-3 and 7-9 ranges were defined as consensus to reject the recommendation. Other combinations were defined as uncertain, indicating the need for modification. Qualifying statements were added to recommendations based on consensus group feedback. This allowed for the necessary clarification and contextualisation to be provided even in cases when consensus was obtained according to the a priori criteria. ## Review No external review process was specified a priori. Recommendations were established by a formal consensus process including national key stakeholders and clinical experts. The guideline was reviewed for completeness of literature review 68 (AT, SHV), clinical sensibility 68 to plastic surgery (AT, SHV) and obstetrics and gynaecology (MKC), and by an expert in systematic review and guideline development (MCB). [bib_ref] Clinical guidelines: developing guidelines, Shekelle [/bib_ref] Further external review was not appropriate and would be redundant.Education of primary care was a goal of the guideline; in cases where there is disagreement between specialists and primary care, and referrals need to be increased, review by primary care may be detrimental. [bib_ref] Understanding variation in rates of referral among general practitioners: are inappropriate referrals..., Fertig [/bib_ref] # Results ## Sources of evidence identification of existing guidelines No existing guideline or set of recommendations adequately addressed the objectives of the working group, or used an optimised synthesis of the OBPI literature. Systematic review and meta-analysis of primary management A systematic review and meta-analysis was completed investigating the effect of primary nerve repair versus non-operative management on physical function. [bib_ref] Primary nerve repair for obstetrical brachial plexus injury: a meta-analysis, Coroneos [/bib_ref] Review of Canadian epidemiology and burden of disease An analysis of Canadian epidemiology and burden was completed establishing quality indicators for referral, and investigating volume and timing of referral to multidisciplinary centres, incidence and risk factors. [bib_ref] Obstetrical brachial plexus injury: burden in a publicly funded, universal healthcare system, Coroneos [/bib_ref] Systematic review of outcome assessment A focused search for systematic reviews of outcome assessment was performed, identifying three reviews. [bib_ref] A systematic review of evaluation methods for neonatal brachial plexus palsy, Chang [/bib_ref] Full results are reported in online supplementary appendix 1. ## Environmental scan The environmental scan identified seven documents advising referral for identified OBPI to specialty care. [bib_ref] Management of Congenital Brachial Plexus Injury, Musson [/bib_ref] Full results are reported in online supplementary appendix 1. ## Recommendations Seven recommendations were developed addressing the topic list. The consensus group supported all recommendations in the first round of review [fig_ref] Table 2: Results of the consensus process for recommendations [/fig_ref]. The evidence was judged to be universally low for all recommendations. Recommendations and qualifying statements were distributed to the consensus group; no member disapproved or provided additional feedback. 1. Physically examine newborns for OBPI if upper extremity movement is asymmetric or delivery was complicated by shoulder dystocia, humeral fracture or clavicular fracture. A primary care physician with experience in newborn assessment should perform a focused physical examination on newborns with an identified deficit or risk factor. 2. Refer all newborns with OBPI to a multidisciplinary centre by 1 month of age. A proportion of newborns will completely recover within days of birth and do not necessitate referral to a multidisciplinary centre. Newborns with complete recovery as assessed by primary care providers experienced in the assessment of musculoskeletal and neurological deficits do not necessitate referral. ▸ The selection of 1 month was informed by the environmental scan, practice patterns, [bib_ref] Obstetrical brachial plexus palsy, Borschel [/bib_ref] [bib_ref] Navigating the gray zone: a guideline for surgical decision making in obstetrical..., Bain [/bib_ref] Malessy et al's 41 referral algorithm and the previous Canadian position statement. 79 ▸ The consensus group formally approved quality indicators for infant age at initial assessment by a multidisciplinary centre; 'good' by 1 month of age, 'satisfactory' by 3 months of age and 'poor' thereafter. 61 ▸ Early referral to a multidisciplinary centre permits guardian education, 42 early treatment by specialised therapists, serial assessment for recovery and appropriate operative assessment. 41 ▸ Guardians prefer early referral to a multidisciplinary centre. [bib_ref] Medical decision-making among adolescents with neonatal brachial plexus palsy and their families:..., Squitieri [/bib_ref] ▸ Neuropraxic injuries recover rapidly, and infants are substantially to completely recovered by 1 month. [bib_ref] Obstetrical brachial plexus palsy, Borschel [/bib_ref] From the meta-analysis of primary management, this proportion is 35% of patients (95% CI 23% to 48%). 2 ▸ Primary care providers may underestimate residual impairment in OBPI. From the meta-analysis of primary management, non-operative management of OBPI in demographic populations results in functional impairment in 18% (95% CI 14% to 23%). Only three reports assess outcomes with physical scales; the remainder rely on subjective assessment. This reflects traditional reports of OBPI from primary care, reporting transient injury without sequelae. [bib_ref] Neurosurgical intervention for birth-related brachial plexus injuries, Laurent [/bib_ref] In contrast, full recovery occurs in 73% (95% CI 64% to 81%) of patients from demographic samples. 'Full recovery' itself is most likely overestimated. [bib_ref] Natural history of obstetric brachial plexus palsy: a systematic review, Pondaag [/bib_ref] Interpreted inversely, the authordefined incidence of any residual impairment is 27% (19% to 36%). This proportion demonstrates that at least 19% to 36% of OBPI cases have an uncharacterised, unidentified residual impairment. 2 ▸ A systematic review by Pondaag et al 10 agreed that OBPI prognosis is worse than that identified in the literature and predicted in practice. 3. With referral, provide complete pregnancy and birth history, and physical examination findings (including Horner's syndrome) at birth. Clinical records should indicate risk factors, severity of injury and course of recovery. While clinical records are important, they are not necessary; do not delay referral to a multidisciplinary centre to obtain records. ▸ No study identified and analysed the impact of referral information or communication on outcome. ▸ Given the absence of a gold standard baseline investigation, [bib_ref] Electromyography, nerve action potential, and compound motor action potentials in obstetric brachial..., Malessy [/bib_ref] serial examination is required to determine severity. Clinical records may provide an estimate of initial severity and progression of recovery. ▸ Discussion of risk factors contributes to guardian education, [bib_ref] Early parental experiences of obstetric brachial plexus palsy, Bellew [/bib_ref] especially for future pregnancies. 82 ▸ Clinical root level involvement (eg, presence of hand paralysis) and Horner's syndrome are discerning characteristics in the Narakas classification 83 for baseline injury classification (recommendation 7). [bib_ref] Universal newborn hearing screening, Patel [/bib_ref]. Teams at multidisciplinary centres should include: i. A dedicated therapist with experience in the assessment and treatment of OBPI. ii. A peripheral nerve surgeon with experience in microsurgical repair of OBPI. Teams at multidisciplinary centres are responsible for the assessment, treatment, rehabilitation and education of children with OBPI and their parents/guardians. Teams should include the personnel necessary to deliver the highest level of treatment available in Canada. The recommendation does not pertain to healthcare providers involved in diagnostic investigations or secondary treatment. A therapist is a physical or occupational therapist, or equivalent. Ideally, the therapist will have paediatric experience and/or be mentored to develop skills to manage patients with OBPI. A peripheral nerve surgeon is a plastic, neurosurgeon or orthopaedic surgeon, or equivalent. The peripheral nerve surgeon will have the training, experience and infrastructure to perform microsurgical nerve reconstruction procedures on paediatric patients. ▸ No study identified and analysed the impact of multidisciplinary teams or their included disciplines on OBPI outcomes. ▸ The meta-analysis of primary management pooled all non-operative management, including natural history; outcomes did not analyse specific non-operative therapy interventions or protocols. Descriptions of nonoperative management protocols were poor. The only reliable factor was involvement of a therapist in management. Among 65 studies with patients treated by specialists, the care team was multidisciplinary in 43. 2 ▸ Two previous systematic reviews [bib_ref] Orthopaedic sequelae in neurologically recovered obstetrical brachial plexus injury. Case study and..., Ter Steeg [/bib_ref] [bib_ref] Effectiveness of primary conservative management for infants with obstetric brachial plexus palsy, Bialocerkowski [/bib_ref] addressed nonoperative interventions excluding natural history. Each review highlighted the importance of therapists delivering non-operative treatment, and suggested that all infants be assessed by a specialised therapist, [bib_ref] Orthopaedic sequelae in neurologically recovered obstetrical brachial plexus injury. Case study and..., Ter Steeg [/bib_ref] for management and parent/guardian education. [bib_ref] Developmental and behavioural outcome in obstetric brachial plexus palsy, Bellew [/bib_ref] Non-operative protocols were descriptively reviewed in these prior reviews; details of interventions were poor prohibiting replication, [bib_ref] Effectiveness of primary conservative management for infants with obstetric brachial plexus palsy, Bialocerkowski [/bib_ref] and insufficient evidence exists to support specific treatment recommendations beyond therapist referral. 5. Non-operative therapy delivered outside of a multidisciplinary centre should be advised by a multidisciplinary team. No qualifying statement. ▸ No study identified and analysed the impact of nonoperative therapy delivered or supervised by a specialised multidisciplinary centre versus in the community. ▸ Community providers may not have the expertise to recognise and characterise residual impairment. Ongoing communication between multidisciplinary and community providers may identify patient issues throughout the child's growth and development, and expedite specialised assessment. 6. Offer microsurgical nerve repair: i. For injuries clinically consistent with root avulsion injury. ii. For all other injuries meeting centre-defined operative criteria applied beginning at 3 months of age. Total plexus injuries with clinical evidence consistent with T1 root avulsion (eg, Horner's syndrome) should be offered nerve repair as soon as the injury pattern is apparent and the child is fit for the procedure. ▸ From the meta-analysis of primary management, pooled analysis of 222 patients from nine cohort studies shows that nerve repair reduces impairment; relative risk (RR) 0.58, 95% CI 0.43 to 0.79, p<0.001, absolute risk reduction (ARR) 19%, number needed to treat (NNT) 6. This outcome may underestimate the effectiveness of primary nerve repair. Results are consistent in analysis of case series, RR 0.39, 95% CI 0.33 to 0.45. 2 ▸ Avulsion injuries are the most severe; these injuries are worse than the severity represented by our pooled analysis. The nerve root is physically separated from the motor cell body within the spinal cord. No motor spontaneous recovery is expected. 12 ▸ From the meta-analysis of primary management, mortality and major adverse events are not common risks of modern microsurgical nerve repair. Adverse events were reported in 19 series of operative management in our review. No deaths were reported. Major events occurred in 1.5% of cases. [bib_ref] Primary nerve repair for obstetrical brachial plexus injury: a meta-analysis, Coroneos [/bib_ref] 7. For objective outcome collection, a common data set includes: i. Clinical distribution using the Narakas classification at the initial multidisciplinary centre assessment. ii. Limb length, [bib_ref] Limb length differences after obstetrical brachial plexus injury: a growing concern, Bain [/bib_ref] Active Movement Scale (AMS) [bib_ref] The active movement scale: an evaluative tool for infants with obstetrical brachial..., Curtis [/bib_ref] and Brachial Plexus Outcome Measure (BPOM) when age applicable 71 at 1, 3, 6, 12 and 24 months of age, then annually for the duration of follow-up. The common data set provides consistent baseline stratification and outcome measurement, facilitating multicentre research. Data set outcomes are not operative indications. Alternatively to the Narakas classification, injury distribution can be classified by involved nerve roots and evidence of Horner's syndrome. For consistency, each outcome should be measured as defined in the primary literature (eg, limb length to nearest 0.5 cm). ▸ For injury baseline classification, the Narakas classification is the most common classification system used, though reliability and validity are not formally established, and modifications have been suggested. 87 ▸ Three systematic reviews suggested assessing OBPI using the ICF domains. An ICF Core Set is currently lacking. 88 ▸ The AMS 86 is validated in OBPI with robust psychometric properties. It measures ICF Body Functions and Structure. ▸ The BPOM 71 is a disease-specific functional assessment tool with excellent construct validity. It complements the AMS. Psychometric evaluation and analysis of evaluative validity are pending. In contrast to other tools, it is practical to administer and score, and evaluates the complete upper extremity. It measures ICF Activity and Participation in the context of a child's own environment. ▸ Physiologically, limb length and circumference 11 are reliable, and discrepancies are detected as early as 1 month in severe lesions. Growth discrepancy is limited with nerve repair, and correlates with impairment. 89 ▸ Timing of outcome assessment was not discussed in reviews. In the meta-analysis of primary management, outcomes were measured until at least 2 years of age for non-operative management, or 2 years following operative management. 2 # Discussion This is the first formal clinical practice guideline for the primary management of OBPI. In situations where practice is heterogeneous and evidence is unclear, rigorous approaches to knowledge synthesis and application have the greatest capacity to impact practice. [bib_ref] What is the best way to produce consensus and buy in to..., Wong [/bib_ref] Context Early referral is guardian important, it provides early coordinated assessment and education at multidisciplinary centres. Recommendations 1-3 address primary care awareness of OBPI, and inform referral. The 1 month time point is conservative, reflecting guardian, physician and therapist preference. The proportion of neuropraxic injuries will recover substantially within 1 month. However, the consensus group reflected each centre's preference to assess all infants identified with OBPI. While a novel algorithm endorses early identification and referral of only potential surgical candidates, [bib_ref] Severe obstetric brachial plexus palsies can be identified at one month of..., Malessy [/bib_ref] it relies on interpretation of electromyography and nerve conduction study. It is feasible that a referral system could be overseen by multidisciplinary centres to interpret history and investigations completed at satellite centres; timing of consultation with physicians and therapists could then be triaged appropriately. This could address geographic distribution of specialists in Canada. Recommendations 4-6 reflect the personnel and management to provide evidence-based care. Evidence is insufficient to recommend specific non-operative interventions or therapy protocols. While functional impairment with nerve repair reduces functional impairment versus non-operative management, recommendations do not differentiate OBPI severity beyond avulsion, or identify the best surgical algorithm and/or nerve repair procedure. While the evidence did not support one surgical algorithm, it is sufficient to support the principle of early nerve repair in patients failing to recover. Further evidence is required to guide specifics of non-operative and operative protocols. Multicentre study is required to achieve sufficient sample size to inform specific therapy recommendations, given the range of OBPI clinical patterns and nerve repair options available. In its design, this guideline has formed a network of opinion leaders with representation from every multidisciplinary centre. An engaged network and consistent outcome assessment will facilitate evaluation of the interventions and algorithms already practised at Canadian centres. [bib_ref] Navigating the gray zone: a guideline for surgical decision making in obstetrical..., Bain [/bib_ref] Strengths Our methodology was rigorous, following an established framework.Guideline implementation and dissemination were considered in design; 49 opinion leaders were chosen for their influence on local health policy and resources. [bib_ref] Opinion leaders' support for tobacco control policies and participation in tobacco control..., Howard [/bib_ref] The formal consensus process 64 was transparent and structured; it accommodated the geographic distribution of the consensus group, [bib_ref] The Delphi methodology ( part one): a useful administrative approach, Jairath [/bib_ref] and anonymity prevented the process from being dominated. [bib_ref] Using and reporting the Delphi method for selecting healthcare quality indicators: a..., Boulkedid [/bib_ref] Two original studies were performed to optimise the evidence base, and clear connections were established between the evidence base and recommendations. The recommendations themselves addressed broad, system-level questions; they provide clinical guidance on the divergence of opinion between primary care and specialists. A baseline for system performance is established with quality indicators for referral. # Limitations In selecting the OBPI Working Group, the positional approach identified only surgeons. Future updates to this guideline will be multidisciplinary. The guideline was reviewed by experts for completeness of literature review, clinical sensibility and methodology; [bib_ref] Clinical guidelines: developing guidelines, Shekelle [/bib_ref] further external review would be redundant.Further, education of primary care and addressing disagreement between specialists and primary care were goals of the guideline. [bib_ref] Understanding variation in rates of referral among general practitioners: are inappropriate referrals..., Fertig [/bib_ref] An estimation of cost was not available. The working group did not formally solicit guardian preferences; recommendations relied on patient preferences for referral, education and management from the literature. [bib_ref] Medical decision-making among adolescents with neonatal brachial plexus palsy and their families:..., Squitieri [/bib_ref] The GRADE approach was not used, reflecting many cancer guideline bodies. [bib_ref] A for effort: learning from the application of the GRADE approach to..., Brouwers [/bib_ref] OBPI is similar to cancer given its small expert pool, treatment at specialised academic centres, and absence of level I evidence. GRADE has a number of limitations in this clinical setting. [bib_ref] A for effort: learning from the application of the GRADE approach to..., Brouwers [/bib_ref] Instead, we followed an established framework,interpreted strength of evidence in every facet of the evidence base and used a formal consensus process. ## Implementation With establishment and baseline measurement of quality indicators for referral, an optimised meta-analysis for nerve repair and a clinical practice guideline, this programme of research provides the tools and means to improve quality of care, health services, patient outcomes and policy for OBPI in Canada. However, without an approach to implementation, recommendations often fail to achieve potential benefits in care process, use of best evidence and practice consistency. [bib_ref] Toward evidence-based quality improvement. Evidence (and its limitations) of the effectiveness of..., Grimshaw [/bib_ref] There is insufficient evidence to support one guideline implementation strategy, or a cluster of strategies. [bib_ref] Effectiveness and efficiency of guideline dissemination and implementation strategies, Grimshaw [/bib_ref] However, integrated knowledge translation (IKT) interventions are suited to OBPI. IKT integrates relevant end users and researchers in intervention design and dissemination. [bib_ref] Applying the knowledge to action framework to plan a strategy for implementing..., Munce [/bib_ref] IKT is particularly relevant to OBPI given the range of providers involved in perinatal care and the multidisciplinary team involved in management. [bib_ref] Applying the knowledge to action framework to plan a strategy for implementing..., Munce [/bib_ref] Collaboration between primary care, parents, specialists and resource managers is critical to timely referral and optimised care. # Conclusions The Canadian OBPI Working Group: next steps Referral to multidisciplinary care is a gap in OBPI care. Referral recommendations are more effective if local specialists are involved in dissemination, and structured referral forms are available. [bib_ref] Interventions to improve outpatient referrals from primary care to secondary care, Akbari [/bib_ref] The Canadian OBPI Working Group already includes leaders at each national multidisciplinary centre. To improve referral, and provide consistent information to primary care and guardians, the working group has developed a national referral form (see online supplementary appendix 2). A multidisciplinary guideline can integrate a fragmented patient management system and enhance implementation. Only a multidisciplinary group can connect public education and awareness, risk factor modification, referral, assessment and therapy. The planned update to this guideline includes all relevant primary care and specialty disciplines: therapists, primary care, obstetrics, perinatal care and child specialists. An introductory multidisciplinary meeting occurred in June 2015. Guideline development formed a network of opinion leaders, and recommendations included outcome assessment to establish a common data set. The working group is endeavouring to establish a shared database for novel research, and multicentre studies. Active national research will improve access to evidence-based therapies and measure outcomes across our healthcare system. Overall, the Canadian OBPI Working Group's goal is to transform OBPI care with a model that recognises patient priorities from labour/delivery to full maturity, while achieving best care at every level of the healthcare system. Resources are available, and our activities can be followed at brachialplexus.ca. [table] Table 2: Results of the consensus process for recommendations [/table]	None	None	Objective The objective of this study was to establish an evidence-based clinical practice guideline for the primary management of obstetrical brachial plexus injury (OBPI). This clinical practice guideline addresses 4 existing gaps: (1) historic poor use of evidence, (2) timing of referral to multidisciplinary care, (3) Indications and timing of operative nerve repair and (4) distribution of expertise. Setting The guideline is intended for all healthcare providers treating infants and children, and all specialists treating upper extremity injuries. Participants The evidence interpretation and recommendation consensus team (Canadian OBPI Working Group) was composed of clinicians representing each of Canada's 10 multidisciplinary centres. Outcome measures An electronic modified Delphi approach was used for consensus, with agreement criteria defined a priori. Quality indicators for referral to a multidisciplinary centre were established by consensus. An original meta-analysis of primary nerve repair and review of Canadian epidemiology and burden were previously completed. Results 7 recommendations address clinical gaps and guide identification, referral, treatment and outcome assessment: (1) physically examine for OBPI in newborns with arm asymmetry or risk factors; (2) refer newborns with OBPI to a multidisciplinary centre by 1 month; (3) provide pregnancy/birth history and physical examination findings at birth; (4) multidisciplinary centres should include a therapist and peripheral nerve surgeon experienced with OBPI; (5) physical therapy should be advised by a multidisciplinary team; (6) microsurgical nerve repair is indicated in root avulsion and other OBPI meeting centre operative criteria; (7) the common data set includes the Narakas classification, limb length, Active Movement Scale (AMS) and Brachial Plexus Outcome Measure (BPOM) 2 years after birth/surgery. Conclusions The process established a new network of opinion leaders and researchers for further guideline development and multicentre research. A structured referral form is available for primary care, including referral recommendations.
1927cf1075d0461f92be1ee3e6d468aa0a530aa1	pubmed	Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021	Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021 of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response. # Introduction Despite the vast literature on managing early-stage breast cancer, not all clinical scenarios can be directly informed by data from randomized trials or other definitive treatment studies. Our approach to breast cancer is becoming progressively individualized, reflecting details of tumor size and nodal status, tumor subsets (and increasingly, subsets of subsets), genomic markers of risk, variations in patient age and health, the evolving and improving efficacy of systemic treatments, the shifting methods of radiation therapy, tailored surgical approaches to management of the axilla, prognostic factors, the widespread use of neoadjuvant treatment that provides information about dynamic response, and the subsequent use of post-neoadjuvant systemic treatment. The result is that, for a surprising number of clinical situations, there are insufficient definitive data from clinical trials to guide recommendations. Clinicians and patients must make inferences from canonical treatment studies, and customize them to individual situations, also informed by patient preferences and evolving clinical data. Since the last Consensus conference in 2019, breast cancer has surpassed lung cancer to become the most frequently diagnosed cancer in the world, underscoring the importance of global guidance for optimal treatment. [bib_ref] Global Cancer Statistics 2020: GLOBOCAN estimates of Incidence and mortality worldwide for..., Sung [/bib_ref] Fortunately, the past 2 years also have seen a continuous outpouring of data on management of breast cancer, reflecting growing understanding of the biology and treatment of early-and late-stage disease [fig_ref] Table 1: New studies in breast cancer since St Gallen 2019 [/fig_ref]. Owing to widespread screening mammography around much of the world, the increasing efficacy of targeted therapies such as endocrine and anti-human epidermal growth factor receptor 2 (anti-HER2) treatments, and greater access to effective health care, the mortality from breast cancer continues to decline in middle-and high-income countries. [bib_ref] Global Cancer Statistics 2020: GLOBOCAN estimates of Incidence and mortality worldwide for..., Sung [/bib_ref] However, there remain profound disparities among and within nations in terms of access to screening programs, high-quality treatment and supportive care for breast cancer. Many services remain unavailable, unaffordable, or beyond the capacity of the local health care system. The disruptions of the COVID-19 pandemic are likely to exacerbate these disparities in the short term, straining the health care resources of every country, affecting access to screening mammography, [bib_ref] Disruptions in preventive care: mammograms during the COVID-19 pandemic, Song [/bib_ref] and sometimes delaying necessary treatment. [bib_ref] The Impact of the COVID-19 pandemic on breast imaging, Freer [/bib_ref] As an international consensus panel, the St Gallen faculty are keenly aware of the differences in resources for detection and treatment of early breast cancer. There is universal commitment to reduce these disparities. At the same time, panelist recommendations are often affected by the availability of certain techniques, imaging modalities, molecular diagnostic approaches or treatment options, which vary from country to country, or even within nations. The Panel sought to provide clinical guidance on common clinical situations in early breast cancer, including refined guidance on local-regional and systemic therapy that builds on its previous recommendations. [bib_ref] Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen..., Burstein [/bib_ref] This year, there were strong interests in refining thresholds for treatment, the use of genomic signatures, evolving practices in radiation oncology, the utilization of ovarian suppression, and the surgical and systemic decision-making following neoadjuvant treatment. In addition, for the first time, the Panel addressed challenges in oligometastatic breast cancer management, and the treatment of ipsilateral recurrences or second cancers. The Panel also devoted more time this year to discussions of breast cancer survivorship, a recognition of the millions of women and men who have personal histories of breast cancer and who are coping with the psychological and physical side-effects of their cancer treatments. Guidance is intended to apply to the vast majority of patients with early breast cancer who are in reasonably good health, and who do not have medical, psychological, or social conditions that would preclude standard treatment. Votes reflect the opinions of the experts based on what they would advise in clinical practice. The Panel recognizes that treatment guidance may not be applicable to selected cases owing to patient preferences, treatment availability, or other individual circumstances. ## Genetic testing and management of hereditary breast cancers and syndromes Hereditary, deleterious mutations account for 8%-10% of all breast cancers. [bib_ref] A study of over 35,000 women with breast cancer tested with a..., Buys [/bib_ref] [bib_ref] A population-based study of genes previously implicated in breast cancer, Hu [/bib_ref] [bib_ref] Breast cancer risk genes e association analysis in more than 113,000 Women, Dorling [/bib_ref] While BRCA1/2 mutations account for about half of these cases, the remainder arise from less prevalent, and often less penetrant mutations found in up to two dozen different genes. As in the past, the Panel favored genetic counseling and germline genetic testing for patients whose age of breast cancer onset, family history of breast or other cancers, presence of male breast cancers and tumor subtype were more likely to identify a familial cause of breast cancer. Similarly, the Panel did not recommend universal genetic testing for all, though a growing percentage of panelists now favor genetic testing for all breast cancer patients diagnosed at age <65 years. The Panel developed guidance for people harboring deleterious, hereditary mutations that predispose to breast cancer but who have not been diagnosed with breast cancer. Recent population-based studies have clarified the risk of breast cancer for many deleterious gene mutations, and clustered them into groups of high penetrance (carrying a threefold or more increased risk of breast cancer relative to the general population), intermediate penetrance (twofold to threefold risk), or low penetrance (onefold to twofold risk). [bib_ref] A population-based study of genes previously implicated in breast cancer, Hu [/bib_ref] [bib_ref] Breast cancer risk genes e association analysis in more than 113,000 Women, Dorling [/bib_ref] There are varied opinions as to the best way to treat or follow women with known genetic predisposition to breast cancer, and the panelists acknowledge that both age and the individual preferences of women, reflecting their perceptions of risk and general comfort with the various approaches, are the key drivers of these choices. The degree of penetrance of the gene, and the age of the woman with a genetic diagnosis, affected the recommendations for prophylactic mastectomy [fig_ref] Table 2: Percentage of panelists recommending prophylactic mastectomy or surveillance for hereditary breast cancer... [/fig_ref]. If a gene panel testing is chosen, the majority (67%) voted that the preferred panel should routinely include: BRCA1, BRCA2, ATM, BARD1, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, STK11, RAD51C and RAD51D, and TP53. A minority (7%) voted that only BRCA1 and BRCA2 should be tested, and 17.2% of the panelists opted for the evaluation of BRCA1/2 and PALB2. In general, the Panel favored consideration of risk-reducing mastectomy for women harboring highly penetrant genes (e.g. BRCA1, BRCA2, TP53, and PALB2), and surveillance with mammography and magnetic resonance imaging (MRI), for women with intermediate penetrance genes (e.g. BARD1, CHEK2, CDH1, STK11). For women with less penetrant gene mutations (such as ATM, BRIP1, NF1, RAD51C, RAD51D), the Panel strongly favored surveillance without prophylactic mastectomy. Separately, the Panel discussed management of hereditary, BRCA1-or BRCA2-associated early-stage breast cancers. Before the conference, press statements became available, outlining the results of the OlympiA trial evaluating olaparib in the adjuvant setting. Following the St Gallen conference, the data from the OlympiA trial were published, showing a significant reduction in recurrence risk with adjuvant olaparib in HER2-negative, BRCA1/2associated breast cancer. [bib_ref] Adjuvant olaparib for patients with BRCA1-or BRCA2-mutated breast cancer, Tutt [/bib_ref] Based on those newly available data, the Panelists were re-canvassed for treatment ## Genetics and hereditary breast cancer Large population-based studies define penetrance and risks of most common hereditary genes associated with breast cancer [bib_ref] A population-based study of genes previously implicated in breast cancer, Hu [/bib_ref] [bib_ref] Breast cancer risk genes e association analysis in more than 113,000 Women, Dorling [/bib_ref] TBCRC048 trial shows that the PARP inhibitor, olaparib, has substantial effect in MBC for tumors with hereditary PALB2 mutation or somatic BRCA1/2 mutation [bib_ref] TBCRC 048: phase II study of olaparib for metastatic breast cancer and..., Tung [/bib_ref] The OlympiA trial demonstrates that adjuvant therapy with olaparib reduces recurrence in BRCA1/2associated breast cancer [bib_ref] Adjuvant olaparib for patients with BRCA1-or BRCA2-mutated breast cancer, Tutt [/bib_ref] Population studies suggest that age and family history criteria may miss many cases of hereditary breast cancer [bib_ref] Prevalence of pathogenic variants in cancer susceptibility genes among women with postmenopausal..., Kurian [/bib_ref] Supportive care Oyxbutynin shown effective for climacteric symptoms in breast cancer patients [bib_ref] Oxybutynin vs placebo for hot flashes in women with or without breast..., Leon-Ferre [/bib_ref] Quality-of-life studies demonstrate profound effects of ovarian suppression on bone health and sexual health in premenopausal women [bib_ref] Treatment-induced symptoms, depression and age as predictors of sexual problems in premenopausal..., Ribi [/bib_ref] COVID pandemic Pandemic disrupts routine patient management, and prompts guideline revisions to prioritize treatment needs amid epidemic [bib_ref] ESMO management and treatment adapted recommendations in the COVID-19 era: breast cancer, De Azambuja [/bib_ref] [bib_ref] International guidelines on radiation therapy for breast cancer during the COVID-19 pandemic, Coles [/bib_ref] [bib_ref] Recommendations for prioritization, treatment, and triage of breast cancer patients during the..., Dietz [/bib_ref] Rates of screening mammography plummet in wake of pandemic [bib_ref] Population-level impact of coronavirus disease 2019 on breast cancer screening and diagnostic..., Nyante [/bib_ref] Radiation therapy Efficacy of hypofractionation for postmastectomy radiation [bib_ref] Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer:..., Wang [/bib_ref] Efficacy of hypofractionation for invasive breast cancer and DCIS after breast conserving surgery [bib_ref] Hypofractionated versus standard fractionated radiotherapy in patients with early breast cancer or..., Offersen [/bib_ref] Use of ultra-hypofractionated radiation schedules after breast conserving surgery [bib_ref] Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy..., Brunt [/bib_ref] [bib_ref] Ten-year results of fast: a randomized controlled trial of 5-fraction whole-breast radiotherapy..., Brunt [/bib_ref] Efforts to standardize variations in radiotherapy practice and access [bib_ref] Internal mammary and medial supraclavicular lymph node chain irradiation in stage IeIII..., Poortmans [/bib_ref] [bib_ref] The financial impact on reimbursement of moderately hypofractionated postoperative radiation therapy for..., Marta [/bib_ref] [bib_ref] ESTRO ACROP consensus guideline for target volume delineation in the setting of..., Kaidar-Person [/bib_ref] [bib_ref] Why is appropriate healthcare inaccessible for many European breast cancer patients? e..., Cardoso [/bib_ref] Partial breast irradiation updates [bib_ref] Endocrine therapy with or without whole breast irradiation in low-risk breast cancer..., Fastner [/bib_ref] [bib_ref] Patient-reported outcomes over 5 years after whole-or partial-breast radiotherapy: longitudinal analysis of..., Bhattacharya [/bib_ref] [bib_ref] Accelerated partial-breast irradiation compared with whole-breast irradiation for early breast cancer: long-term..., Meattini [/bib_ref] [bib_ref] External beam accelerated partial breast irradiation versus whole breast irradiation after breast..., Whelan [/bib_ref] [bib_ref] Apples and oranges: comparing partial breast irradiation techniques, Kaidar-Person [/bib_ref] [bib_ref] Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for..., Vicini [/bib_ref] Long-term follow-up of the PRIME2 study confirms absence of survival benefit but reduction in local recurrence for postlumpectomy radiation in older women [bib_ref] Abstract GS2-03: prime 2 randomised trial (postoperative radiotherapy in minimum-risk elderly): wide..., Kunkler [/bib_ref] DCIS 'Boost' after radiation therapy reduces in-breast recurrence; hypofractionation is as effective as 25 Fx treatments for DCIS after breast-conserving surgery [bib_ref] Hypofractionated versus standard fractionated radiotherapy in patients with early breast cancer or..., Offersen [/bib_ref] [bib_ref] Abstract GS2-04: a randomized phase III study of radiation doses and fractionation..., Chua [/bib_ref] Surgery E2108, a randomized trial of surgery in women with de novo stage IV breast cancer, showed that breast surgery does not improve overall survival, thereby contradicting the results of multiple observational studies, while prior randomized trials have provided conflicting data. [bib_ref] A randomized phase III trial of systemic therapy plus early local therapy..., Khan [/bib_ref] BOMET MF 14-01: timing of primary breast surgery either at diagnosis or after systemic therapy provided a survival benefit similar to ST alone in de novo stage IV BOM BC patients. This is the followup study to their randomized trial. [bib_ref] The effect of primary surgery in patients with de novo stage IV..., Soran [/bib_ref] Several single-center series demonstrated low nodal failure rates in patients with biopsy proven clinically node-positive breast cancer undergoing sentinel lymph node surgery without axillary dissection, despite considerable false-negative rate after neoadjuvant chemotherapy [bib_ref] Long-term standard sentinel node biopsy after neoadjuvant treatment in breast cancer: a..., Kahler-Ribeiro-Fontana [/bib_ref] [bib_ref] Oncologic outcomes of sentinel lymph node surgery after neoadjuvant chemotherapy for nodepositive..., Piltin [/bib_ref] [bib_ref] Oncologic safety of sentinel lymph node biopsy alone after neoadjuvant chemotherapy for..., Wong [/bib_ref] SenTa, a prospective multicenter study, showed that targeted axillary dissection minimizes the falsenegative rate of sentinel lymph node surgery after neoadjuvant chemotherapy in patients with nodepositive breast cancer, but detection rate of clipped lymph node was only 86.9%.The Oncoplastic Breast Consortium ranked optimal type and timing of reconstruction in the setting of postmastectomy radiotherapy as the most important of a list of 38 knowledge gaps in the field of oncoplastic breast surgery [bib_ref] Knowledge gaps in oncoplastic breast surgery, Weber [/bib_ref] The Lucerne Toolbox: Consensus and Guideline that summarizes surgery after neochemo [bib_ref] Breast conservation and axillary management after primary systemic therapy in patients with..., Dubsky [/bib_ref] Early-stage, ER-positive breast cancer: clinical First reports of adjuvant CDK4/6 inhibitors show mixed results The MONARCH-E trial showed that adjuvant abemaciclib reduced recurrence in high-risk, ERþ breast cancer [bib_ref] Abemaciclib combined with endocrine therapy for the adjuvant treatment of HRþ, HER2À,..., Johnston [/bib_ref] The PALLAS trial showed that adjuvant palbociclib did not reduce recurrence in high risk ERþ breast cancer [bib_ref] Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis..., Mayer [/bib_ref] The PENELOPE-b trial showed that adjuvant palbociclib did not reduce recurrence in high-risk ERþ breast cancer [bib_ref] Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancerdThe Penelope-B..., Loibl [/bib_ref] Data from ABCSG 16 suggest that extended duration adjuvant endocrine therapy beyond 7/8 years does not improve outcomes [bib_ref] Abstract GS3-01: a prospective randomized multi-center phase-III trial of additional 2 versus..., Gnant [/bib_ref] Data from NSABP B-42 suggest that 5 years of AI therapy after an initial 5 years of endocrine therapy can reduce breast cancer recurrence [bib_ref] Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG..., Mamounas [/bib_ref] Ongoing follow-up of the SOFT and TEXT trials confirms the importance of tumor stage and grade as prognostic factors in premenopausal breast cancer [bib_ref] Absolute improvements in freedom from distant recurrence to tailor adjuvant endocrine therapies..., Pagani [/bib_ref] Long-term follow-up from the TAILORx and MINDACT trials shows that there is no benefit to chemotherapy in postmenopausal women with tumors bearing low-risk genomic scores, but that chemotherapy can reduce the risk of recurrence in premenopausal women, likely due to chemotherapy-induced amenorrhea [bib_ref] 70-gene signature as an aid for treatment decisions in early breast cancer:..., Piccart [/bib_ref] [bib_ref] Clinical and genomic risk to guide the use of adjuvant therapy for..., Sparano [/bib_ref] The RxPonder study shows that there is no benefit to chemotherapy in postmenopausal women with node-positive tumors bearing low-risk genomic scores, but that chemotherapy can reduce the risk of recurrence in premenopausal women, possibly due to chemotherapy-induced amenorrhea [bib_ref] Abstract GS3-00: first results from a phase III randomized clinical trial of..., Kalinsky [/bib_ref] Early-stage, ER-positive breast cancer: translational Endopredict and response to neochemo and neoendocrine therapydfor gene expression and neochemo questions [bib_ref] The EndoPredict score predicts response to neoadjuvant chemotherapy and neoendocrine therapy in..., Dubsky [/bib_ref] Independent validation of the PAM50-based Chemo-Endocrine Score in hormonal receptor-positive HER2-positive breast cancer treated with neoadjuvant therapydalso for use of gene expression before neochemo questions [bib_ref] Independent validation of the PAM50-based chemo-endocrine score (CES) in hormone receptor-positive HER2-positive..., Pascual [/bib_ref] ADAPT trialdusing oncotype and ki-67 for chemotherapy versus no chemotherapy [bib_ref] Abstract GS4-04: endocrine therapy alone in patients with intermediate or high-risk luminal..., Harbeck [/bib_ref] HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: a systematic review and meta-analysis [bib_ref] HER2-enriched subtype and pathological complete response in HER2-positive breast cancer: a systematic..., Schettini [/bib_ref] A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation [bib_ref] A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast..., Prat [/bib_ref] ## Continued ## Annals of oncology recommendations. Nearly all panelists (>93%) strongly endorsed adjuvant olaparib for women with stage II or III, HER2-negative cancers meeting the eligibility criteria of the OlympiA study. The majority of panelists (64%) favored olaparib therapy for all such patients, irrespective of estrogen receptor (ER) status or prior treatment with platinum-based chemotherapy. As a corollary, the Panel voted nearly unanimously (95%) to recommend genetic testing of patients meeting the OlympiA trial criteria to identify candidates for olaparib-based therapy. ## Pathology and subsets In clinical practice, early-stage breast cancers are divided into three subgroups based on expression of ER, progesterone receptor (PR), and HER2. Tumors are classified as ER-and/or PR-positive and HER2-negative (hereafter, ERpositive), HER2-positive, or by default, triple-negative breast cancer (TNBC). Approximately half of HER2-positive tumors are also ER-positive. These categorizations have definitive consequences for systemic treatment. Nearly all ER-positive tumors will be candidates for adjuvant endocrine therapy. The majority of TNBCs will warrant adjuvant chemotherapy, and the majority of HER2-positive cancers warrant anti-HER2 therapy in combination with chemotherapy. The historic 1% threshold for ER expression to justify endocrine therapy remains controversial. Studies suggest that tumors with 1%-9% ER expression on immunohistochemical staining, which account for <2% of all ER- The PIK3CA kinase inhibitor, alpelisib, improves PFS in PIK3CA-mutated ERþ breast cancer [bib_ref] Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer, André [/bib_ref] Entinostat, an HDAC inhibitor, does not improve outcomes in advanced breast cancer [bib_ref] Abstract GS4-02: E2112: randomized phase 3 trial of endocrine therapy plus entinostat/placebo..., Connolly [/bib_ref] Early-stage, HER2-positive breast cancer Long-term follow-up of the APHINITY trial shows OS benefit for pertuzumab in node-positive but not node-negative breast cancer [bib_ref] Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY..., Piccart [/bib_ref] The ATEMPT study shows equivalent long-term tumor control with trastuzumab emtansine compared with trastuzumab þ paclitaxel for stage I breast cancer but without safety benefits [bib_ref] Abstract GS1-05: TBCRC 033: a randomized phase II study of adjuvant trastuzumab..., Tolaney [/bib_ref] Long-term follow-up of the ExteNet study suggests benefit for adjuvant neratinib in women with ERþ HER2þ breast cancer [bib_ref] Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer..., Chan [/bib_ref] The KRISTINE study showed the TCHP was associated with improved disease-free survival compared with pertuzumab þ trastuzumab emtansine owing to differences in local-regional recurrence [bib_ref] Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2-positive..., Hurvitz [/bib_ref] Advanced-stage, HER2-positive breast cancer The HER2CLIMB trial demonstrates that adding tucatinib to capecitabine plus trastuzumab improves OS in advanced breast cancer [bib_ref] Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer, Murthy [/bib_ref] The DESTINY trial shows high response rates for trastuzumab deruxtecan in advanced breast cancer [bib_ref] Trastuzumab deruxtecan in previously treated HER2-positive breast cancer, Modi [/bib_ref] The NALA study shows that neratinib þ capecitabine improve PFS but not OS compared with lapatinib þ capecitabine [bib_ref] Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer..., Saura [/bib_ref] Early-stage, triple-negative breast cancer The SYSUCC trial shows that metronomic, adjuvant capecitabine reduces recurrence risk The CBCSG-10 trial showed that adding capecitabine to adjuvant chemotherapy reduces recurrence risk The Keynote-522 study showed that adding neoadjuvant pembrolizumab to AC/paclitaxel plus carboplatin chemotherapy improves rate of pCR and may reduce recurrence risk [bib_ref] Pembrolizumab for early triplenegative breast cancer, Schmid [/bib_ref] The IMPASSION031 study showed that adding neoadjuvant atezolizumab to nab-paclitaxel and anthracycline chemotherapy improves the rate of pCR [bib_ref] Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracyclinebased chemotherapy versus placebo..., Mittendorf [/bib_ref] The NeoTrip study showed that adding neoadjuvant atezolizumab to nab-paclitaxel and carboplatin chemotherapy did not improve the rate of pCR [bib_ref] Abstract GS3-04: pathologic complete response (pCR) to neoadjuvant treatment with or without..., Gianni [/bib_ref] Advanced-stage, triple-negative breast cancer The KEYNOTE-199 trial showed that single-agent checkpoint inhibition did not improve OS compared with chemotherapy [bib_ref] Pembrolizumab versus investigatorchoice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised,..., Winer [/bib_ref] In contrast to the IMPASSION130 study of nab-paclitaxel AE atezolizumab, the IMPASSION131 trial did not show benefit for adding atezolizumab to paclitaxel in first-line therapy for PD-L1-positive breast cancer [bib_ref] LBA15 Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial..., Miles [/bib_ref] The KEYNOTE-355 trial showed that adding pembrolizumab to chemotherapy improved outcomes in first-line therapy for tumors with CPS score >10% [bib_ref] Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent..., Cortes [/bib_ref] The ASCENT trial showed that sacituzumab govitecan improved PFS and OS compared with standard chemotherapy in refractory TNBC [bib_ref] LBA17 ASCENT: a randomized phase III study of sacituzumab govitecan (SG) vs..., Bardia [/bib_ref] Pathology An international consensus committee endorsed thresholds of Ki67 5% and 30% for rejecting or recommending adjuvant chemotherapy in ERþ early breast cancer [bib_ref] Assessment of Ki67 in breast cancer: updated recommendations from the international Ki67..., Nielsen [/bib_ref] AC, doxorubicin/cyclophosphamide; AI, aromatase inhibitor; AR, androgen receptor; BOM BC, bone-only metastatic breast cancer; CDK4/6, cyclin dependent kinase 4 or 6; CPS, combined positive score; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HDAC, histone deacetylase; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer; OS, overall survival; PARP, poly (ADP-ribose) polymerase; pCR, pathological complete response; PD-L1, programmed death-ligand 1; PFS, progression-free survival; PIK3CA, phosphatidylinositol 3-kinase alpha; PR, progesterone receptor; ST, systemic therapy; TCHP, docetaxel/carboplatin/trastuzumab/pertuzumab; TNBC, triple-negative breast cancer. positive cancers, have a less favorable prognosis than ERpositive cancers with !10% expression, often have a basal-like genomic signature 9 and respond to neoadjuvant chemotherapy akin to TNBC. [bib_ref] Therapy response and prognosis of patients with early breast cancer with low..., Villegas [/bib_ref] Yet other large retrospective studies suggest that outcomes for tumors with 1%-9% ER expression are intermediate between those truly ERnegative and ER-positive !10%. [bib_ref] Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone..., Viale [/bib_ref] The Panel was once more divided on the optimal ER threshold for initiation of endocrine therapy. Determination of grade, proliferation (such as the Ki67 labeling index), and multigene assays such as the 70-gene signature test and 21-gene recurrence score help characterize the heterogeneity of ER-positive, early-stage breast cancers, and serve as prognostic markers for recurrence risk. ER-positive cancers are sometimes classified as 'luminal A-like' (lower grade, lower Ki67, strong ER/PR expression), or 'luminal B-like' (higher grade, higher Ki67, lower levels of ER/PR expression), subtype associations that tend to correlate with genomic markers of risk. There is persistent controversy over the precise thresholds for Ki67 that would justify chemotherapy treatment or not. The Panel generally supported recent working group recommendations that tumors with Ki67 5% do not receive chemotherapy, whereas tumors with Ki67 !30% receive chemotherapy. [bib_ref] Assessment of Ki67 in breast cancer: updated recommendations from the international Ki67..., Nielsen [/bib_ref] Most early-stage, ER-positive tumors, however, fall between these extremes. [bib_ref] Clinical and analytical validation of Ki-67 in 9069 patients from IBCSG VIII..., Denkert [/bib_ref] When polled, the Panel could not define a consistent Ki67 threshold between 10% and 25% for recommending chemotherapy in ER-positive, nodenegative breast cancer, and a large fraction of the Panel believe that such a threshold was simply not known [fig_ref] Figure 1: Defining threshold for Ki67 to recommend adjuvant chemotherapy in ER-positive, HER2-negative, node-negative... [/fig_ref]. Data continue to accumulate for utility of genomic signatures to identify the benefit of chemotherapy in earlystage, ER-positive, HER2-negative breast cancer. Adoption of these signatures in clinical practice has dramatically lowered the use of adjuvant chemotherapy in this subset of breast cancers, without adversely affecting clinical outcomes. The Panel's deliberations reflected the maturation of prospective studies built around these assays, including emerging data for use of the assays in both node-negative and limited (1-3 positive) node-positive cases. With mature data from prospective studies such as MINDACT, ADAPT, TAILORx, and RxPonder, in which patients were stratified for treatment based on well-established genomic signatures, panelists favored consideration of genomic signature testing in the vast majority of instances when chemotherapy is being considered for ER-positive, HER2negative cancers, irrespective of grade or patient menopausal status (and in male breast cancer), and in both N0 or N1 clinical stage cases, but not in N2 or higher stage where chemotherapy is standard (see discussion below, and [fig_ref] Figure 2: Panel recommendations for genomic signature testing in ER positive, HER2 negative early... [/fig_ref]. The Panel's enthusiasm for genomic assays is accompanied by the understanding that access to such testing is not available to most women around the world, a disparity in care that needs rectifying. As gene expression signatures are not universally accessible, by necessity the Ki67 score serves as a surrogate for defining proliferation and biological risk, particularly when combined with semiquantitative measures of grade, ER, PR, and HER2 for many women. 14 Given the high-level evidence for clinical utility demonstrated by the genomic signatures in ER-positive breast cancer, and challenges in defining thresholds for treatment (above), Ki67 assessment will remain a necessary but less proven strategy for determining the role of adjuvant chemotherapy in ER-positive breast cancer for many women. The Panel believes it is critical that patients around the world have secure access to important, evolving molecular diagnostic assays for optimal management of breast cancer and determination of treatment value.Tumor infiltrating lymphocytes (TILs) and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) expression may serve as prognostic markers in early-or late-stage TNBC, and PD-L1 testing is a predictive marker for the benefit of checkpoint inhibitors in advanced TNBC. However, the Panel again declined to endorse either of these approaches as routine pathological markers in earlystage TNBC. TILs appear to serve as a prognostic marker for response to neoadjuvant chemotherapy, but data are not considered adequate for choosing specific regimens or deciding whether to withhold chemotherapy treatment. PD-1/PD-L1 expression predicts benefit from addition of checkpoint inhibitors to chemotherapy in the treatment of metastatic TNBC. However, trials have not shown that PD-L1 expression predicts the improvement in pathological complete response (pCR) when checkpoint inhibitors are added to neoadjuvant chemotherapy, an approach which (as of this date) remains investigational for early-stage TNBC. a Includes mammogram and breast magnetic resonance imaging, with or without antiestrogen prevention. ## Annals of oncology ## Local-regional therapy Historically, surgery was the initial treatment of women with newly diagnosed breast cancer. That remains true for most women diagnosed with early-stage tumors, where deciding between a mastectomy and breast-conserving surgery depends on the size of the tumor, the extent of radiological changes in the breast, the anticipated cosmetic outcomes and the patient's candidacy for radiation treatment and personal preferences. Surgical resection to remove known malignancy and achieve 'no ink on tumor' margins is the standard, regardless of tumor histology or grade, or the patient's age. At the time of breast surgery, women additionally undergo axillary surgery to stage the axillary lymph nodes. Sentinel node biopsy (SNB) is the standard approach in patients presenting with a clinically negative axilla, whether undergoing mastectomy or breastconserving surgery. Patients with negative sentinel nodes require no further axillary surgery. Women with T1-T2, clinically node-negative cancers with positive sentinel nodes who meet the criteria of the ACOSOG Z0011 trial [bib_ref] Effect of axillary dissection vs no axillary dissection on 10-year overall survival..., Giuliano [/bib_ref] radiation therapy is to be omitted, or in the clinical situations when knowing the extent of axillary involvement would affect systemic or radiation recommendations. ## Imaging and breast surgery Most women presenting with screen-detected or other early breast cancers are potential candidates for breastconserving surgery. Nonetheless, rates of mastectomy including contralateral mastectomy are increasing in many countries, reflecting patient preferences, fears of recurrence, improvements in reconstruction techniques, more widespread use of MRI imaging during the diagnostic evaluation, genetic testing 18 and lack of adequate physicianpatient communication. [bib_ref] Contralateral prophylactic mastectomy decisions in a population-based sample of patients with early-stage..., Jagsi [/bib_ref] For women undergoing mastectomy who are likely to warrant postmastectomy radiation and wish breast reconstruction, the Panel favored autologous reconstruction approaches, either immediate or delayed with implant as the first step. Among women undergoing breast-conserving surgery, the Panel did not identify a routine role for post-excision mammography provided that excision-specimen X-rays confirmed removal of known microcalcifications. The Panel supported baseline MRI imaging before neoadjuvant therapy for women who are potential candidates for breast conservation, though such MRI imaging is often highly sensitive while less specific, and is associated with a greater likelihood of (sometimes unnecessary) mastectomy. [bib_ref] Meta-analysis of pre-operative magnetic resonance imaging (MRI) and surgical treatment for breast..., Houssami [/bib_ref] Some elderly patients may not require SNB, as finding metastatic disease to axillary nodes is not likely to change treatment recommendations. However, because the morbidity associated with SNB is relatively low, and because the finding of nodal involvement might alter treatment plans in a minority of patients, the majority of the Panel favored the procedure in women even those aged in their 80s who were undergoing surgery for breast cancer. Radiation therapy. Radiation therapy is standard treatment following breast conserving surgery. Until recently, this meant treatment courses of 25 fractions of radiation therapy. Based on longer follow-up from multiple randomized trials, emerging studies, the 2021 Panel strongly recommended moderately hypofractionated radiation treatment courses, consisting of 15 or 16 treatments, as standard therapy, irrespective of tumor subtype or patient age. The Panel also strongly endorsed routine use of moderate hypofractionation in women receiving postmastectomy radiation and/or regional nodal irradiation (RNI), irrespective of patient age or tumor subtype, and endorsed these hypofractionated radiation therapy schedules among patients with reconstructions after mastectomy [fig_ref] Figure 3: Moderately hypofractionated radiation therapy [/fig_ref]. There is growing interest in ultra-short course (five fractions) treatment approaches, [bib_ref] Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy..., Brunt [/bib_ref] [bib_ref] Ten-year results of fast: a randomized controlled trial of 5-fraction whole-breast radiotherapy..., Brunt [/bib_ref] but the Panel did not endorse these as standard treatment as yet. The Panel urged caution in the use of partial breast irradiation, which has been studied largely in older patients with low-risk tumors, and recommended against partial breast approaches in lobular tumors or when lymphovascular invasion was present, in women <40 years of age, and in women with hereditary cancer syndromes. While genomic signatures have become highly influential in adjuvant Percentage of panelists endorsing moderately hypofractionated schedules of radiation therapy. After immed recon, after immediate reconstruction; PMRT, postmastectomy radiation therapy; RNI, regional nodal irradiation. ## Annals of oncology treatment decisions for ER-positive, HER2-negative breast cancer, panelists recommended against using genomic signatures to determine whether to use radiation treatment after breast-conserving surgery, or to inform decisions on regional nodal or postmastectomy radiation. The Panel considered the role of RNI in a variety of contexts. The Panel strongly voted against RNI for women with T2N0 tumors, regardless of tumor subtype, even when patients were receiving postsurgical breast or chest wall irradiation. Similarly, the Panel recommended against RNI in women with triple-negative or HER2-positive tumors, presenting with T2 stage tumors but a clinically negative axilla, who achieve a pCR to neoadjuvant treatment. However, the Panel strongly favored RNI for patients who initially presented with a clinically positive axillary node(s), even when such patients achieve a pCR with neoadjuvant therapy. The Panel customized its approach to boost following breast-conserving surgery with radiation. Boost was favored in cases of high-grade cancers, extensive intraductal component [extensive intraductal component (EIC)-positive], or TNBC or HER2-positive subtypes, and in women <50 years of age. Studies of radiation therapy in older (age !70 years) women with ER-positive breast cancers who are taking adjuvant endocrine therapy have shown that radiation therapy does not improve survival but can lower in-breast recurrence. [bib_ref] Abstract GS2-03: prime 2 randomised trial (postoperative radiotherapy in minimum-risk elderly): wide..., Kunkler [/bib_ref] [bib_ref] Lumpectomy plus tamoxifen with or without irradiation in women age 70 years..., Hughes [/bib_ref] [bib_ref] Endocrine therapy with or without whole breast irradiation in low-risk breast cancer..., Fastner [/bib_ref] For older women with a life expectancy of >10 years, the panelists took a nuanced, customized approach to radiation treatment, explicitly rejecting the notion that no such patients should receive radiotherapy. In general, the Panel favored radiation treatment of tumors >2.5 cm, cases of positive axillary node(s), or tumors with adverse biological features, and favored omitting radiation treatment in patients with shorter life expectancies, and those with stage I, ER-positive cancers, who are likely to be adherent with adjuvant endocrine therapy. It was, in part, to inform this decision that many panelists favor SNB even in older patients with ERpositive, HER2-negative cancers. ## Neoadjuvant therapy For women with stage II or III tumors, preoperative or neoadjuvant systemic therapy offers clinical advantages, including tumor downstaging which may affect surgical options in the breast or axilla. Additionally, the use of preoperative treatment invites customization of therapy based on the extent of treatment response, which serves as a prognostic marker and can identify women with residual cancer who may require additional adjuvant systemic therapy. In 2019, the St Gallen panel endorsed preoperative systemic therapy as the preferred approach for women with stage II or III, HER2-positive or triple-negative cancers. Neoadjuvant therapy is also the standard for women with inflammatory breast cancer, who then undergo mastectomy if operable after induction treatment, and in other presentations of inoperable, locally advanced breast cancer. ## Systemic treatments Neoadjuvant therapy remains preferred for stage II or III, HER2-positive or TNBCs, and for many higher stage ERpositive breast cancers. Nearly a decade ago, regulatory authorities proposed using the surrogate, prognostic measurement of pCR as an endpoint for accelerated approval of regimens in the neoadjuvant setting. [bib_ref] Pathological complete response and accelerated drug approval in early breast cancer, Prowell [/bib_ref] Despite dozens of randomized trials with different regimens and agents, only one drug (pertuzumab) to date has garnered approval based on pCR. The audience and Panel were asked to reflect on that experience, and whether pCR was a suitable endpoint for defining standard regimens in early-stage breast cancer. The majority of both the Panel (60%) and the audience (83%) believed that pCR was not the appropriate endpoint for defining standard neo/adjuvant systemic regimens, favoring longer term endpoints such as diseasefree or overall survival, typically required for full regulatory approval of new treatments. Of interest, the Panel strongly believed that 'all pCRs are the same.' That is, that the prognosis after achieving pCR in a given tumor subtype was similar whatever treatment was used to achieve that end. The implications of these two findings are that neoadjuvant trials intended to define standards of care should include long-term follow-up with robust data on recurrence and survival, and that risk stratification based on pCR following neoadjuvant therapy is a strategy for optimizing post-neoadjuvant treatment. Preferred neoadjuvant regimens for HER2-positive tumors (trastuzumab and pertuzumab, paired with taxane chemotherapy and either anthracycline-or platinum-based chemotherapy), and for TNBC (dose-dense anthracyclineand taxane-based chemotherapy) were unchanged from 2019 [fig_ref] Table 3: Systemic therapy for HER2-positive or triple-negative breast cancers [/fig_ref]. For triple-negative tumors, the Panel did not recommend the addition of immune checkpoint inhibitors as neoadjuvant therapy, and panelists remain divided on the role of carboplatin in addition to anthracycline-, taxane-, and alkylator-based therapy; a majority (60%) voted against routine use of carboplatin. There is growing interest in the use of neoadjuvant endocrine therapy in the treatment of ER-positive primary tumors. Small clinical experiences have suggested equal rates of clinical response for endocrine therapy as for chemotherapy, though neither approach routinely achieves a rate of pCR >10%. [bib_ref] Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal..., Semiglazov [/bib_ref] [bib_ref] Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in premenopausal patients..., Kim [/bib_ref] For select individuals who might benefit from treatment response to optimize surgery in the preoperative setting, panelists favored neoadjuvant endocrine therapy in women with low-grade and/or lowgenomic risk tumors, and endorsed genomic assays on core biopsies as a strategy for choosing which type of neoadjuvant therapy (chemotherapy or endocrine therapy) to pursue. Several studies suggest that a short-term decline in Ki67 during initial neoadjuvant endocrine therapy is a favorable prognostic finding, identifying a cohort of patients with endocrine-sensitive tumors, unlikely to benefit from neo/adjuvant chemotherapy. [bib_ref] Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in..., Smith [/bib_ref] [bib_ref] Abstract GS4-04: endocrine therapy alone in patients with intermediate or high-risk luminal..., Harbeck [/bib_ref] Post-neoadjuvant therapy is often customized by the extent of residual cancer following the preoperative treatment. Patients achieving a pCR after standard neoadjuvant chemotherapy should proceed to standard adjuvant therapy (for instance, maintenance anti-HER2 therapy, or endocrine therapy). The Panel endorsed adjuvant capecitabine for patients with residual TNBC, 31,32 and trastuzumab emtansine for patients with residual HER2-positive breast cancers, after standard neoadjuvant regimens, with a low threshold for treatment (including residual cancers <5 mm and node-negative). Most women with ER-positive cancer will have residual invasive cancer despite neoadjuvant chemotherapy or endocrine therapy. All women should receive adjuvant endocrine therapy regardless of response to neoadjuvant chemotherapy. [bib_ref] Systemic therapy for estrogen receptor-positive, HER2-negative breast cancer, Burstein [/bib_ref] For women with higher burdens of residual cancer after neoadjuvant endocrine therapy (tumor >5 cm, residual positive lymph nodes), with adverse biological features (higher grade, higher genomic risk scores 34 ), or with tumor progressing during neoadjuvant endocrine treatment, the Panel recommended adjuvant chemotherapy. ## Axillary management after neoadjuvant therapy Patients with clinically positive axillary lymph nodes after neoadjuvant therapy require axillary node dissection, whereas patients who present with a clinical N1 axilla, and who convert to a clinically negative axilla (cN0) after neoadjuvant treatment, are potential candidates for SNB. Those without residual nodal disease, when the initially sampled and clipped or at least three sentinel nodes are identified and resected, do not require axillary dissection. [bib_ref] Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast..., Boughey [/bib_ref] [bib_ref] Long-term standard sentinel node biopsy after neoadjuvant treatment in breast cancer: a..., Kahler-Ribeiro-Fontana [/bib_ref] [bib_ref] Identification and resection of clipped node decreases the false-negative rate of sentinel..., Boughey [/bib_ref] However, retrospective data show that patients with residual cancer in sentinel nodes including micrometastases [bib_ref] Is low-volume disease in the sentinel node after neoadjuvant chemotherapy an indication..., Moo [/bib_ref] have a substantial risk of additional nodal metastases in axillary nodes. Real-world data from the National Cancer Database suggested lower survival when substituting SNB and RNI for axillary dissection when residual nodal disease is present, unless patients were selected for limited residual nodal burden (only one positive node) and ER-positive tumors. [bib_ref] Omission of axillary lymph node dissection is associated with inferior survival in..., Almahariq [/bib_ref] The Panel debated whether axillary radiation could replace axillary dissection in a patient who presented with a clinically negative axilla but was found to have residual cancer in sentinel nodes after neoadjuvant chemotherapy. The Panel recommended completion axillary dissection for patients with residual macrometastases; the majority of the Panel (73%) voted that axillary lymph node dissection (ALND) should be indicated following neoadjuvant chemotherapy when there is any residual macrometastatic cancer (>2 mm) in the SNB, or in 'just' one of three sentinel nodes . There was controversy in discussing individual situations of lower sentinel node tumor burdens (for instance, a micrometastasis in one of three sentinel nodes, or isolated tumor cells in one of three sentinel nodes). Many panelists felt axillary radiation could be an alternative to axillary dissection in such situations. Other panelists urged caution, noting persistent risks of residual axillary nodal involvement, and recommended awaiting the results of ongoing phase III trials 40,41 that compare axillary radiation with axillary dissection in this setting to determine whether axillary radiation can substitute for axillary surgery in the setting of chemotherapy resistant nodal disease, as has been shown in the chemotherapy-naive adjuvant setting after surgery. [bib_ref] Radiotherapy or surgery of the axilla after a positive sentinel node in..., Donker [/bib_ref] Panelists did not believe that the availability of systemic treatment options such as capecitabine or trastuzumab emtansine for residual invasive cancer were sufficient to allow patients to avoid surgical management with axillary dissection. ## Systemic therapy: adjuvant treatment Nearly all patients with invasive breast cancer are advised to receive adjuvant systemic therapy.The threshold for initiation of treatment is very low, even among nodenegative cancers . Panelists recommended adjuvant endocrine therapy for nearly all patients with ERpositive tumors that were even only microinvasive or !1 mm in size, for reducing distant recurrence, in-breast recurrence, and second breast cancers. The threshold for recommending adjuvant chemotherapy in TNBC, or chemotherapy plus anti-HER2 therapy in HER2-positive breast cancer, is w5 mm. Indeed, nearly half of the panelists recommended chemotherapy and anti-HER2 therapy also for ER-negative, HER2-positive tumors <5 mm in size. ## Annals of oncology ## Her2-positive or triple-negative tumors Adjuvant regimen recommendations for triple-negative or HER2-positive therapy were largely unchanged from 2019 [fig_ref] Table 3: Systemic therapy for HER2-positive or triple-negative breast cancers [/fig_ref]. Neoadjuvant treatment is preferred for stage II or III tumors of these subtypes. For triple-negative cancers, dose-dense anthracycline and taxane-based regimens are preferred for stage II or III tumors. Panelists recommended against neoadjuvant or adjuvant use of immune checkpoint inhibitors in early-stage TNBC, pending maturation of disease-free and overall survival data. As mentioned above, panelists were again divided on the question of adding carboplatin in the neo/adjuvant treatment of TNBC; 60% recommend against adding to dose-dense anthracycline and taxane-based treatments. As in the past, panelists favored paclitaxel/trastuzumab for stage I, HER2-positive breast cancer. For stage II or III, HER2-positive cancers, panelists were split between anthracycline, taxane, and anti-HER2 regimens, and taxanecarboplatin and anti-HER2 regimens [fig_ref] Table 3: Systemic therapy for HER2-positive or triple-negative breast cancers [/fig_ref]. Pertuzumab was recommended for neoadjuvant treatment of clinical stage II or III, HER2-positive cancers, or in adjuvant therapy for node-positive cancers. ## Adjuvant endocrine therapy for er-positive cancers Recommendations for adjuvant endocrine therapy are outlined in [fig_ref] Table 4: Systemic therapy for ERD HER2L breast cancer [/fig_ref]. The Panel favors 5 years of tamoxifenor aromatase inhibitor (AI)-based therapy for stage I, ER-positive cancers. For node-positive cancers, the Panel recommended extended therapy towards a duration of 10 years based on persistent risks of recurrence among such patients. [bib_ref] 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years, Pan [/bib_ref] For premenopausal women who received an initial 5 years of ovarian function suppression (OFS) and tamoxifen for higher risk cancers, the Panel favored extended therapy with either ongoing tamoxifen or an AI (if the woman is postmenopausal, or with ongoing OFS), typically towards a goal of 10 years of therapy, though there may be negligible benefits of treatment beyond 7.5-8 years for average-risk tumors. [bib_ref] Abstract GS3-01: a prospective randomized multi-center phase-III trial of additional 2 versus..., Gnant [/bib_ref] The Panel voted against the use of molecular diagnostics for deciding whether to extend adjuvant endocrine therapy. As ongoing maturation of the SOFT and TEXT trials show persistent benefits for OFS in premenopausal women with ER-positive breast cancer, the Panel was more inclined this year to recommend OFS in younger women [fig_ref] Table 4: Systemic therapy for ERD HER2L breast cancer [/fig_ref] , [bib_ref] Tailoring adjuvant endocrine therapy for premenopausal breast cancer, Francis [/bib_ref] [bib_ref] Absolute improvements in freedom from distant recurrence to tailor adjuvant endocrine therapies..., Pagani [/bib_ref] while also noting the importance of patient preferences here as OFS carries more substantial patient-reported sideeffects. [bib_ref] Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early..., Bernhard [/bib_ref] The Panel favored OFS in stage II or higher breast cancer, particularly among women <40 years of age, and those with higher grade, higher Ki67, or higher risk genomic signatures. Many panelists favored OFS in stage T1c, node-negative cancers with those same features. For premenopausal women who meet the criteria for adjuvant chemotherapy for ER-positive cancers, the Panel also recommended ovarian suppression. In 2020, three large, randomized trials reported on shortterm outcomes from adjuvant trials adding cyclin dependent kinase 4 or 6 inhibitors to standard adjuvant endocrine therapy in women [bib_ref] Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis..., Mayer [/bib_ref] [bib_ref] Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancerdThe Penelope-B..., Loibl [/bib_ref] [bib_ref] Abemaciclib combined with endocrine therapy for the adjuvant treatment of HRþ, HER2À,..., Johnston [/bib_ref] with stage II or III, ERpositive breast cancers. Of these, the PALLAS and PENELOPE-B studies using palbociclib did not show improvement in disease-free survival, while the MONARCH-E trial using abemaciclib did find improvement in the limited (<2 years) follow-up. To date, there are no known clinical or tumor-related factors to account for these differences. The Panel was divided on whether to endorse abemaciclib adjuvant therapy. A slim majority favored abemaciclib in cases of four or more positive axillary nodes, while a slim majority voted against abemaciclib in cases of stage II or III breast cancer. Longer term follow-up from these trials is awaited to settle this question. ## Adjuvant chemotherapy for er-positive breast cancer Genomic signatures are increasingly driving customized, biologically-informed decisions on whether to offer chemotherapy in addition to endocrine therapy for women with ER-positive, HER2-negative early-stage breast cancers. Ongoing analyses of the TAILORx, RxPonder, MINDACT, and related studies of genomically-informed chemotherapy decision making deeply affected Panel recommendations for adjuvant chemotherapy in cases of ER-positive breast cancer. [bib_ref] 70-gene signature as an aid for treatment decisions in early breast cancer:..., Piccart [/bib_ref] [bib_ref] Clinical and genomic risk to guide the use of adjuvant therapy for..., Sparano [/bib_ref] [bib_ref] Abstract GS3-00: first results from a phase III randomized clinical trial of..., Kalinsky [/bib_ref] Based on the convergent results from these studies, the Panel recommended against routine use of adjuvant chemotherapy in postmenopausal women with stage I or II (including one to three positive lymph nodes) breast cancers that had lower risk genomic signatures (defined as a recurrence score 25, or 'low risk' result on the 70-gene signature) [fig_ref] Table 4: Systemic therapy for ERD HER2L breast cancer [/fig_ref]. The recommendations for premenopausal women with lower-risk genomic signatures and tumor stage were more ## Annals of oncology complicated, however, as subset analyses from each these trials indicate that premenopausal women derive clinically important benefits from chemotherapy, though some panelists believe ovarian suppression could be an appropriate substitute for chemotherapy. The dilemma in understanding each of these trials is the confounding effect of chemotherapy-induced ovarian function suppression, a common consequence of adjuvant chemotherapy in premenopausal women, and known to reduce recurrence. [bib_ref] Longer therapy, Iatrogenic amenorrhea, and survival in early breast cancer, Swain [/bib_ref] A question is: how much of the chemotherapy-related reduction in recurrence among premenopausal women with ER-positive breast cancer is due to direct, 'cytotoxic' effects of chemotherapy, and how much is due to an indirect, ovarian suppression effect of chemotherapy? Several lines of evidence suggest that ovarian suppression effects may account for part of the benefit of chemotherapy in this cohort. The likelihood of chemotherapy-induced amenorrhea depends on patient age. An analysis according to age subgroups in TAILORxdnamely age <40, 40-45 and 45-50 yearsdsupports the argument that some chemotherapy benefits relate in part to ovarian suppression; benefits of chemotherapy were least noticeable in women least likely to experience chemotherapy-induced menopause (aged <40 years) and more pronounced among those more likely to experience treatment-related amenorrhea (aged >40 years). [bib_ref] Clinical and genomic risk to guide the use of adjuvant therapy for..., Sparano [/bib_ref] And of course, OFS itself, achieved through gonadotropin-releasing hormone (GnRH) analogues or oophorectomy, shows substantial clinical benefit and enables AI-based therapy in younger women, interventions known to reduce risk as shown in the SOFT and TEXT trials 'STEPP' analyses. [bib_ref] Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor-positive,..., Regan [/bib_ref] Thus, it is possible, but not proven, that the use of endocrine treatment strategies beyond tamoxifen alone, such as OFS plus an AI, could account for the benefit seen with chemotherapy. Resolving this question definitively will require a large adjuvant trial fully dedicated to premenopausal women and investigating whether adjuvant chemotherapy adds any meaningful benefit to an 'optimal' endocrine treatment strategy in the presence of favorable gene expression signatures. The PERCHE trial, designed 15 years ago by the International Breast Cancer Study Group (IBCSG) under the leadership of A. Goldhirsch, attempted this but was closed due to limited accrual. Given these considerations, the Panel was surveyed on their approach to shared decision making with premenopausal women with ER-positive, HER2-negative cancers and lower-risk genomic signatures, and whether such patients should consider ovarian suppression with tamoxifen or an AI in lieu of chemotherapy. Three-quarters of the Panel believe that at least half of the 'benefit' of chemotherapy in this situation is due to ovarian suppression, with a majority of the Panel even believing that 75%-100% of the effect was due to ovarian suppression . These impressions affected panel recommendations [fig_ref] Table 4: Systemic therapy for ERD HER2L breast cancer [/fig_ref]. For premenopausal women with node-negative cancers and recurrence scores 16-25, or other lower risk genomic signatures, threequarters of the Panel voted for endocrine therapy, including half who favored ovarian suppression, while only onequarter favored chemotherapy and endocrine therapy [fig_ref] Figure 7: Panelist recommendations for optimal therapy for premenopausal, ER-positive cancers by stage and... [/fig_ref]. For premenopausal women with one to three positive axillary nodes and recurrence score 25 or other lower risk genomic signatures, the Panel was divided None <25% 50% >75% All . Estimated percentage of chemotherapy benefit due to ovarian suppression in premenopausal women with lower risk genomic signatures (recurrence score £25). between ovarian suppression and endocrine therapy versus chemotherapy and endocrine therapy [fig_ref] Figure 7: Panelist recommendations for optimal therapy for premenopausal, ER-positive cancers by stage and... [/fig_ref]. There are no data as yet for using genomic signatures to define the role of adjuvant chemotherapy in ER-positive, stage III breast cancers. The historical standard is adjuvant chemotherapy, though the growing evidence in stages I and II breast cancer suggest that there may be a minimal role for chemotherapy in many such tumors. Nonetheless, the Panel consistently favored adjuvant chemotherapy in stage III cancers including lobular breast cancers [fig_ref] Table 4: Systemic therapy for ERD HER2L breast cancer [/fig_ref]. Concern was raised by half of the panelists regarding the use of genomic signatures in patients with high-risk tumors such as pT3N1 or patients with more than three positive nodes, as in these settings, the use of adjuvant chemotherapy would be recommended regardless of the genomic signature results. Only in the instance of very low risk biologydrecurrence score <11, or grade 1 with Ki67 <10%, did a substantial fraction of the Panel believe that chemotherapy might be omitted in stage III, ER-positive breast cancer. ## Ductal carcinoma in situ Ductal carcinoma in situ (DCIS) is a precursor lesion to invasive breast cancer, usually identified through mammographic screening. Surgical excision is the mainstay of therapy; most women are candidates for breast-conserving surgery, whereas some may require mastectomy based on the extent of DCIS in the breast. Radiation therapy after breast-conserving surgery reduces the recurrence risk of DCIS or invasive breast cancer in the ipsilateral breast; moderately hypofractionated treatment schedules are as effective as standard fractionation treatment schedules in management of DCIS. [bib_ref] Hypofractionated versus standard fractionated radiotherapy in patients with early breast cancer or..., Offersen [/bib_ref] [bib_ref] Abstract GS2-04: a randomized phase III study of radiation doses and fractionation..., Chua [/bib_ref] The addition of boost lowers recurrence rates in non-low-risk DCIS cases. The Panel recommended boost in cases with larger areas of DCIS or other factors associated with increased risk of recurrence including margins <2 mm and the presence of comedonecrosis, but not in low-risk cases. As with management of invasive breast cancer in older women, the Panel supported omission of radiation therapy in women >70 years of age with DCIS bearing low risk features. Adjuvant endocrine therapy can further reduce the risk of recurrence in DCIS treated with breast conservation and radiation therapy, as well as prevent contralateral disease. Either tamoxifen or an AI are options; 58 panelists tended to favor tamoxifen based on the side-effect profile. ## Ipsilateral breast cancer recurrence Even with contemporary management of breast-conserving surgery and radiation therapy, isolated, in-breast recurrences account for 5%-15% of all recurrent cancer events in women with early-stage breast cancer. [bib_ref] Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy..., Fisher [/bib_ref] [bib_ref] Adjuvant chemotherapy guided by a 21-Gene expression assay in breast cancer, Sparano [/bib_ref] In addition, some patients develop true, second cancers in the ipsilateral breast. Traditionally, the recommended treatment was mastectomy in light of the previous breast radiation. Limited single-center experiences have suggested that repeat breast-conserving surgery could be an effective option for women with isolated, in-breast recurrences. [bib_ref] Repeating conservative surgery after Ipsilateral breast tumor reappearance: criteria for selecting the..., Gentilini [/bib_ref] In the 2021 consensus voting, repeat attempts at breast conservation were particularly favored by the Panel in the setting of low-risk (small, luminal A-type) breast cancers, presumably when additional radiation therapy might not be required. The Panel acknowledged that breast conservation with re-irradiation could be an option instead of mastectomy for some women with ipsilateral recurrence or second breast cancer arising >5 years after initial breast conservation and radiation. However, the Panel was split 50/50 on offering second attempts at breast conservation when reirradiation was not a clinical option. In any case, mastectomy need no longer be considered absolutely 'obligatory' for ipsilateral breast recurrence. Following ipsilateral breast recurrence, it is usually standard to offer further adjuvant therapy informed by prior treatment and tumor biology, including consideration of: endocrine therapy for ERpositive tumors; anti-HER2 therapy for HER2-positive tumors; and chemotherapy for TNBCs 62 and in other select cases. [bib_ref] Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial, Aebi [/bib_ref] [bib_ref] Impact of breast surgery in primary metastasized breast cancer, Fitzal [/bib_ref] [bib_ref] Randomized trial comparing resection of primary tumor with no surgery in stage..., Soran [/bib_ref] OLIGOMETASTATIC BREAST CANCER Some breast cancer patients are diagnosed with de novo, stage IV breast cancer at the time of presentation. Randomized trials have compared optimal systemic therapy with or without breast surgery among such patients; breast surgery in the setting of stage IV breast cancer does not improve overall survival, [bib_ref] A randomized phase III trial of systemic therapy plus early local therapy..., Khan [/bib_ref] though it is still widely used. [bib_ref] Surgical resection of the primary tumor in women with de novo stage..., Lane [/bib_ref] Occasionally, women with newly diagnosed breast cancer are found to have oligometastatic cancer on staging evaluation, usually defined as having one, or possibly two sites of metastatic cancer outside the breast and regional lymph nodes. One example would be a patient with an isolated metastasis to the sternum or other solitary bone lesion; another would be an isolated pulmonary nodule or lymph node. Such possible metastatic sites warrant tissue biopsy to clarify the diagnosis, as other benign or malignant conditions can have similar radiological appearances. The Panel considered specific instances of a patient presenting after surgery for stage II breast cancer, then found to have an isolated metastasis in the sternum, or other isolated bone metastasis or lung nodule, that could be treated with definitive radiation therapy (bone) or excision (lung). In each instance, the Panel favored treating the patient with multi-modality, curative intent, including definitive additional treatment to the site of metastatic disease. For patients in whom more sites of metastatic cancer were identified, such as three or more bone lesions, the Panel favored following standard treatments for advanced breast cancer, with palliation of the metastatic sites through local therapy as indicated by symptoms. ## Survivorship Breast cancer treatments bring a myriad of side-effects, including changes to the body, hair loss, chemotherapyrelated toxicities, and health and well-being consequences from estrogen deprivation. [bib_ref] Systemic therapy for estrogen receptor-positive, HER2-negative breast cancer, Burstein [/bib_ref] Many supportive care Annals of Oncology interventions have been developed to mitigate some of these side-effects. The Panel this year addressed emerging data on several interventions that can improve quality of life in breast cancer survivors. It strongly endorsed the routine use of scalp cooling 'cold-caps' to reduce alopecia, particularly for non-anthracycline-based chemotherapy regimens. [bib_ref] Association between use of a scalp cooling device and alopecia after chemotherapy..., Rugo [/bib_ref] The Panel endorsed mindfulness-based stress reduction as a proven strategy to alleviate depressive symptoms in younger breast cancer survivors, [bib_ref] Abstract GS2-10: targeting depressive symptoms in younger breast cancer survivors: a randomized..., Ganz [/bib_ref] and endorsed aerobic exercise as a standard way to address a variety of adverse effects including fatigue and sleep disturbance. Symptoms of vaginal atrophy are common in women on adjuvant endocrine therapy. While these symptoms may be relieved with topical vaginal estrogens, there are concerns that such products could cause transient clinically relevant increases in systemic estrogen levels. [bib_ref] A phase II prospective, randomized, double-blind, placebo-controlled and multicenter clinical trial to..., Sánchez-Rovira [/bib_ref] [bib_ref] Vaginal testosterone cream vs estradiol vaginal ring for vaginal dryness or decreased..., Melisko [/bib_ref] Nonetheless, panelists indicated that they would commonly prescribe intravaginal estrogens to relieve symptoms of vaginal atrophy in women on AIs and symptoms unresponsive to non-hormonal interventions, with the acknowledgement that we are not fully certain of their safety. Because of epidemiological studies linking alcohol consumption to breast cancer risk, breast cancer survivors often ask about the safety of drinking alcohol following a breast cancer diagnosis. Panelists overwhelming believed that some alcohol consumption after breast cancer diagnosis was unlikely to affect recurrence; the majority suggested limiting consumption to an average of one drink per day or less [fig_ref] Figure 8: Panelists advice on alcohol consumption [/fig_ref] ; none suggested that abstinence was necessary. ## Summary The 2021 St Gallen Consensus Conference highlighted important strategies to customize treatment of patients with early-stage breast cancer. Significant changes from past guidance include: evolving practices in management of the axilla after neoadjuvant therapy; broader utilization of hypofractionated approaches to radiation therapy; omission of chemotherapy in postmenopausal women with one to three positive axillary nodes and low-risk genomic signatures; adjuvant-type therapy for women with oligometastatic breast cancer; and advances in supportive care and survivorship that hopefully will allow women with a history of early-stage breast cancer to have fewer side-effects from treatment. The Panel will reconvene in 2023 for the next consensus conference. # Funding [fig] Figure 1: Defining threshold for Ki67 to recommend adjuvant chemotherapy in ER-positive, HER2-negative, node-negative breast cancer. Numbers are percentage of panelists endorsing a Ki67 level. HER2, human epidermal growth factor receptor 2. -n e g a t i v e L N -p o s i t i v e 1 -3 L N -p o s i t i v e ≥ 4 L o w -g r a d e I n t e r m e d i a t e -g r a d e H i g h -g r a d e Routine testing Testing in select cases No testing [/fig] [fig] Figure 2: Panel recommendations for genomic signature testing in ER positive, HER2 negative early stage breast cancer. Numbers denote percentage of panelists favoring routine testing, testing in select cases or no testing zones. [/fig] [fig] Figure 3: Moderately hypofractionated radiation therapy. [/fig] [fig] Figure 4, Figure 5: Is axillary dissection required for residual cancer in lymph nodes after standard neoadjuvant chemotherapy? a Percentage of panelists favoring axillary dissection. ITC, isolated tumor cells; SLN, sentinel lymph nodes. a It was assumed that post-surgical radiation therapy would be given regardless. Size threshold for initiating systemic therapy by tumor type and treatment. Percentage of panelists recommending therapy by tumor size. CT, computed tomography; ER, estrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; TNBC, triple-negative breast cancer. [/fig] [fig] Figure 7: Panelist recommendations for optimal therapy for premenopausal, ER-positive cancers by stage and recurrence score (RS). (A) Node-negative, RS 16-25. (B) Node-positive (one to three positive nodes), RS 25. Chemo, chemotherapy; ET, endocrine therapy; OFS, ovarian function suppression. [/fig] [fig] Figure 8: Panelists advice on alcohol consumption: how many drinks can a breast cancer survivor consume without increasing the risk of cancer recurrence? Percentage of panelists voting in favor. Avg, average. [/fig] [table] Table 1: New studies in breast cancer since St Gallen 2019 [/table] [table] Table 2: Percentage of panelists recommending prophylactic mastectomy or surveillance for hereditary breast cancer syndromes as a function of age and gene mutation [/table] [table] Table 3: Systemic therapy for HER2-positive or triple-negative breast cancers [/table] [table] Table 4: Systemic therapy for ERD HER2L breast cancer [/table]	None	http://www.annalsofoncology.org/article/S0923753421021049/pdf	None
8181fea91709c37941f841a5803e9efb848fc2c7	pubmed	Clinical practice guidelines for pre-operative evaluation of breast cancer: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021	Clinical practice guidelines for pre-operative evaluation of breast cancer: Chinese Society of Breast Surgery (CSBrS) practice guidelines 2021 ## Level of evidence and recommendation strength Level of evidence standard [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] Recommendation strength standard [bib_ref] Clinical practice guidelines for sentinel lymph node biopsy in patients with early-stage..., Ye [/bib_ref] Recommendation strength review committee A total of 84 members of the voting committee of this guideline, including 71 breast surgeons (84.52%), four oncologists (4.76%), four radiologists (4.76%), two pathologist (2.38%), two radiation therapist (2.38%), and one epidemiologist (1.19%). ## Target audience Chinese breast disease specialists. ## Recommendations Recommendation 1: General evaluation. ## Component ## Level of evidence Strength of recommendation 1.1 Evaluation of vital signs [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.2 Laboratory evaluation [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.3 Clinical examination [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.4 Blood pressure monitoring and related pre-operative managementI A 1.5 Glucose monitoring and related pre-operative managementI A 1.6 Specific clinical conditions in patients with breast cancer 1.6.1 Cardiovascular disease or risk factors [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac..., Fleisher [/bib_ref] I A 1.6.2 Respiratory disease, smoking habit, obstructive sleep apnea syndrome [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.6.3 Liver disease [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.6.4 Renal disease [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.6.5 Diabetes [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.6.6 Old age [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Risk assessment for and strategies to reduce perioperative pulmonary complications for patients..., Qaseem [/bib_ref] I A 1.6.7 Obesity [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Risk assessment for and strategies to reduce perioperative pulmonary complications for patients..., Qaseem [/bib_ref] I A 1.6.8 Anemia [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.6.9 Coagulation disorders [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I A 1.6.10 Risk factors for thrombosis [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Guidelines for the prevention and management of perioperative thrombosis in general surgery..., Liu [/bib_ref] I A 1.6.11 Electrolyte disturbances [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] I AII A b. To define extent of cancer or presence of multifocal or multicentric cancer in the ipsilateral breastII A c. Occult (or unidentified) primary breast cancer with axillary lymph node metastasesII A 3.1.4 Determination of tumor estrogen/progesterone receptor and human epidermal growth factor receptor-2 statusI A 3.2 Evaluation of regional lymph nodes 3.2.1 Needle biopsy of suspicious lymph nodesI A ## Component ## Level of evidence Strength of recommendation standard staging studies, locally advanced breast cancer (IIIA and above), and/or distant metastases3.4 Concomitant evaluation of patients with breast cancer 3.4.1 Genetic counseling if patient is at risk of hereditary breast cancer [bib_ref] Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up..., Cardoso [/bib_ref] II A 3.4.2 Pregnancy testing in all potentially pregnant womenII A 3.4.3 Assessment of mental health statusII A 3.5 Evaluation of neoadjuvant therapy 3.5.1 Marking of tumor before commencing neoadjuvant therapyII A 3.5.2 Imaging evaluation every two cyclesII A 3.5.3 Primary tumor evaluation after neoadjuvant therapy a. Breast ultrasound [bib_ref] ACR appropriateness criteria( ® ) monitoring response to neoadjuvant systemic therapy for..., Slanetz [/bib_ref] I A b. Breast MRI [bib_ref] ACR appropriateness criteria( ® ) monitoring response to neoadjuvant systemic therapy for..., Slanetz [/bib_ref] II A c. If the lesion was clearly shown on a pre-treatment mammogram, mammography can be repeated after neoadjuvant therapy [bib_ref] ACR appropriateness criteria( ® ) monitoring response to neoadjuvant systemic therapy for..., Slanetz [/bib_ref] II A 3.5.4 Regional lymph node evaluation after neoadjuvant therapy a. Breast ultrasound [bib_ref] ACR appropriateness criteria( ® ) monitoring response to neoadjuvant systemic therapy for..., Slanetz [/bib_ref] I A b. Breast MRI [bib_ref] ACR appropriateness criteria( ® ) monitoring response to neoadjuvant systemic therapy for..., Slanetz [/bib_ref] II A CT: Computed tomography; MRI: Magnetic resonance imaging; PET: Positron emission tomography. # Discussion Pre-operative evaluation is an important aspect of the surgical treatment of breast cancer, basically determining the success or failure of such surgery, including whether it is curative. Surgeons should make pre-operative evaluation a high priority, especially for older or frail patients and those with serious comorbidities. [bib_ref] Pre-operative evaluation of adults undergoing elective noncardiac surgery: updated guideline from the..., Hert [/bib_ref] [bib_ref] Practice advisory for preanesthesia evaluation: an updated report by the American Society..., Apfelbaum [/bib_ref] The CSBrS panel recommends that patients with breast cancer should also be subjected to pre-operative oncology evaluation [bib_ref] Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up..., Cardoso [/bib_ref] by breast ultrasound, mammography, and breast magnetic resonance imaging (MRI) to identify the number of lesions, their locations and size, regional lymph node status, and distant metastases. [bib_ref] Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up..., Cardoso [/bib_ref] [bib_ref] AGO recommendations for the diagnosis and treatment of patients with early breast..., Ditsch [/bib_ref] [bib_ref] ACR appropriateness criteria( ® ) palpable breast masses, Moy [/bib_ref] Tumor node metastasis stage should be determined in accordance with the eighth edition of the Cancer Staging Manual issued by the American Joint Committee on Cancer. The CSBrS panel stresses that the application value of breast MRI should be fully understood: it has high sensitivity and can show multi-focal, multi-centric, or occult tumors, the relationship between tumor and chest wall, and axillary lymph node metastasis, thus providing a reliable basis for development of a surgical plan. However, it is only moderately specific, does not satisfactorily display microcalcification, and sometimes produces false positives. Thus, decisions about surgery cannot be made purely on the basis of MRI findings. [bib_ref] Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up..., Cardoso [/bib_ref] [bib_ref] AGO recommendations for the diagnosis and treatment of patients with early breast..., Ditsch [/bib_ref] [bib_ref] ACR appropriateness criteria( ® ) palpable breast masses, Moy [/bib_ref] Appendix: Additional discussion section (Supplementary file, http://links.lww.com/CM9/A804) ## Conflicts of interest The expert committee for these guidelines declares no conflict of interest. These guidelines are a reference for breast disease specialists in clinical practice. However, the guidelines are not to be used as the basis for medical evaluation, and do not play an arbitrating role in the handling of any medical disputes. The guidelines are not a reference for patients or non-breast specialists. The Chinese Society of Breast Surgery assumes no responsibility for results involving the inappropriate application of these guidelines, and reserves the right to interpret and revise the guidelines. List of compiling committees (In alphabetical order by surname) Chinese Medical Journal 2021;134(18) www.cmj.org	None	None	Breast cancer is the most common cancer in women in China. Since Halsted introduced radical mastectomy, surgery has remained the cornerstone of breast cancer treatment. Before performing such surgery, a comprehensive and standardized evaluation should be undertaken. This should include identification of factors that could increase the risk of surgery or prejudice recovery, as well as factors that may affect the subsequent course of the disease. The Chinese Society of Breast Surgery (CSBrS) has conducted a literature review and experts have discussed key clinical issues related to standardizing pre-operative evaluation of patients with breast cancer; evaluated the relevant evidence with reference to the grading of recommendations assessment, development, and evaluation system; combined the accessibility under China’s national conditions; and formulated the following written Clinical Practice Guidelines for Pre-operative Evaluation of Breast Cancer (2021 Edition) with the aim of providing a reference for Chinese breast surgeons.
2fd4d3b23719f7bf6f9021b96befff06539cce97	pubmed	Scandinavian guidelines for initial management of minor and moderate head trauma in children	Scandinavian guidelines for initial management of minor and moderate head trauma in children Background: The management of minor and moderate head trauma in children differs widely between countries. Presently, there are no existing guidelines for management of these children in Scandinavia. The purpose of this study was to produce new evidence-based guidelines for the initial management of head trauma in the paediatric population in Scandinavia. The primary aim was to detect all children in need of neurosurgical intervention. Detection of any traumatic intracranial injury on CT scan was an important secondary aim. Methods: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used. Systematic evidence-based review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology and based upon relevant clinical questions with respect to patient-important outcomes. Quality ratings of the included studies were performed using Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and Centre of Evidence Based Medicine (CEBM)-2 tools. Based upon the results, GRADE recommendations, a guideline, discharge instructions and in-hospital observation instructions were drafted. For elements with low evidence, a modified Delphi process was used for consensus, which included relevant clinical stakeholders. Results: The guidelines include criteria for selecting children for CT scans, in-hospital observation or early discharge, and suggestions for monitoring routines and discharge advice for children and guardians. The guidelines separate mild head trauma patients into high-, medium-and low-risk categories, favouring observation for mild, low-risk patients as an attempt to reduce CT scans in children.Conclusions:We present new evidence and consensus based Scandinavian Neurotrauma Committee guidelines for initial management of minor and moderate head trauma in children. These guidelines should be validated before extensive clinical use and updated within four years due to rapid development of new diagnostic tools within paediatric neurotrauma. # Background Head trauma is a common reason for an emergency department (ED) visit, especially among adolescents and adults [bib_ref] Incidence, risk factors and prevention of mild traumatic brain injury: results of..., Cassidy [/bib_ref]. The incidence of head trauma in the paediatric population is estimated to 180 -300 per 100,000 [bib_ref] Incidence of hospital referred head injuries in Norway: a population based survey..., Heskestad [/bib_ref] [bib_ref] Incidence and descriptive epidemiologic features of traumatic brain injury in King County, Koepsell [/bib_ref]. About 80-90 % of these injuries are classed as minor head traumas (MHT), which includes both minimal and mild head trauma, whilst approximately 10 % have moderate to severe head trauma (Glasgow Coma Scale [GCS] score 3-8) [bib_ref] Incidence, risk factors and prevention of mild traumatic brain injury: results of..., Cassidy [/bib_ref] [bib_ref] Incidence of hospital-admitted severe traumatic brain injury and in-hospital fatality in Norway:..., Andelic [/bib_ref]. According to the Head Injury Severity Scale (HISS) classification [bib_ref] The Head Injury Severity Scale (HISS): a practical classification of closed-head injury, Stein [/bib_ref] , mild head injury patients are initially conscious at first assessment (GCS score [bib_ref] Increased number of cancer cases following computer tomography in children. Radiation dosage-and..., Hall [/bib_ref] [bib_ref] Estimated risks of radiation-induced fatal cancer from pediatric CT, Brenner [/bib_ref] , may have had a brief loss of consciousness (LOC) or amnesia, but do not have any focal neurological deficits on admission. Mortality and the need for neurosurgical interventions are rare in this patient group (0.1-0.2 %) [bib_ref] Variation in utilization of computed tomography scanning for the investigation of minor..., Klassen [/bib_ref] [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] , and about 4-6 % have trauma related abnormality on the initial computed tomography (CT) scan [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] [bib_ref] Indications for brain computed tomography and hospital admission in pediatric patients with..., Guzel [/bib_ref] [bib_ref] Effect of the duration of emergency department observation on computed tomography use..., Schonfeld [/bib_ref]. Although serious complications after MHT in children are rare, intracranial lesions, such as epidural haematomas, can have major consequences and be potentially life-threatening if left untreated. Immediate CT scanning and in-hospital clinical observation are considered equally good strategies in triaging patients after MHT with respect to intracranial complications and medical outcome [bib_ref] Medical outcome after immediate computed tomography or admission for observation in patients..., Af Geijerstam [/bib_ref] , although CT scanning and early discharge are economically more advantageous [bib_ref] Immediate computed tomography or admission for observation after mild head injury: cost..., Norlund [/bib_ref]. Due to the large number of head trauma patients and the low number of intracranial complications, CT scanning is both a public health issue as well as an economic dilemma. During the last decades, CT use has rapidly increased. In the USA, more than half of the children seen in the ED for MHT will receive a head CT [bib_ref] Diagnosis and acute management of patients with concussion at children's hospitals, Colvin [/bib_ref]. In 2012, the Nordic Radiation Protection Authorities published a joint statement concerning the increased use of CT in the Nordic countries, advocating for increased awareness of radiation risks and urging that CT scans only be done when clinically justified. A previous study from Sweden has also showed that CT of the head is the most common CT investigation (50 % of all CTs performed) which was especially true among 0 -4 year-olds (59 % of all CTs) [bib_ref] Increased number of cancer cases following computer tomography in children. Radiation dosage-and..., Hall [/bib_ref]. Especially, children are of concern since they are more sensitive to radiation-induced malignancies, such as leukaemia and brain tumours, and have a longer lifespan with ongoing harmful effects of radiation [bib_ref] Estimated risks of radiation-induced fatal cancer from pediatric CT, Brenner [/bib_ref] [bib_ref] Computed tomography-an increasing source of radiation exposure, Brenner [/bib_ref]. Induction of leukaemia or brain tumours has been estimated to be 1 in 10,000 from a single CT scan in children younger than ten years. The same study also estimated a substantially increased risk of cancer after multiple scans with radiation doses from two to three head CTs (about 60 mGy cumulative brain dose) to triple the risk of brain tumours (RR 3.32) compared with doses less than 5 mGy [bib_ref] Radiation exposure from CT scans in childhood and subsequent risk of leukaemia..., Pearce [/bib_ref]. Recent decision rules and head trauma guidelines from the USA and the UK have tried to address this issue. The PECARN study [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] has not been validated in the Scandinavian setting, but follow-up studies after implementation in the USA have shown a decrease in CT rate from 21 % to 15 % [bib_ref] Quality improvement effort to reduce cranial CTs for children with minor blunt..., Nigrovic [/bib_ref]. Presently, there are no specific guidelines for children with MHT available in Scandinavia. According to the survey of the management of paediatric MHT in both Sweden and Denmark, predominately local guidelines exist, often based on the adult head injury guidelines from the Scandinavian Neurotrauma Committee (SNC) from the year 2000 [bib_ref] Survey of the management of children with minor head injuries in Sweden, Astrand [/bib_ref] [bib_ref] A survey of the management of paediatric minor head injury, Vestergaard [/bib_ref] [bib_ref] Scandinavian guidelines for initial management of minimal, mild, and moderate head injuries.The..., Ingebrigtsen [/bib_ref]. As a result of the lack of guidelines, there are large discrepancies in the management within and between the Scandinavian countries [bib_ref] Survey of the management of children with minor head injuries in Sweden, Astrand [/bib_ref] [bib_ref] A survey of the management of paediatric minor head injury, Vestergaard [/bib_ref]. International efforts have resulted in several paediatric guidelines [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] [bib_ref] Derivation of the children's head injury algorithm for the prediction of important..., Dunning [/bib_ref]. Although these are based upon sound methodology, they were not designed for the Scandinavian health care system. Also, during the validation process and introduction of the revised adult head injury guidelines [bib_ref] Scandinavian guidelines for initial management of minimal, mild and moderate head injuries..., Unden [/bib_ref] , including the clinical introduction of serum marker S100B, interest has been raised for the possible use of this biomarker in paediatric head trauma management. The development of a head trauma guideline specifically for children, with the Scandinavian health care setting in mind, is therefore warranted. ## Aim of the study, target population In the present report we aim to present evidence-and consensus-based guidelines for initial management of minor and moderate head trauma in children. The purpose of the proposed guidelines is to assist physicians in the initial management of children (<18 years of age) with head trauma within the first 24 hours following trauma, particularly to determine those children who need a head CT and/or in-hospital observation and those who can be directly discharged from the ED. The guidelines exclude children with severe head trauma as defined below (see definitions). They are intended for use by physicians in the ED, including paediatric EDs and to some extent general practitioners; hence, with focus on physicians who are not experts in the field of head trauma management. The guidelines are not intended for nurses or non-medical professionals. The primary goal of the study was to identify all paediatric patients in need of intervention, such as neurosurgical and/or intensive care or who have an intracranial injury (critical patient-important outcome), and secondarily, those paediatric patients with any traumatic intracranial injury, including skull fractures (important patient-important outcome) following minor and moderate head trauma. # Methods The fundamental policy for developing the guidelines was to follow the Appraisal of Guidelines for Research and Evaluation (AGREE)-II guideline development framework [bib_ref] AGREE II: advancing guideline development, reporting and evaluation in health care, Brouwers [/bib_ref]. Standardised and recommended assessment tools, such as the QUADAS (Quality Assessment of Diagnostic Accuracy studies)-2 tool [bib_ref] QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies, Whiting [/bib_ref] and CEBM (Centre of Evidence Based Medicine)-2, were used for the assessment of the quality of evidence for the different studies, as well as the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system for development and assessment of proposed recommendations [bib_ref] Understanding GRADE: an introduction, Goldet [/bib_ref] [bib_ref] Grading quality of evidence and strength of recommendations for diagnostic tests and..., Schunemann [/bib_ref]. As evidence in some areas was absent and/or inadequate, a modified Delphi process was used for certain issues and for agreement on the recommendations and guideline. The methodological process and work flow is shown in . ## Task force, working group and stakeholders The SNC consists of neurosurgeons, anaesthesiologists, neuroanaesthesiologists, neurologists and radiologists with special expertise in neurotrauma. A task force was formed within the SNC, consisting of the three authors (RÅ, CR, and JU), tasked to initiate the research by retrieving and assessing the evidence, determining the quality and drafting the recommendations as well as the guideline proposal. The working group, consisting of all the SNC members, were updated on the process twice yearly. Stakeholders consisting of paediatricians, neuropaediatricians, paediatric anaesthesiologists and paediatric surgeons from the Scandinavian countries were invited to comment upon and evaluate the proposed guidelines following the AGREE II method during the Delphi process. A modified Delphi process, including the task force, the working group and stakeholders, was held for the consensus part of the process. Since the SNC working group mainly consists of neurosurgeons, anaesthesiologists and neurologists, we chose to invite stakeholders within the field of paediatrics in order to get the expert opinion from care-givers who manage these children in the paediatric ED, paediatric wards, paediatric intensive care units and rehabilitation departments. Stakeholders known to have a paediatric trauma interest were asked to participate. ## Definitions Head trauma is defined as any physical hit or blow towards the head, which may or may not lead to an injury of the underlying brain. We consider a traumatic brain injury (TBI) to be a possible consequence of the traumatic event towards the head. The severity of head trauma was defined according to a modification of the HISS classification [bib_ref] The Head Injury Severity Scale (HISS): a practical classification of closed-head injury, Stein [/bib_ref] , similar to the definitions in the revised Scandinavian adult head injury guidelines [bib_ref] Scandinavian guidelines for initial management of minimal, mild and moderate head injuries..., Unden [/bib_ref]. In this modified classification, moderate head trauma was defined as GCS scores of 9 to13 on admission [bib_ref] Minor head injury: 13 is an unlucky number, Stein [/bib_ref] , mild head trauma represented patients with an initial GCS score of 14 to 15, with or without neurological deficits, and minimal head trauma with GCS score of 15 and no other risk factors. Risk factors are considered to be any symptom or condition specified in the guidelines as a predictive factor of intracranial complication after the head trauma. Severe head trauma (GCS score ≤ 8) [bib_ref] EBIC-guidelines for management of severe head injury in adults. European Brain Injury..., Maas [/bib_ref] [bib_ref] Assessment of coma and impaired consciousness. A practical scale, Teasdale [/bib_ref] was not included in the guidelines, since these patients are managed using a different protocol and always receive both immediate head CT and in-hospital admission due to a high risk of intracranial injury. Neurological deficit was defined as any focal deficit or pathological finding in the clinical neurological examination, e.g. paresis of the extremities, cranial nerve affection, anisocoria, ataxia or aphasia. The definition of children was predefined as any person below the age of 18 years. The search criteria included synonyms for "children" and were not limited by any specific age range. [fig_ref] Figure 6: Scandinavian guidelines for initial management of minor and moderate head trauma in... [/fig_ref] , Additional files 10, 11, 12 and 13 Final guideline Diagram of the overall work process and methodology "CT findings" were defined as any traumatic finding on head CT, including linear skull fractures. The CT findings group was added since it was not always possible to separate linear non-depressed skull fractures from the statistical data given in the study. Intracranial injury (ICI) was pre-defined as any intracranial pathology on head CT, such as intracerebral haematomas, epidural and subdural haematomas, traumatic subarachnoid haemorrhage, pneumocephalus, depressed skull fracture and presence of skull base fracture, except isolated linear non-depressed skull fractures. Neurosurgical intervention was defined as any neurosurgical procedure for cranial or intracranial injury within the first week following trauma, but also included neurointensive care measures as not all ICIs are subjected to neurosurgery. Patient-important outcomes (neurosurgery, ICI and "CT findings") were rated according to GRADE methodology as having a "critical" or an "important" level of outcome importance [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref]. Both ICI and neurosurgical intervention were assigned a level of "critical patientimportant outcome". The group "CT findings" was assigned a non-critical but still important level of outcome importance, thus weighted slightly less in the assessment of relevant risk factors and recommendations. ## A priori assumptions and decisions The task force decided that the initial head CT would be considered the method of choice for acute diagnosis of intracranial complications following head injury. The use of magnetic resonance imaging (MRI) was not considered to be useful in initial management, mainly due to the lack of availability, as well as current practical issues, of acute MRI in the Scandinavian countries in present clinical care. Although MRI is generally better at detecting intracranial injuries, the duration of MRI is much longer and requires full co-operation from the child. An acute MRI is less time consuming, but the quality is presently similar to a CT in detecting intracranial pathology, however, with a higher risk of missing a skull fracture [bib_ref] Magnetic resonance imaging as an alternative to computed tomography in select patients..., Roguski [/bib_ref]. The use of skull radiographs as an initial method of diagnosing skull fractures before considering a head CT or observation was discussed within the task force and working group but unanimously rejected to be included in the guidelines. Former studies have recommended skull radiography in otherwise asymptomatic infants with a head trauma and scalp haematoma in order to find a skull fracture [bib_ref] Evaluation and management of children younger than two years old with apparently..., Schutzman [/bib_ref] [bib_ref] Clinical significance of scalp abnormalities in asymptomatic head-injured infants, Greenes [/bib_ref]. In these patients, a CT would be indicated, as the risk of intracranial injury is higher when a skull fracture is present. However, skull radiographs are no longer used in the Scandinavian countries as the primary radiologic investigation as they do not reflect intracranial injury with sufficient sensitivity or specificity [bib_ref] Value of radiological diagnosis of skull fracture in the management of mild..., Hofman [/bib_ref]. Also, recent data show that isolated skull fractures, in children who are otherwise neurologically intact following head trauma, have little impact on patient outcome [bib_ref] Isolated linear skull fractures in children with blunt head trauma, Powell [/bib_ref]. We do not consider later aspects of management of e.g. post-concussion syndrome, rehabilitation or any surgical specifics concerning surgical or medical management of intracranial complications. We also agreed that any pathological traumatic CT finding should lead to a period of in-hospital admission and observation. Not all patients, especially children, can be subjected to an initial head CT, and absence of ICI was considered for all those who were not diagnosed with neurological deficits, ICI or death, determined after clinical followup. In this sense, absence of ICI is more correctly describing absence of clinically important brain injury, rather than ICI. However, for practical purposes, the term ICI was used. A few studies used a reference standard of "clinically important traumatic brain injury" (ciTBI), defined as death from traumatic brain injury, neurosurgery, intubation >24 h or hospital admission ≥2 nights. With similar reasoning as above, ciTBI lies between ICI and neurosurgery in terms of outcome importance but was for practical reasons classified as ICI. During the GRADE assessment, these data were weighted higher with reference to critical patient-important outcomes [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref]. The subject of non-accidental injury (NAI) or child abuse is complex. The proposed guidelines are mainly based on data relying on proper history and assessable symptoms, both of which can be difficult to assess, especially due to weak or potential bias information about the historical event in NAI children. The task force, therefore, chose not to include studies focussing on NAI in the guidelines, but to rather raise increased awareness of the problem. In the Scandinavian countries, suspicion of child abuse should immediately be reported to the social services and, due to legal aspects, be thoroughly investigated and injuries extensively documented both clinically and radiologically. The Scandinavian health care system is somewhat different from the US and the UK systems. Clinical observation can be done by admission to the hospital children's ward and in some hospitals there is a shortterm observation ward in close vicinity of the ED. These short-term observation wards are not exactly similar to the paediatric observation units in the USA [bib_ref] Pediatric closed head injuries treated in an observation unit, Holsti [/bib_ref] since the Scandinavian short-term observation wards may have their paediatric resources reallocated to the children's wards during evenings and nights. Direct admission for in-hospital observation to the children's ward was recommended in the guidelines when the required observation time exceeded 24 hours. Children requiring observation for a shorter time can be admitted for observation in the short-term observation ward or children's ward, depending on the resources of the hospital. This is defined in the guidelines as short-term observation. ## Search strategy Two clinical search questions were assessed within the task force group: (Q1) "Which paediatric patients with head trauma need a head CT and which may be directly discharged?" and (Q2) "Which paediatric patients with head trauma need in-hospital observation and/or repeat head CT?" Original studies were found by searching Medline (PubMed), EMBASE, and the Cochrane library. Since the Cochrane library includes review articles only, the reference lists of potentially interesting reviews were checked for original papers missed in Medline search, but still fulfilling the search criteria for inclusion. The reference lists of all included studies were also handsearched for additional investigations. Publication dates between 1 January 1985 and 18 November 2013 were used as a time frame in all searches. Before 1985, CT was not used widely in this patient group. The pre-specified key words used for Q1 were: ("head trauma" OR "brain injury" OR "head injury" OR "traumatic head injury" OR "traumatic brain injury") AND (management OR prediction OR predictor OR decision rule) AND (children OR infant OR neonate OR pediatric OR paediatric). The key words "concussion" and "commotio cerebri" are common denominates for mild head trauma, but are most commonly affiliated with "post-concussion syndrome" and sports concussion. A separate search for ("concussion" OR "commotio cerebri") AND (management OR prediction OR predictor OR decision rule) AND (children OR infant OR neonate OR pediatric OR paediatric) was made without finding any additional studies suitable for inclusion in the final review. The key words for the Q2 search were: ("head trauma" OR "brain injury" OR "head injury" OR "traumatic head injury" OR "traumatic brain injury") AND (management OR prediction OR predictor OR decision rule) AND (children OR infant OR neonate OR pediatric OR paediatric) AND (hospitalization OR hospitalisation OR observation OR admission OR discharge OR delayed) OR (normal OR negative OR repeat OR multiple OR serial OR follow-up) AND (CT OR CCT OR computed tomography). ## Selection criteria and study eligibility The searches were independently performed by two authors (RÅ and CR). Study titles were examined independently (RÅ, CR) and studies were chosen very liberally. Titles that were clearly irrelevant were excluded. Abstracts were examined independently by RÅ and CR and any discrepancies were solved by discussion and consultation with the third author (JU). Full text papers were retrieved by accessing different institutional libraries and, as the last attempt, by trying to contact the authors of the studies. All retrieved full-text papers were independently examined by two authors (RÅ, CR) and any discrepancies were resolved and discussed with the third author (JU). Additional papers from references were contributed by all three authors (RÅ, CR, and JU) and examined independently by the whole task force group. The retrieved full-text papers in languages other than English were translated and reviewed by RÅ and CR. Only original studies were selected for inclusion in the final review. Systematic reviews, reviews or editorial letters were excluded, though the bibliographies were first examined for potentially interesting articles. Studies were included for further analysis if more than 50 % of the patients had a GCS score of 9 to15 on arrival to ED. Any study including children with severe head trauma only was excluded. Studies were also excluded if the patient material included fewer than 30 children or if it was not possible to separate children's data from adult's data. We did not set any further specifications to the definition of "a child". Two studies included "children" up to 21 years of age, although with a mean age below 9 years. Regarding the clinical question, Q1, studies were included if they reported at least one predictive risk factor related to either positive CT findings, ICI or need for neurosurgery. Studies were included in the final review if information regarding true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN) could be extracted. This was important for further data analysis in order to be able to compare and evaluate the clinical relevance of the different risk factors reported. For the second clinical question, Q2, studies including paediatric patients with an initial CT scan (normal or abnormal) after minimal to moderate head injury were initially included. Studies containing information about the clinical relevance of repeat or routine CT scan and/or the necessity of in-hospital observation after head injury were included. ## Data extraction and quality assessment Data were mainly extracted by one author (RÅ) and checked by random sampling by a second author (CR). All data were entered into a predefined protocol containing information regarding the number of patients included, inclusion and exclusion criteria, number of CTs, ICIs and neurosurgeries related to specific risk factors. Evidentiary tables were constructed to summarise the Q1 and Q2 studies. Quality assessment was independently performed by two authors (RÅ, CR) for all studies included in the final review. Quality of studies was assessed according to the CEBM-2 diagnostic criteriaand the QUADAS-2 tool [bib_ref] QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies, Whiting [/bib_ref]. Quality ratings for CEBM-2 range from 1 to 5, where 1 is the highest rating, given to systematic reviews or cross sectional studies with a consistently applied reference standard and blinding and 5 the lowest rating for papers with mechanism-based reasoning. No papers were given the ratings 1 or 5, since there were no systematic reviews included or any without acceptable statistical reasoning. The QUADAS-2 includes four key domains regarding: 1) patient selection, 2) index tests, 3) reference standard, and 4) flow and timing. All domains are rated with regard to risk of bias, and the first three items are also rated in terms of concerns regarding applicability to the research question. The domains are rated as high, low or unclear risk/concern. Discrepancies were first discussed between the two authors RÅ and CR and if uncertainties still remained, a third author (JU) was consulted. Discussions were made until full agreement was achieved in the task force. # Data analysis In accordance with the previous methodology for the Scandinavian head injury guidelines for adults, we did not perform a meta-analysis on the data prior to the development of the guidelines. Such an analysis, especially in the presence of heterogeneous data, may be misleading. Instead the task force group presented the non-combined data and quality assessment for the working group and stakeholders prior to the consensus process. This data gives the process more transparency and avoids misleading interpretations. Individual positive likelihood ratios (PLR) and negative likelihood ratios (NLR) were calculated for each risk factor related to the corresponding reference test (CT findings, ICI or neurosurgery). The prevalence of the risk factors and the positive reference test for the given risk factor were also calculated. These values are important in judging the impact on a risk factor on patient flow and for considerations included in the GRADE process. For the clinical question, Q2, we present only descriptive analysis. Evidence summary and recommendation draft The GRADE system for diagnostic accuracy studies was used for grading of the important risk factors in relation to the pre-specified critical and important outcomes (neurosurgery, ICI or CT findings) [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref]. The GRADE system is widely used in development of recommendations and allows consideration of aspects other than the level of evidence when determining the strength of the recommendations [fig_ref] Table 1: GRADE system for rating quality of evidence and strength of recommendation[41] Considerate... [/fig_ref] [bib_ref] Scandinavian guidelines for initial management of minimal, mild and moderate head injuries..., Unden [/bib_ref] [bib_ref] Going from evidence to recommendations, Guyatt [/bib_ref] [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref]. The evidence for the clinical predictor was initially considered high if derived from cohort studies reporting patients with diagnostic uncertainty and appropriate reference standards. Evidence could be downgraded or upgraded based on six different parameters: 1) risk of bias (bias of selection, verification, observer, or reporting), 2) outcome indirectness (the balance between the presumed influence on patient outcome of the test result in relation to the complications and resource use of the test), 3) inconsistency (large differences in prevalence of reference tests, prevalence of risk factors, PLR or NLR; or differing general results between studies), 4) impreciseness (studies with small number of patients and few positive CT, ICI or neurosurgery events), 5) suspicion of publication bias (small number of studies, industry funding), and 6) large effect (exceptional study with presumed large influence on patient-important outcome) [bib_ref] GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles-continuous outcomes, Guyatt [/bib_ref]. Very low quality Little confidence in the effect estimate. Any change of effect is uncertain. ## Recommendation Strong: "We recommend…" A strong recommendation indicates that most well-informed people will make the same choice. Weak: "We suggest…" A weak recommendation indicates that the majority of well-informed people will make the same choice but a substantial minority will not Uncertain: "We cannot recommend…" ## No specific recommendation for or against Factors influencing the strength of the recommendation include quality of evidence, risk/benefit aspects of presumed patient-important outcomes, costs and uncertainty concerning values and preferences GRADE Grading of Recommendations Assessment, Development and Evaluation All three authors in the task force graded the clinical predictors and formed the recommendation draft and flow-chart of the guidelines. Recommendations and guideline developmentthe modified Delphi process Based upon the recommendations, a draft of the guidelines was constructed by the task force. Following this, we used a modified Delphi process including a nominal group technique for consensus measure and development [bib_ref] Consensus on Outcome Measures for Glaucoma Effectiveness Trials: Results From a Delphi..., Ismail [/bib_ref] [bib_ref] A comparison of formal consensus methods used for developing clinical guidelines, Hutchings [/bib_ref] , involving the working group and stakeholders as previously described. The Delphi process typically involves three e-mail rounds in which a group of experts give their opinions and rate the research questions. The results are summarised and re-distributed for re-rating where the participants have the opportunity of changing their score in view of the group's response. The nominal group technique is a structured meeting gathering relevant experts to discuss and reach consensus about a given issue. Each participant, in turn, contributes and comments on the issues, a method which facilitates equal participation of all group members [bib_ref] Delphi method and nominal group technique in family planning and reproductive health..., Van Teijlingen [/bib_ref] [bib_ref] Developing templates for uniform data documentation and reporting in critical care using..., Lossius [/bib_ref]. According to an a priori decision, at least two rounds of consensus would be performed, irrespective of the results from the first round. The ratings of the recommendations and guideline drafts were done according to a 7-point scale of the AGREE-II instrument. The a priori criteria for consensus (acceptance or rejection) or the lack of consensus are shown in [fig_ref] Table 2 A: priori established seven-point response scale and criteria to determine acceptance, rejection or... [/fig_ref]. In the first round, the recommendations, data from included studies (including data for CEBM-2, QUADAS-2, and GRADE evaluations), together with the guideline draft, were sent by e-mail to the working group and stakeholders. Ratings, which includes rating of the: 1) scope and purpose, 2) stakeholder involvement, 3) rigour development, 4) clarity of presentation, 5) applicability, 6) editorial independence, and 7) an overall guideline assessment, including feedback, were collected and the task force summarised the ratings and opinions and adjusted the guideline draft based upon the response. The adjusted guideline draft was sent out by e-mail a week before the following consensus meeting. The ratings and comments on the recommendation and guideline draft were presented at the consensus meeting (one day), which was held in conjunction with a two-day SNC-meeting in January 2015 in Copenhagen, Denmark. Results were discussed and additional suggestions for improvements were made. During the consensus meeting the task force revised the recommendations and guidelines accordingly and the second Delphi round was performed. The results were summarised after the consensus meeting and it was agreed upon that in the event of the working group and stakeholders not reaching consensus on some of the issues, a third Delphi process would be performed by e-mail in April 2015. # Results A flow diagram of the working process is given in . The search and selection process for the two clinical questions is shown in [fig_ref] Figure 2: PRISMA [/fig_ref]. For the first clinical question, 52 papers satisfied the inclusion criteria [fig_ref] Figure 2: PRISMA [/fig_ref]. These studies included 118,265 individual children, 25,794 below 2 years of age. Head CT was reported for 46,218 children (39 %). Of these, 4486 (9.7 %) had a trauma related CT finding, mainly skull fracture. ICI's were reported for 2569 children (2.2 %; 2184 ICI and 385 ciTBI), and neurosurgery for 702 children (0.6 % of the whole study population). For clinical question 2, we included 12 papers [fig_ref] Figure 3: PRISMA [/fig_ref] , which included a total of 16,181 individual children. Descriptive data for the included studies of both clinical questions are shown in the evidentiary tables (Additional files 1 and 2: Tables S1 and S2). For clinical question 1, CEBM-2 varied between 2 and 4, with a median of 3. For question 2 the studies reached a CEBM-2 score of 3 to 4, with a median of 3.5. The QUADAS-2 evaluation of question 1 showed substantial bias regarding the reference standard and also flow and timing. The reference standards were of varying quality in the studies, some lacking adequate follow-up for those not receiving a CT scan. Thus, not all patients received the same reference standard, and some did not receive a reference standard at all. QUADAS-2 evaluation of the clinical question 2 studies showed substantial bias, especially regarding the index test (not blinded to reference standard) and the reference standard (lack of follow-up and results not blinded to the index tests) (Figs. 4 and 5, Additional files 3 and 4: Tables S3 and S4). Clinical predictors with the according source study, PLR, NLR, prevalence of risk factors, and prevalence of . ## Recommendations Based upon the evidence and the evaluation using the GRADE system, drafts of recommendations were made (Additional file 6: . Proposed guidelines based on the recommendations, including a flowchart, written discharge advice and observation schedule, were constructed by the task force. The recommendation draft and proposed guidelines, accompanied by all tables and figures, were reviewed by the working group and stakeholders in the Delphi process previously described. Following round 1, the discussion mainly concerned points 4 and 5, but minor adjustments were also made to points 3 and 10, the latter being the guideline flowchart. The changes all complied with the evidence summarised in Additional file 7: . During the consensus meeting it was decided to split "LOC" into "LOC ≥ 1 min" and "suspected/brief LOC", due to slight differences in their predictive risk, and the wording "altered mental status" was changed to GCS 14, as discussed below. Point 7 was vividly discussed as the majority did not agree on recommending early discharge of a child e.g. with clinical evidence of skull base fracture or following a seizure, despite a normal initial head CT. Following round 2, consensus was not reached for points 7, 8, and 9. The task force revised the recommendation for point 7 and it was made more specific in regard to which patients could be discharged after a normal head CT. Improvements of the written discharge information and observation schedule were also made according to earlier discussions at the consensus meeting (Additional file 8: . A third Delphi round was therefore performed by e-mail in early spring 2015. Ratings were made for points 7-9 and consensus was reached for all three points (Additional file 9: . The final evidence-based recommendations are presented below. For clinical question 1: "Which paediatric patients with head trauma need a head CT and which may be directly discharged?" 1. We recommend that all children with an ED admission GCS score 13 or below after head trauma should have a head CT scan. (Evidence grade: very low, Recommendation: strong). The evidence was initially of moderate quality but downgraded due to limitations in study design (mainly selection bias towards a more severely injured patient group), indirectness and inconsistency (large differences between the prevalence of risk factors and likelihood ratios). The evidence level was upgraded due to a large effect of one of the studies for the important outcome of ICI. The strength of the recommendation was, however, by the task force perceived as strong, when considering the seriousness of the potential intracranial complication and the health economic impact of missing a patient with a neurosurgical lesion [bib_ref] Derivation of the children's head injury algorithm for the prediction of important..., Dunning [/bib_ref] [bib_ref] Clinical predictors of abnormal computed tomography scans in paediatric head injury, Ng [/bib_ref] [bib_ref] CATCH: a clinical decision rule for the use of computed tomography in..., Osmond [/bib_ref] [bib_ref] Neuroprotein s-100B -a useful parameter in paediatric patients with mild traumatic brain..., Castellani [/bib_ref] [bib_ref] A clinical decision rule for cranial computed tomography in minor pediatric head..., Atabaki [/bib_ref] [bib_ref] Characteristics of children with vomiting after minor head trauma: a case-control study, Da Dalt [/bib_ref] [bib_ref] Performance of a decision rule to predict need for computed tomography among..., Oman [/bib_ref] [bib_ref] Association among duration of unconsciousness, Glasgow Coma Scale, and cranial computed tomography..., Ratan [/bib_ref] [bib_ref] The utility of head computed tomographic scanning in pediatric patients with normal..., Schunk [/bib_ref] [bib_ref] Risk factors in the outcome of children with minor head injury, Hahn [/bib_ref] [bib_ref] How should we manage children after mild head injury?, Mandera [/bib_ref] [bib_ref] Skull radiographs and computed tomography scans in children and adolescents with mild..., Melo [/bib_ref] [bib_ref] International study of emergency department care for pediatric traumatic brain injury and..., Murgio [/bib_ref] [bib_ref] Registry of mild craniocerebral trauma: multicentre study from the Spanish Association of..., Garcia [/bib_ref]. The evidence was initially of high quality, but downgraded due to limitations in study design (selection bias), indirectness (lack of description of outcome measures and follow-up) and inconsistency (large differences in prevalence of risk factors and likelihood ratios). There was no upgrading of the evidence level. The recommendation was perceived as strong when considering the relatively low prevalence of the predictive factors compared to the severe influence on patient outcome if the patients with ICI or a neurosurgical lesion were missed; (a) [bib_ref] Indications for brain computed tomography and hospital admission in pediatric patients with..., Guzel [/bib_ref] [bib_ref] Derivation of the children's head injury algorithm for the prediction of important..., Dunning [/bib_ref] [bib_ref] Clinical predictors of abnormal computed tomography scans in paediatric head injury, Ng [/bib_ref] [bib_ref] A clinical decision rule for cranial computed tomography in minor pediatric head..., Atabaki [/bib_ref] [bib_ref] Characteristics of children with vomiting after minor head trauma: a case-control study, Da Dalt [/bib_ref] [bib_ref] Performance of a decision rule to predict need for computed tomography among..., Oman [/bib_ref] [bib_ref] S-100B in serum and urine after traumatic head injury in children, Hallen [/bib_ref] [bib_ref] Evaluation of decision rules for identifying serious consequences of traumatic head injuries..., Klemetti [/bib_ref] [bib_ref] Clinical performance of NICE recommendations versus NCWFNS proposal in patients with mild..., Fabbri [/bib_ref] [bib_ref] A decision rule for identifying children at low risk for brain injuries..., Palchak [/bib_ref] [bib_ref] Head trauma in children younger than 2 years: are there predictors for..., Gruskin [/bib_ref] [bib_ref] Predictive value of skull radiography for intracranial injury in children with blunt..., Lloyd [/bib_ref] [bib_ref] Diagnostic testing for acute head injury in children: when are head computed..., Quayle [/bib_ref] [bib_ref] Skull fractures in infants and predictors of associated intracranial injury, Shane [/bib_ref] [bib_ref] Cranial computed tomography scans in children after minimal head injury with loss..., Davis [/bib_ref] [bib_ref] Evaluation of minor head injury in children, Mitchell [/bib_ref] [bib_ref] Clinical predictors of computed tomographic abnormalities following pediatric traumatic brain injury, Ramundo [/bib_ref] [bib_ref] Pediatric head injuries: can clinical factors reliably predict an abnormality on computed..., Dietrich [/bib_ref] [bib_ref] The significance of skull fracture in acute traumatic intracranial hematomas in adolescents:..., Chan [/bib_ref] , (b) . Suspicion or evidence of skull fracture was found to be a strong predictor for ICI, and especially high risk was found for evidence of depressed skull fractures and clinical signs of skull base fractures . A palpable fracture will automatically give a suspicion of depressed skull fracture. Linear skull fractures are generally not palpable, but might give rise to a scalp haematoma. The prevalence of linear fractures was relatively high and linear fractures are less predictive of intracranial injury compared to depressed or skull base fractures. The task force therefore chose to separate these according to their risks, such that patients with clinical evidence of depressed or skull base fractures are recommended for a CT and those with temporal scalp hematomas alone are recommended for observation, according to recommendation 5. The initial recommendation draft included "altered mental status", defined according to Kupperman et al as a predictor [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref]. Since irritability, somnolence and confusion are all included in the definition of a GCS score lower than 15, the "altered mental status" was changed to "GCS score 14" after the first Delphi round . The evidence for prolonged LOC (≥1 min) as a predictive factor for intracranial complications was slightly higher (low evidence) than for unspecified LOC (very low evidence) . This is mainly due to imprecision and indirectness, and with a very high prevalence of the risk factor in some studies. An obvious bias was also that some studies also had LOC as inclusion criteria, increasing the prevalence and severity level of the study population. There was also a slight increased risk of ICI for LOC of 1 min or longer. Most studies excluded patients with coagulopathy, as this has been considered to be associated with high risk for developing intracranial bleeding after trauma. Two studies investigated coagulopathy as a potential risk factor [bib_ref] Performance of a decision rule to predict need for computed tomography among..., Oman [/bib_ref] [bib_ref] Clinical performance of NICE recommendations versus NCWFNS proposal in patients with mild..., Fabbri [/bib_ref] and especially one study found coagulopathy to be a strong predictive factor for intracranial injury [bib_ref] Performance of a decision rule to predict need for computed tomography among..., Oman [/bib_ref]. The evidence for this predictor was very low, as there was no further description of the risk factor or potential confounding factors. Selection, imprecision, and publication bias were the main parameters that lowered the evidence level. The prevalence of children having coagulopathy or in anticoagulant treatment is very low and the number of children with coagulopathy and head injury can be considered to be even lower. The task force therefore concluded that due to the potentially increased risk, these children should not be sent home immediately from the ER and thus instead are recommended in-hospital observation to follow development of eventual symptoms or a CT scan. Admission, rather than CT only, was chosen as children with coagulation issues are often subjected to numerous radiological procedures, most of them following trauma. We therefore allowed for the treating physician to choose one of these management options. 4. We recommend that children after head trauma with (a) posttraumatic amnesia or (b) vomiting of two or more times [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] [bib_ref] Derivation of the children's head injury algorithm for the prediction of important..., Dunning [/bib_ref] [bib_ref] CATCH: a clinical decision rule for the use of computed tomography in..., Osmond [/bib_ref] [bib_ref] Characteristics of children with vomiting after minor head trauma: a case-control study, Da Dalt [/bib_ref] [bib_ref] Performance of a decision rule to predict need for computed tomography among..., Oman [/bib_ref] [bib_ref] Registry of mild craniocerebral trauma: multicentre study from the Spanish Association of..., Garcia [/bib_ref] [bib_ref] Clinical performance of NICE recommendations versus NCWFNS proposal in patients with mild..., Fabbri [/bib_ref] , should be admitted for clinical observation in the hospital (Evidence grade: very low, Recommendation: strong). The evidence regarding posttraumatic amnesia [bib_ref] Indications for brain computed tomography and hospital admission in pediatric patients with..., Guzel [/bib_ref] [bib_ref] Derivation of the children's head injury algorithm for the prediction of important..., Dunning [/bib_ref] [bib_ref] Characteristics of children with vomiting after minor head trauma: a case-control study, Da Dalt [/bib_ref] was initially high but downgraded due to selection bias and publication bias (very few studies) and indirectness (no specified reference standard for outcome measures). We decided to include prolonged amnesia (> 5 min) [bib_ref] Derivation of the children's head injury algorithm for the prediction of important..., Dunning [/bib_ref] in the evaluation of posttraumatic amnesia, since it was considered a strong predictor with moderate level of evidence. Duration of amnesia, especially in a child, is very difficult to determine and impractical, and cannot be properly evaluated in a preverbal child. Following the consensus meeting we therefore decided not to include any time limit for amnesia in the recommendations. The prevalence of both these predictive factors was relatively high in the investigated studies and when considering the health economic consequences compared to the risk of missing an important intracranial complication, the task force did not find the evidence strong enough for recommending an immediate CT scan. Therefore, we instead recommend in-hospital observation. ## We suggest that children displaying a gcs score 15 with (a) severe or progressive headache, (b) abnormal behaviour according to guardian [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] [bib_ref] Performance of a decision rule to predict need for computed tomography among..., Oman [/bib_ref] [bib_ref] Evaluation of decision rules for identifying serious consequences of traumatic head injuries..., Klemetti [/bib_ref] [bib_ref] Clinical performance of NICE recommendations versus NCWFNS proposal in patients with mild..., Fabbri [/bib_ref] [bib_ref] Head trauma in children younger than 2 years: are there predictors for..., Gruskin [/bib_ref] , (c) brief LOC or (d) if age < 2 years and with irritability or a large or temporal/parietal scalp haematoma, should be observed in the hospital. (Evidence grade: very low, Recommendation: weak). The quality of the evidence was initially high, but down rated due to selection bias (some studies only included infants), impreciseness, inconsistency, and indirectness. Severe progressive headache was considered a moderate to weak predictor of intracranial complications and the evidence level was very low mainly due to the high and variable prevalence of the predictor (2-60 %) in the included studies [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] [bib_ref] Characteristics of children with vomiting after minor head trauma: a case-control study, Da Dalt [/bib_ref] [bib_ref] Performance of a decision rule to predict need for computed tomography among..., Oman [/bib_ref] [bib_ref] Diagnostic testing for acute head injury in children: when are head computed..., Quayle [/bib_ref]. Irritability was not included in the definition of "GCS score 14 or lower", since the task force and the working group found irritability more similar to abnormal behaviour than to decreased level of consciousness or confusion. Irritability can be misinterpreted in many ways, and should be understood as an abnormal behaviour to a normal stimulus, not only an angry child. Only two studies investigated irritability as a risk factor for ICI among children [bib_ref] The utility of head computed tomographic scanning in pediatric patients with normal..., Schunk [/bib_ref] [bib_ref] Clinical indicators of intracranial injury in head-injured infants, Greenes [/bib_ref]. It is a weaker predictor of ICI compared to GCS score 14 or drowsiness, and the level of evidence was very low. Three studies investigated the occurrence of scalp haematoma based on size or location. All but one study only included children younger than two years old. Size of haematoma was divided into "small, barely palpable", "moderate and easily palpable" and "large, boggy consistency". Only children with large boggy haematomas had a clearly increased risk of intracranial complication [bib_ref] Clinical significance of scalp abnormalities in asymptomatic head-injured infants, Greenes [/bib_ref] [bib_ref] CATCH: a clinical decision rule for the use of computed tomography in..., Osmond [/bib_ref] [bib_ref] Clinical indicators of intracranial injury in head-injured infants, Greenes [/bib_ref]. Temporal haematoma was found to be a moderate predictive risk factor for ICI, whereas occurrence of parietal haematoma was considered to be a weak risk factor for ICI [bib_ref] Clinical significance of scalp abnormalities in asymptomatic head-injured infants, Greenes [/bib_ref]. The prevalence of scalp haematomas after head trauma in this patient population is large and the occurrence of ICI low. Recommending a CT would lead to an enormous increase in unnecessary radiation to the child. We therefore recommend inhospital observation for these children. For the second clinical question "Which children with non-severe head trauma need a repeat CT and/or inhospital admission?" the following recommendations were made: 6. We recommend that repeat CT should be performed in patients with clinical or neurological deterioration. (Evidence grade: very low, Recommendation: strong). Evidence was initially considered of moderate quality (studies 1-7 in Evidentiary table Q2), but was downgraded due to serious selection bias, inconsistency and impreciseness [bib_ref] Mild and moderate pediatric traumatic brain injury: replace routine repeat head computed..., Aziz [/bib_ref] [bib_ref] Is repeat head computed tomography necessary in children admitted with mild head..., Dawson [/bib_ref] [bib_ref] The use of repeated head computed tomography in pediatric blunt head trauma:..., Hollingworth [/bib_ref] [bib_ref] Are serial brain imaging scans required for children who have suffered acute..., Schnellinger [/bib_ref] [bib_ref] Value of repeat cranial computed tomography in pediatric patients sustaining moderate to..., Da Silva [/bib_ref] [bib_ref] Utility of serial computed tomography imaging in pediatric patients with head trauma, Durham [/bib_ref] [bib_ref] Reimaging in pediatric neurotrauma: factors associated with progression of intracranial injury, Givner [/bib_ref]. Routine repeat CT is not recommended for all admitted children after head trauma. Patients with mild head trauma and a normal initial head CT have a very low risk of radiological progression on a routine repeat CT if symptoms are unchanged or improved [bib_ref] Mild and moderate pediatric traumatic brain injury: replace routine repeat head computed..., Aziz [/bib_ref] [bib_ref] Is repeat head computed tomography necessary in children admitted with mild head..., Dawson [/bib_ref] [bib_ref] The use of repeated head computed tomography in pediatric blunt head trauma:..., Hollingworth [/bib_ref]. The evidence did not give any conclusive results for children whose initial head CT showed an intracranial injury. One study showed that repeat CT only had a clinical consequence in the case of clinical deterioration or if the patient was suspected to be a victim of NAI, despite ICI on initial CT [bib_ref] Are serial brain imaging scans required for children who have suffered acute..., Schnellinger [/bib_ref]. Another study concluded that children with moderate or severe head trauma and improvements of GCS score after the initial CT do not require routine repeat CT within 48 hours [bib_ref] Value of repeat cranial computed tomography in pediatric patients sustaining moderate to..., Da Silva [/bib_ref]. Three other studies have concluded that patients with high-risk intracranial lesions on the initial CT should have a repeat CT within 24-48 hours, due to the risk of radiological progression and change in management. The definition of high-risk and low-risk lesions varies in the different studies [bib_ref] The use of repeated head computed tomography in pediatric blunt head trauma:..., Hollingworth [/bib_ref] [bib_ref] Utility of serial computed tomography imaging in pediatric patients with head trauma, Durham [/bib_ref] [bib_ref] Reimaging in pediatric neurotrauma: factors associated with progression of intracranial injury, Givner [/bib_ref] , thus any specific recommendations were not possible to be based upon these studies. 7. We suggest that those patients with mild head injury and a normal neurological examination and with an initial head CT without any pathological findings related to the head trauma, can be discharged (Evidence grade: low evidence, Recommendation: weak). Evidence based on Q2 studies 8-12 was initially considered of high quality, but downgraded due to impreciseness and indirectness [bib_ref] Pediatric closed head injuries treated in an observation unit, Holsti [/bib_ref] [bib_ref] The use of cranial CT scans in the triage of pediatric patients..., Davis [/bib_ref] [bib_ref] Do children with blunt head trauma and normal cranial computed tomography scan..., Holmes [/bib_ref] [bib_ref] Necessity of hospital admission for pediatric minor head injury, Spencer [/bib_ref] [bib_ref] Minimal head trauma in children revisited: is routine hospitalization required?, Roddy [/bib_ref]. All five studies included a total of 14,486 children with MHT, primarily GCS score 14 to 15, although two studies also included some with GCS score 9 to 13. Although not consequently specified, we could assume that none of the patients included in these studies had focal neurological deficits. We therefore conclude and suggest that patients with GCS scores of 14 to 15 and no neurological deficits and without any pathological findings on CT related to the trauma can be discharged. Three out of five studies included patients with a normal CT only [bib_ref] Do children with blunt head trauma and normal cranial computed tomography scan..., Holmes [/bib_ref] [bib_ref] Necessity of hospital admission for pediatric minor head injury, Spencer [/bib_ref] [bib_ref] Minimal head trauma in children revisited: is routine hospitalization required?, Roddy [/bib_ref] , one study concluded that the finding of a skull base fracture on CT might imply a high risk of the child requiring a longer observation time (>24 h) than provided in their observation unit [bib_ref] Pediatric closed head injuries treated in an observation unit, Holsti [/bib_ref] and in the last study, although it included patients with basilar skull fractures [bib_ref] The use of cranial CT scans in the triage of pediatric patients..., Davis [/bib_ref] , there were not enough data to draw conclusions about early discharge when there is no intracranial injury in the presence of a basilar skull fracture. This latter issue was discussed in the consensus part before finalisation of the guidelines (see Guidelines). ## Guidelines Based upon the recommendations, the guidelines and the guideline flow-chart were constructed [fig_ref] Figure 6: Scandinavian guidelines for initial management of minor and moderate head trauma in... [/fig_ref] , Additional file 10: Help sheet). Similar to the Scandinavian adult head injury guidelines, the recommendations were divided into moderate, mild and minimal head injury groups and the mild head injury group was further sub-divided into highrisk, medium-risk and low-risk depending on the GCS score and predictive risk factors. During consensus discussion, the working group agreed to add the occurrence of shunts into the guidelines. Thus, we suggest that children with ventricular shunts and no specific symptoms should be observed for at least six hours. According to available evidence, patients with shunts do not have an increased risk of intracranial injury or neurosurgery compared to those without. Most studies, however, excluded children with shunts or other known neurological disorders in their analysis. Only one study by Nigrovic et al. focusses specifically on 98 children with shunts admitted to the ED after minor head injury [bib_ref] The prevalence of traumatic brain injuries after minor blunt head trauma in..., Nigrovic [/bib_ref]. They found that the risk of having a clinically important traumatic brain injury was very small; only one child had a chronic subdural haematoma which was larger than seen on the previous CT. In the event of an intracranial haematoma, there is a theoretical risk of a more rapid expansion of the haematoma among patients with a ventricular shunt, due to the increased drainage of cerebrospinal fluid resulting in less counter-pressure against the hematoma. For shunted children, there is also the constant question of possible malfunction of the shunt after head trauma and the study by showed that these children, in comparison to children without shunts, are more subjected to CT scanning after head trauma [bib_ref] The prevalence of traumatic brain injuries after minor blunt head trauma in..., Nigrovic [/bib_ref]. Additional factors, such as age < 1 year, bulging fontanel and high-energy trauma, were discussed but not included in the recommendations or guidelines. Our analysis did not show an increased risk of intracranial injury or neurosurgery in younger children or infants. Infants are in general more difficult to diagnose. They may present with fewer and more unspecific symptoms late in the process. For this reason, it was discussed whether to admit all infants for observation regardless of symptoms (or lack of symptoms) after head trauma, but there was no clinical consensus regarding this. Instead, the task force decided to raise awareness regarding infants by adding this in the NB-box in the help-sheet. A bulging fontanel as a sign of increased intracranial pressure may be a predictor of intracranial injury after head trauma in infants [bib_ref] Clinical indicators of intracranial injury in head-injured infants, Greenes [/bib_ref]. A bulging fontanel is normally seen in a crying and tense child (< 2 years), which can be difficult to differentiate from more serious causes, especially for the inexperienced doctors usually on call in the ED. Children with this finding may need a CT scan, although a child with intracranial pathology severe enough to cause bulging of the fontanel should also present with other symptoms, such as irritability, decreased level of consciousness or focal neurological deficits. Therefore, bulging fontanel was for practical reasons omitted in the recommendations, but is mentioned in the guidelines as an extra precaution in the NB-box. High-velocity road traffic accidents and fall from > 3 m were considered moderate predictors of intracranial injury. The evidence was very heterogeneous with most studies showing a relatively low predictive value, in contrast to some studies showing extremely high predictive values, especially for road traffic accidents [bib_ref] Derivation of the children's head injury algorithm for the prediction of important..., Dunning [/bib_ref]. These studies were biased towards selecting any severity of head trauma, and there was no further description of the level of consciousness or severity of the patients admitted due to traffic accidents. High-speed traffic accidents and falls from > 3 m of height are considered highenergy trauma, and these patients will be treated in the Scandinavian EDs according to a trauma protocol; these children routinely receive an extensive full-body examination, often a whole body trauma CT, and are always admitted for in-hospital observation. The task force decided therefore not to specifically include these predictors in the recommendations, but point out that these children should not be immediately discharged from the ED. During the consensus meeting, the length of inhospital observation was discussed. The studies from the Q2 search mainly used an observation time of 12-24 hours, even after a normal head CT, but no evidencebased conclusions regarding the duration of in-hospital observation could be drawn from the studies. Consensus regarding a 24 h, 12 h and 6 h observation time, depending on the risk factors, was reached and added in the guidelines. There was a unanimous consensus that children with moderate head trauma and those in the mild, high-risk group, should be observed for at least 24 hours post trauma, regardless of a normal initial head CT, and that children with mild, medium-risk should be observed for at least 12 hours post trauma. The majority of children entering an ED after head injury will be in the mild, low-risk or minimal head trauma groups. After discussion among the working group and stakeholders, there was an agreement to lower the recommended observation time to at least 6 hours for the mild, low-risk group, taking into consideration the impact a longer observation time would have on the paediatric wards, as well as an increased economic impact. There were divergent opinions regarding the early discharge of MHT patients with normal neurology if initial head CT is normal or without intracranial haemorrhage. The main concern was that this suggests early discharge for children who have had a posttraumatic seizure or have clinical signs of skull base fracture. Children presenting with posttraumatic seizures or skull base fractures are relatively rare, and are more often related to [bib_ref] Management and outcome of pediatric skull base fractures, Perheentupa [/bib_ref]. So far the evidence for early discharge of these children who also have a normal CT scan is still very weak. Some larger studies exclude patients with basilar skull base fractures [bib_ref] Do children with blunt head trauma and normal cranial computed tomography scan..., Holmes [/bib_ref] [bib_ref] Neurologically intact children with an isolated skull fracture may be safely discharged..., Rollins [/bib_ref] , although there are some former studies suggesting discharge of these children from the ED [bib_ref] Pediatric basilar skull fracture: do children with normal neurologic findings and no..., Kadish [/bib_ref] [bib_ref] Immediate posttraumatic seizures: is routine hospitalization necessary?, Dias [/bib_ref]. During the consensus discussion it was stated that according to good clinical practice, these children should not be discharged without proper in-hospital observation, as these clinical risk factors are relatively worrying, both to health care professionals and to patients/guardians. There was therefore a consensus that children with a mild, high-risk head trauma should be admitted for observation regardless of a normal head CT. The length of observation was kept to more than 24 h after the trauma, this still being a consensus decision in lack of better evidence. ## In-hospital observation and discharge information to patient and guardian There were no information regarding the quality of the inhospital observation routine, nor concerning the discharge information given to parents and children in the included studies. The task force therefore searched the available information sheets from existing head injury guidelines, including the recently revised SNC head injury guidelines for adults [bib_ref] Scandinavian guidelines for initial management of minimal, mild and moderate head injuries..., Unden [/bib_ref] [bib_ref] Updated guidelines for the management of sports-related concussion in general practice, Makdissi [/bib_ref]. A draft for discharge information and in-hospital observation was made and sent to all involved stakeholders and the working group before the consensus meeting. During the consensus meeting, the working group and stakeholders agreed upon the basic information of a refined draft, also including recommendations for "return to play" after concussion. The finalized versions were revised by the task force, and sent out by e-mail for the 3 rd modified Delphi round (Additional files 11, 12 and 13). The observation sheet is intended as guidance for physicians and nurses in the paediatric wards managing children with mild to moderate head injuries with or without a verified intracranial injury. It includes the minimum requirements for observing a child with head trauma. The advice regarding stepwise return to play is mainly based on the consensus statement on concussion in sports by McCrory et al. It was agreed upon that children (< 18 years of age) should have a more conservative approach than adults before return to play, as the brain is more vulnerable to second impact syndrome or increased risk of brain swelling in children and adolescents [bib_ref] Second impact syndrome or cerebral swelling after sporting head injury, Mccrory [/bib_ref]. ## Implementation, monitoring and future aspects The value of these guidelines lies in widespread use and implementation. Before widespread implementation of the guidelines, they first need to be externally validated. The proposed guidelines are therefore planned for clinical validation in the Scandinavian paediatric population in both a retrospective and in a prospective cohort study, primarily to determine the safety of the proposed guidelines, but also to compare the performance of our guidelines to other decision rules. The validation process is similar to the validation of adult head trauma guidelines, which is currently ongoing. The guidelines will be translated into the different Scandinavian languages and published in the national medical journals, which are routinely read by the members of the national medical societies. Once the guidelines have been validated, further implementation will be led by the SNC members in their respective countries. Educational meetings, pocket cards and guideline apps are known to be useful tools and will be used in the implementation process. Follow-up on the implementation process will be made one year after commencement by a questionnaire similar to the one developed for follow-up of the adult head injury guidelines. There is rapid development in this area, especially regarding radiologic diagnostic procedures and concerning biomarkers for brain damage following MHT. We estimate that a revision of the guidelines should be performed within four years of publication. # Discussion The new Scandinavian head trauma guidelines are primarily aimed as guidance to detect intracranial complications after head trauma in patients needing neurosurgery or medical intervention. They are complementary to the newly revised adult head injury guidelines [bib_ref] Scandinavian guidelines for initial management of minimal, mild and moderate head injuries..., Unden [/bib_ref] by using the same severity classification, and apply to all children and adolescents below the age of 18 years. It is a requirement that the physicians have a basic knowledge of the GCS and, although not specified in the guidelines, the paediatric GCS is also applicable for children younger than five years [bib_ref] Performance of the pediatric glasgow coma scale in children with blunt head..., Holmes [/bib_ref]. The guidelines are primarily intended as guidance for physicians who meet this patient category and who are not experts in this field. Physicians who have considerable experience with these patients should naturally be allowed to deviate from these guidelines according to best clinical judgement. In developing the SNC guidelines, we have taken into account the potentially harmful long-term effect of ionizing radiation derived from diagnostic CT [bib_ref] Radiation exposure from CT scans in childhood and subsequent risk of leukaemia..., Pearce [/bib_ref] and therefore only recommend referral to CT when clinically justified. The guidelines separate mild, high-risk and mild, low-risk head trauma patients, favouring shortterm observation for mild, low-risk patients as an attempt to reduce unnecessary CT scans in children. In comparison, international guidelines, such as the AAP guidelines, the CATCH, the CHALICE guidelines and, to some extent, the PECARN decision rule, seem to advocate a more liberal view on CT scanning of children [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] [bib_ref] Derivation of the children's head injury algorithm for the prediction of important..., Dunning [/bib_ref] [bib_ref] CATCH: a clinical decision rule for the use of computed tomography in..., Osmond [/bib_ref] , where our guidelines recommend observation. In the study by af Geijerstam et al, similar patient satisfaction and outcome with either immediate CT and early discharge or in-hospital observation was found [bib_ref] Medical outcome after immediate computed tomography or admission for observation in patients..., Af Geijerstam [/bib_ref]. The use of acute MRI would omit the radiation issue, but there are still major issues regarding this technique at the present time, including availability, risks of missing skull fractures [bib_ref] Magnetic resonance imaging as an alternative to computed tomography in select patients..., Roguski [/bib_ref] , and need for sedatives or anaesthesia during the procedure [bib_ref] Paediatric MRI under sedation: is it necessary? What is the evidence for..., Edwards [/bib_ref]. Eventually, this modality will become more practical, faster, cheaper, and more widely available and could then potentially replace CT scanning for this patient group. However, until this is a clinical reality, CT scanning, with the associated risk, is the diagnostic method of choice. Due to these risks, clinical observation can be used in the intermediate risk group of children with MHT. Children from these groups who display clinical deterioration or fail to improve should have a CT scan. Children with higher risks of brain injury should naturally receive a CT scan as the primary management. The economic impact of TBI has so far been poorly investigated, especially with regards to minor and moderate head injuries [bib_ref] The costs of traumatic brain injury: a literature review, Humphreys [/bib_ref]. A recent epidemiological study from New Zealand has investigated the incidence of TBI across different age-groups and TBI severities, including both non-hospitalised and hospitalised patients, and found that the incidence of mild TBI was far greater than estimated in the previous studies from other highincome countries (749 vs 200-550 per 100,000 per year) [bib_ref] Incidence of traumatic brain injury in New Zealand: a population-based study, Feigin [/bib_ref]. In a follow-up study based on these results, the authors also made an estimate of the cost of TBI, according to severity, during the first year and included an estimated life-time cost, where the latter cost-estimate varied from USD 4.636 for mild cases to USD 36.648 for moderate -severe cases [bib_ref] Cost of traumatic brain injury in New Zealand: evidence from a populationbased..., Ao [/bib_ref]. Proper and early diagnosis and avoiding unnecessary hospitalisations and investigations, as well as adequate discharge information for patients and guardians, could help decrease the overall costs. Morbidity rates are high for moderately and severely brain injured patients [bib_ref] Long-term survival after traumatic brain injury Part II: life expectancy, Brooks [/bib_ref]. Rehabilitation of both motor and cognitive skills is required and, even if some patients fully recover with respect to their neurological functions, many still suffer from memory, psychological, and social problems [bib_ref] Surviving severe traumatic brain injury in Denmark: incidence and predictors of highly..., Odgaard [/bib_ref]. Children have a higher percentage of good outcomes and lower mortality rates than adults [bib_ref] Outcome from head injury related to patient's age. A longitudinal prospective study..., Luerssen [/bib_ref]. Post-concussive symptoms have been described in 15-50 % of the adult population [bib_ref] Symptoms at one year following concussion from minor head injuries, Rutherford [/bib_ref] , but exist even in the paediatric population causing memory problems and impaired school performance [bib_ref] Predicting and preventing postconcussive problems in paediatrics (5P) study: protocol for a..., Zemek [/bib_ref] [bib_ref] Duration and course of post-concussive symptoms, Eisenberg [/bib_ref]. The risks and long-term effects of post-concussion syndrome and the socio-economic impacts are not handled in the present guidelines, and are yet to be determined. The present guidelines do not include the biomarker S100B, since the evidence was considered too low and the number of studies too few. Additionally, the studies included had different cut-off values and various commercially available methods for S100B analysis were used. Serum S100B has been extensively studied among adults and has recently been introduced in the SNC adult head injury guidelines. With proper use of the adult guidelines including S100B, the number of unnecessary CT scans can be reduced up to 30 %, which would naturally be desirable in a paediatric setting. However, the reference levels for children are highly age dependent [bib_ref] Reference values for venous and capillary S100B in children, Astrand [/bib_ref] [bib_ref] Reference ranges for serum S100B protein during the first three years of..., Bouvier [/bib_ref] , and a large study confirming the positive results from Bouvier et al is needed before S100B can be included in paediatric guidelines [bib_ref] Serum S100B determination in the management of pediatric mild traumatic brain injury, Bouvier [/bib_ref]. We intend to follow-up on this important issue in future clinical studies. There are limitations to this study. The poor quality of the evidence is of major concern mainly due to selection as well as verification bias. Some studies excluded patients with LOC and others included patients with pre-specified symptoms only. The majority of studies excluded patients with bleeding disorders and penetrating injuries. Some older studies performed skull radiography on subsets of patients with suspected skull fractures. CT was only performed if the x-ray showed a fracture. The largest study in our material, by Kupperman et al [bib_ref] Identification of children at very low risk of clinically-important brain injuries after..., Kuppermann [/bib_ref] with a primary endpoint of clinically important TBI, has naturally had a large impact on these guidelines as it includes more than 42,000 children and the study quality is exceptionally good. Since the commencement of the guideline process in 2013, there have been several subanalyses from the same PECARN cohort. These studies analyse the different symptoms (headache, presence of scalp haematoma, and vomiting) as possible predictive risk factor for ciTBI [bib_ref] Association of traumatic brain injuries with vomiting in children with blunt head..., Dayan [/bib_ref] [bib_ref] Headache in traumatic brain injuries from blunt head trauma, Dayan [/bib_ref] [bib_ref] Risk of traumatic brain injuries in children younger than 24 months with..., Dayan [/bib_ref] , and confirm the results of these guidelines. Isolated headache, isolated vomiting, and isolated LOC in children with MHT were considered to indicate a considerably lower risk of ciTBI, and the authors suggest that these children could be observed in the ED without an initial CT scan [bib_ref] Association of traumatic brain injuries with vomiting in children with blunt head..., Dayan [/bib_ref] [bib_ref] Headache in traumatic brain injuries from blunt head trauma, Dayan [/bib_ref] [bib_ref] Isolated loss of consciousness in children with minor blunt head trauma, Lee [/bib_ref]. These studies will be included for consideration in the next update of these guidelines. Although the recommendations are based on evidence, there are elements based on consensus in the final guidelines. The invited stakeholders have the largest expertise and interest in paediatric head trauma in Scandinavia and were therefore essential to the consensus process. We chose not to perform a meta-analysis due to obvious heterogeneous data and the questionable value of the summarised values in these cases. We followed the GRADE methodology for guideline development as this also gave us the possibility of considering other aspects, such as health economic issues and the Scandinavian setting, other than the level of evidence. This methodology was judged as the most feasible considering the Scandinavian target population. # Conclusion We present the first evidence and consensus based Scandinavian guidelines for initial management of children with minor and moderate head trauma. They address aspects such as selection to CT or admission, repeat CT, monitoring routines and discharge. These guidelines should be validated before extensive clinical use and updated within 4 years due to rapid development of new diagnostic tools within paediatric neurotrauma. [fig] Figure 2: PRISMA (adapted preferred reporting items for systematic reviews and meta-analyses) diagram showing the review process for clinical question 1: Which paediatric patients with (non-severe) head trauma need a head CT and which patients may be directly discharged? [/fig] [fig] Figure 3: PRISMA (adapted preferred reporting items for systematic reviews and meta-analyses) diagram showing the review process for clinical question 2: Which paediatric patients with (non-severe) head trauma need in-hospital observation and/or repeat head CT?Fig. 4 Summary of QUADAS-2 for clinical question 1: Which paediatric patients with (non-severe) head trauma need a head CT and which patients may be directly discharged? skull fracture should have a head CT scan. (Evidence grade: very low, Recommendation: strong). [/fig] [fig] 3: We recommend that children with (a) GCS score 14, (b) loss of consciousness for > 1 min after head trauma or (c) children with coagulation disorders or with anticoagulation therapy should be either admitted for in-hospital observation or have a head CT. (Evidence grade: very low, Recommendation: strong). [/fig] [fig] Figure 5: Summary of QUADAS-2 for clinical question 2: Which paediatric patients with (non-severe) head trauma need in-hospital observation and/or repeat head CT? [/fig] [fig] Figure 6: Scandinavian guidelines for initial management of minor and moderate head trauma in children more severe head traumas [/fig] [table] Table 1: GRADE system for rating quality of evidence and strength of recommendation[41] Considerate confidence of the estimate effect. Further research is very unlikely to change our confidence in the estimated effect.Moderate qualityConfidence that the estimate is close to the truth. Further research is likely to have an important impact on our confidence in the estimate effect and may change the estimate.Low quality Limited confidence in the effect. Further research is likely to have an important impact on our confidence in the estimate effect and is likely to change the estimate. [/table] [table] Table 2 A: priori established seven-point response scale and criteria to determine acceptance, rejection or lack of consensus for recommendations and guidelines [/table]	None	https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-016-0574-x	None
783354563513e591e27e365b28e28e39177a81cc	pubmed	Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)	Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG) Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. # Abstract Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk. ## Objective To provide a clear strategy for the management of people at hereditary risk of colorectal cancer (CRC), which includes diagnosis, endoscopic management, prevention and surgical care. # Aims and methods An estimated 35% of CRC is due to heritable factors, [bib_ref] Environmental and heritable factors in the causation of cancer -analyses of cohorts..., Lichtenstein [/bib_ref] with approximately 29% of the UK population having a family history of a first-degree relative (FDR) or second degree relative (SDR) with CRC. [bib_ref] Prevalence of family history of colorectal cancer in the general population, Mitchell [/bib_ref] While highly penetrant syndromes such as Lynch syndrome (LS), familial adenomatous polyposis (FAP) and other polyposis syndromes account for account for only 5-10% of all CRC diagnoses, advances in genetic diagnosis, improvements in endoscopic surgical control, and medical and lifestyle interventions provide opportunities for CRC prevention and effective treatment in susceptible individuals. The purpose of this guideline is to provide an evidence-based framework for the optimal management of hereditary CRC for clinicians involved in their management, including gastroenterologists, nurse practitioners, physicians, colorectal surgeons, clinical geneticists, genetic counsellors and pathologists. This guideline was commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG), via the colorectal section, and a guideline chair selected. It is an update of the previous iteration of the BSG/Association of Coloproctology of Great Britain and Ireland (ACPGBI) guideline published in 2010 and developed in accordance with the BSG National Institute for Health and Care Excellence (NICE)-compliant guideline process. The Guideline Development Group (GDG), which included gastroenterologists from the BSG, clinical geneticists from United Kingdom Cancer Genetics Group (UKCGG), colorectal surgeons from the ACPGBI, a pathologist, a genetic counsellor and a patient representative, was selected to ensure wide-ranging expertise across all relevant disciplines. Members of the GDG, and participants in the eDelphi process, completed a Declaration of Conflict of Interests (COI) form which was reviewed and vetted by the BSG. A scoping meeting was held on 13 October 2017, and in advance of this meeting the GDG was asked to develop key priorities and questions. The GDG determined that the primary measure of effectiveness of any intervention was a reduction of the lifetime risk of CRC, and the following secondary outcome measures: Guidelines i. Reduction in the incidence of advanced adenomas at colonoscopy ii. Prevention of CRC iii. Reduced morbidity related to CRC, or morbidity secondary to complications of surveillance and treatment iv. Improved identification of hereditary CRC syndromes v. Improved pathways from diagnosis to treatment in susceptible populations. We sought a consistent approach in our assessment of the relative effectiveness of interventions. In principle we agreed that surveillance should only be offered to individuals who remain at higher risk of developing CRC than the general population. As CRC risk is not always clearly defined, as a surrogate we accepted that advanced adenoma yield on surveillance should be approximately double that in susceptible populations compared with the average risk population. A relative threshold for genetic testing was agreed for people with a 10% or greater probability of having a germline pathogenic variant in a cancer susceptibility gene in accordance with previous UK guidelines. However the GDG agreed that the arbitrary nature of this threshold meant that it could be modified in cases where objective risk assessment was difficult to attain, and clinicians had sufficient clinical suspicion of risk. Key questions we sought to cover included the following: 1. Which aspects of the previous guidelines require updating? 2. What is the lifetime CRC risk and optimal surveillance for those with a family history of CRC (where LS and polyposis syndromes have been excluded)? 3. What is the diagnostic yield of genetic testing and/or surveillance for high-risk populations? 4. What is the optimal gastrointestinal (GI) surveillance for patients at hereditary risk GI cancer? 5. What is the impact of high-quality endoscopy in patients with known or suspected hereditary cancer syndromes? 6. Should we develop gene-or gender-specific guidelines for surveillance? 7. What is the optimal diagnostic assessment and surveillance interval for 'Lynch-like' syndrome patients? 8. How can we improve recognition, diagnosis and treatment of patients at hereditary risk of CRC? 9. Which diagnostic genetic tests should we offer serrated polyposis syndrome (SPS), multiple colorectal adenoma (MCRA) and early onset CRC (EOCRC) patients (if any)? 10. When should colonoscopic surveillance for familial risk patients stop, because it is no longer necessary, or because the patient should be referred for surgery? 11. Which are the optimal surgical approaches in patients with hereditary CRC syndromes? 12. What is the evidence for chemoprophylaxis in patients who are at hereditary risk of CRC? 13. What is the evidence for the effect of lifestyle modification on hereditary risk of CRC? 14. What information do we need to share with our patients at inherited risk of GI cancer? Twenty-three PICOs (Patients, Interventions, Controls and Outcomes) were developed which considered these questions. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework.A literature search was commissioned externally, with search strategies agreed, and was performed by the Yorkshire Healthcare Consortium, which returned publications. Returned abstracts were reviewed for relevance. Additional references were obtained by cross-referencing and by recommendation from the GDG. Relevant published national and international guidelines were also scrutinised. After each round of Delphi, and before the guideline was finalised, the search was repeated and any important studies published since the initial evidence search were incorporated. A modified electronic Delphi process 6 was used to develop and refine statements. Initial draft statements formulated by the writing committee were reviewed by the GDG to allow for modification and to identify additional references. After a preliminary discussion, formal anonymous voting rounds were undertaken using SurveyMonkey. Each statement was scored by each member of the GDG using a five-point scale. We also invited key national and international opinion leaders from the UKCGG steering group, ACPGBI, BSG, the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE) to participate in the modified Delphi process. We included additional patient and public involvement in the Delphi process by inviting participants through the national charities Bowel Cancer UK and Lynch Syndrome UK. Consensus required at least 80% agreement, and consensus of over 70% was accepted if the GDG felt a statement was required for clinical practice. Where consensus was not reached, feedback from the GDG members was disseminated after each round to allow members to reconsider their original position. [bib_ref] Use of grade grid to reach decisions on clinical practice guidelines when..., Jaeschke [/bib_ref] Where appropriate, revisions to statements were made and a further voting round was undertaken in second and third rounds. A final (fourth) round of voting for statements where consensus had not been reached for 11 statements was performed within the GDG only. Surveillance and molecular testing recommendations are summarised in [fig_ref] Table 1: Summary of surveillance recommendations Amsterdam criteria families where MMR testing is not... [/fig_ref] respectively. The GDG also developed 10 research recommendations (online supplementary file 1) which were prioritised by electronic voting. The GRADE (Grading of Recommendations, Assessment, Development and Evaluations) tool 8 was used to evaluate the strength of evidence and the strength of recommendations made (see executive summary). The GRADE system specifically separates the strength of evidence from the strength of a recommendation. While the strength of a recommendation may often reflect the evidence base, the GRADE system allows for occasions where this is not the case-for example, where it seems good sense to make a recommendation despite the absence of high-quality scientific evidence such as a large randomised controlled trial (RCT). We recommend that the moderate risk category of family history of CRC (FHCC) is the minimum threshold for referral from primary care (GRADE of evidence: very low; Strength of recommendation: strong) ► We recommend that individuals with a FHCC, which meets this referral criteria, be referred to a specialist familial CRC clinic in secondary or tertiary care (GRADE of evidence: low; Strength of recommendation: weak) ► We recommend that patients should be referred to a specialist service which includes access to constitutional genetic testing in the presence of either deficient mismatch repair (MMR) (with no evidence of MLH1 promoter methylation or BRAF V600E), or polyposis. (GRADE of evidence: low; Strength of recommendation: strong) ► There are insufficient clinical data to develop specific guidance for patients with very rare conditions such as polymerase proofreading associated polyposis (PPAP), or NTHL1-associated polyposis (NAP); therefore, we suggest patients with these syndromes should be referred to Consensus reached: 95% agreement People at hereditary CRC risk require coordinated, timely and high-quality care to reduce their cancer risk and should have access to a full range of management options that minimise the risk of morbidity and mortality. [bib_ref] Urgent improvements needed to diagnose and manage Lynch syndrome, Monahan [/bib_ref] A structured referral pathway may ensure better inter-specialty communication and timely, efficient management of hereditary risk from primary through to tertiary care provision. It also facilitates an audit trail and subsequent monitoring of performance. Patients should have access to a full range of management options that minimise the risk of morbidity and mortality. [bib_ref] Urgent improvements needed to diagnose and manage Lynch syndrome, Monahan [/bib_ref] Moreover, studies consistently report that high quality screening and surveillance services result in a reduction of CRC incidence and mortality in individuals with FAP and LS. [bib_ref] Systematic review of the impact of registration and screening on colorectal cancer..., Barrow [/bib_ref] Registries of high-risk patients should be linked to robust quality assurance mechanisms for interventions, such as colonoscopy, with effective recall mechanisms in place to ensure high-risk individuals receive surveillance procedures on schedule. ## Executive summary of key recommendations service provision, communication and management principles ## Guidelines Awareness of hereditary conditions may be inadequate, resulting in an inconsistent approach to the management of these individuals. Many patients do not have personalised management strategies and there is a failure to provide adequate follow-up. Patient advocacy organisations recommend improvements in the detection of pre-cancerous polyps, early diagnosis of CRC, and personalised treatment options for LS individuals, who should be seen by a team of specialists. 14 The relevance of genomics is growing in clinical practice, and is increasingly relevant across the cancer multidisciplinary teams, with improving access to constitutional genetic testing.Genetic testing and/or counselling may resolve uncertainty about personal and familial cancer risk and provide information to guide and personalise decisions about future health care in anyone with an FHCC. It has been recommended that a dedicated clinical champion for hereditary CRC should be established in each colorectal multidisciplinary team (MDT) to oversee service coordination and to ensure patient pathways. The establishment of these champions will be another critical component in establishing equity of care. We recommend the establishment of family cancer specialist services by CRC teams in secondary care to ensure local pathways for patients at hereditary risk of CRC, and which can arrange testing of relatives for MMR status. This service should be supported by commissioners and incorporate a multidisciplinary approach involving geneticists, gastroenterologists and colorectal surgeons with links between secondary and tertiary care. Adherence to surveillance recommendations should be monitored at least annually. We suggest a minimum standard of ≥90% compliance. Non-compliant cases should be reviewed to determine whether reason for deviation from surveillance recommendations was clearly documented and clinically appropriate. Thus patients with a family history of CRC may be managed by their local hospital, and patients who require constitutional gene testing be managed by a tertiary care clinic, for example, in clinical genetics, either locally or regionally. ## Family history of crc (fhcc) definitions and terminology A substantial proportion of the UK population have an FHCC without evidence of an inherited CRC syndrome. These individuals have a moderately increased relative risk (RR) of CRC (2-6 fold) compared with the general population. [bib_ref] A systematic review and meta-analysis of familial colorectal cancer risk, Johns [/bib_ref] Lifetime CRC risk may be inferred from the age of onset of CRC in affected relatives, and familial aggregation, that is, the number of family members affected with CRC. This section refers to asymptomatic patients referred for optimal management of a family history of either CRC or multiple polyps. The GDG agreed three categories of familial risk (in the absence of known hereditary CRC syndromes) which were determined according to lifetime CRC risk and the diagnostic yield of colorectal surveillance (box 1). Familial clusters (or aggregations) are of affected family members with CRC who are FDRs of each other. The individual referred for assessment should be an FDR of at least one affected member of such families. Patients with average risk include those without an FHCC, or with an FHCC which does not significantly increase their lifetime CRC risk, that is, below the level of the moderate risk population. For the average risk populations surveillance may be effectively managed via national bowel cancer screening programmes. Those people in moderate-or high-risk categories require additional surveillance above and beyond national screening however (figure 1). ## Assessment of tumours in the affected relatives of those with an fhcc ## We recommend that for all patients referred from primary care for assessment for an fhcc, mmr status should be assessed in tumour tissue from a close affected family member. (GRADE of evidence: Moderate; Strength of recommendation: strong) Consensus reached: 82% agreement. ## We recommend that a reported family history of polyposis should be verified by review of histopathology and/or endoscopy reports which confirm the presence of a minimum of 10 adenomas or serrated lesions in an fdr. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 90% agreement. Histopathological confirmation of CRC alters management of familial CRC surveillance in 20% of UK patients through verification of a diagnosis of CRC, multiple adenomas or other relevant features. [bib_ref] The impact of cancer pathology confirmation on clinical management of a family..., Edwards [/bib_ref] Similarly review of endoscopy reports may assist in identification of patients with suspected familial risk such as those with polyposis syndromes. When LS and Lynch-like tumours are excluded in families, their lifetime risk of CRC decreases. To quantify familial CRC risks associated with MMR deficient (dMMR) or MMR proficient (pMMR) tumours, a UK group analysed 2941 populationbased cases of CRC. [bib_ref] Implications of familial colorectal cancer risk profiles and microsatellite instability status, Lubbe [/bib_ref] CRC risks in FDRs were strongly associated with dMMR tumours, early-onset disease and more than one affected FDR. In a study by Bapat et al of 3143 CRC patients, dMMR tumours were associated with increasing numbers of FDRs with CRC (p=0.002); this association disappeared, however, when dMMR cases meeting Amsterdam criteria were removed from the analysis. [bib_ref] The association of tumor microsatellite instability phenotype with family history of colorectal..., Bapat [/bib_ref] A multicentre international registry based study [bib_ref] Role of tumour molecular and pathology features to estimate colorectal cancer risk..., Win [/bib_ref] An important question is whether the adenoma detection rate in those with an FHCC is higher than the detection rate in the general population. Most CRCs develop from adenomas and "advanced" adenomas (AAs, defined as either an adenoma size of at least 10 mm, villous architecture of at least 25%, or high grade dysplasia [bib_ref] Surveillance of colonic polyps: are we getting it right?, Bonnington [/bib_ref] are considered to be the precursors of CRC. The term "advanced neoplasia" (AN) refers to the identification of either AAs or CRC. The effectiveness and requirement for familial risk surveillance may be best determined by comparing the long-term CRC risk of a defined cohort of at-risk patients not undergoing surveillance with that of the general population. Theoretical relative risks of CRC <2 may be dominated by other genetic or environmental effects (and may require complex and validated risk modelling tools to determine suitability for surveillance). [bib_ref] Familial risk and heritability of colorectal cancer in the Nordic twin study..., Graff [/bib_ref] Where long-term CRC data are not available, the findings at surveillance may be used as a surrogate means to determine the need for post-polypectomy surveillance, although this method is inferior. In this context, that surveillance procedure may not have been warranted where the AA yield on that surveillance was less than doubled compared with a comparable yield in a control population. There is a low prevalence of CRC in studies of surveillance in familial risk populations. There are limited data suggesting that metachronous CRC risk may be higher in patients at moderate familial risk versus population risk. [bib_ref] Metachronous colorectal cancer risk in patients with a moderate family history, Newton [/bib_ref] As AAs are strongly associated with CRC development, AAs may be considered a proxy for CRC risk. In studies of patients with a moderate familial risk there is considerable heterogeneity in the prevalence of AA with a typical prevalence of between 8% and 10%; approximately double that of those without a family history (online supplementary tables 1-GRADE table 1). There is evidence from observational studies that the diagnostic yield of colonoscopy has increased in familial CRC risk cohorts over the past two decades, consistent with improvements in endoscopic technique, equipment and quality assurance. [bib_ref] Prevalence of adenomas and advanced adenomas in patients in the 40-to 49-year..., Gupta [/bib_ref] In the German bowel cancer screening population (an average risk population) the prevalence of AAs measured between 2003 and 2012 increased from 7.4% to 9.0% among men, and from 4.4% to 5.2% among women. In meta-analysis, [bib_ref] Increased risk of adenomas in individuals with a family history of colorectal..., Wilschut [/bib_ref] the prevalence of adenomas is significantly higher in individuals with an FHCC than in controls (OR 1.7, 95% CI 1.4 to 3.5). Many observational control studies of surveillance colonoscopy for familial risk report a lower prevalence of AAs in the average risk population compared with the data from this German screening cohort. This may be related to lower ages of familial risk populations studied, and that many of the studies pre-date improvements in colonoscopic quality standards. There is some observational evidence that colonoscopic surveillance mitigates this increased risk. In a German casecontrol study of CRC patients with an FHCC, those who had had a prior colonoscopy had a lower CRC risk that individuals without a family history who had not undergone colonoscopy. In the E3N French prospective study of 92 078 women, 692 CRCs were diagnosed after a median follow-up of 15.4 years 31 ; women with FHCC who had not had a previous colonoscopy had a 80% higher CRC risk than those without FHCC. In women who had had a previous colonoscopy, CRC risk was similar in women with and without FHCC. ## Age and risk of aas in those with an fhcc Projected annual transition rates from advanced adenomas to CRC strongly increase with age, with annual transition rates increasing from 2.6% in patients in their 50 s to >5% in their 80s. [bib_ref] Risk of progression of advanced adenomas to colorectal cancer by age and..., Brenner [/bib_ref] In an influential prospective study from 1994 32 FDRs of CRC patients had a risk of CRC at the age of 40 years equivalent to that of the average risk population aged 50 years. Notably, this historical study did not exclude patients with LS, and the increased risk conferred was predominantly in individuals with an affected FDR diagnosed under of 45 years. Age is a strong predictor for adenomas and AAs in both familial risk individuals and controls in a series of observational studies. The incidence of AAs in patients aged 40-49 years in a surveillance cohort is equivalent to the general population, although the age of diagnosis of CRC in the affected FDR is not a predictor of risk of AAs. While adenomas but not AAs are more common in these studies, this may reflect the natural history of the adenoma to carcinoma sequence, whereby patients derive more benefit from surveillance colonoscopy from the age of 50 onwards, due to resection of AAs. The subdivision of FHCC risk into those with 2× FDRs who were affected over or under 60 years of age is not associated with any difference in the diagnostic yield on colonoscopic surveillance. [bib_ref] High detection rate of adenomas in familial colorectal cancer, Van Der Meulen-De Jong [/bib_ref] Although this age criterion was used in previous iterations of this guideline 35 to subdivide into "low-moderate" and "high-moderate"risk, no evidence was identified to support this differentiation. Several studies of cohorts of patients with moderate FHCC have demonstrated a negligible incidence in AAs in colonoscopic surveillance before the age of 50 years, but an increased risk after this age. [bib_ref] Family history of colorectal cancer: a determinant of advanced adenoma stage or..., Wark [/bib_ref] [bib_ref] A pooled analysis of the outcome of prospective colonoscopic surveillance for familial..., Mesher [/bib_ref] [bib_ref] Yield from colonoscopic screening in people with a strong family history of..., Dowling [/bib_ref] [bib_ref] Prevalence of colonic neoplasia and advanced lesions in the normal population: a..., Forsberg [/bib_ref] [bib_ref] Colonoscopy surveillance of individuals at risk of familial colorectal cancer, Bradshaw [/bib_ref] [bib_ref] Impact of a family history of colorectal cancer on the prevalence of..., Tsai [/bib_ref] There is little evidence in case-control series of significant differences in AA incidence between patients with one FDR diagnosed under the age of 50 years, and those families with a cluster of two FDRs diagnosed at any age. The prevalence of AAs under the age of 50 years is not significantly increased in patients under surveillance for FHCC compared with the average risk population. This supports commencing colonoscopic surveillance at the age of 50-55 years for those at moderate familial risk. As the incidence of CRC is increasing in younger patients, this age recommendation may need to be reviewed in future guideline iterations-pending further relevant data specifically in those with a FHCC. ## Surveillance in patients with a moderate familial risk of crc To exclude LS in those with an FHCC, a close affected relative's tumour should undergo MMR tumour testing. A pathology review of the relative's tumour should also be undertaken to ensure that there is no evidence of multiple polyps. After this risk Guidelines assessment a decision about colonoscopic intervention should be considered. The risk of AAs in surveillance colonoscopy (ie, after index/ screening procedure) is largely determined by the presence of advanced neoplasia at the index procedure. In a surveillance programme from St Mark's Hospital, London, with well-organised recall of high and moderate risk families, AAs and cancer were more common in families who fulfilled Amsterdam criteria compared with those at moderate risk (on initial colonoscopy 5.7% and 0.9%, respectively). [bib_ref] Prevention of colorectal cancer by colonoscopic surveillance in individuals with a family..., Dove-Edwin [/bib_ref] In families with moderate risk, advanced pathology was particularly uncommon under the age of 45 (1.1% and 0%) and on follow-up colonoscopy if AAs were absent initially (1.7% and 0.1%). With colonoscopic surveillance the incidence of CRC was substantially lower (80% in families with moderate risk (p=0.00004) and 43% in families with LS (p=0.06)) than the expected incidence in the absence of surveillance. Registry data from other populations also suggest a benefit in selected moderate familial risk populations undergoing surveillance colonoscopy. These studies also confirm an association of AAs at the index procedure with advanced neoplasia in subsequent surveillance procedures (GRADE online supplementary tables 1-GRADE table 1). In a Swedish moderate familial risk cohort 43 the risk of future AAs was associated with the prevalence of advanced lesions at the screening colonoscopy (multivariate analysis OR 5.22, 9% CI 2.3 to 9.94). It is of interest that adenomas and advanced lesions were not associated with the same risk factors: family history was predictive of advanced adenomas but not adenomas at the index screening colonoscopy. The FACTS (Familial CRC Surveillance) randomised controlled trial compared intervals of surveillance in familial CRC. [bib_ref] Randomized comparison of surveillance intervals in familial colorectal cancer, Hennink [/bib_ref] Individuals aged between 45 and 65 years with moderate familial CRC risk, where LS had been largely excluded, were randomly assigned to either a colonoscopy at 6 years or a colonoscopy at 3 and 6 years. Intention-to-treat analysis showed no significant difference in the proportion of patients with AAs (the primary outcome measure) at the first follow-up examination at 6 years (6.9%) versus 3 years (3.5%). The presence of AAs at the index colonoscopy was the only significant predictor for the presence of AAs at first follow-up (OR 5.2, 95% CI 1.6 to 16.87). Thus a 6 yearly interval was non-inferior to a 3 yearly surveillance interval, with the exception being that an AA at index colonoscopy predicts further advanced neoplasia at 3 years. ## Surveillance for colorectal neoplasia in those with a high familial risk of crc ## We suggest that in high-risk families (a cluster of 3× fdrs with crc across >1 generation) a 5 yearly colonoscopy should be performed from the age of 40 years until the age of 75. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 86% agreement. Families who fulfil Amsterdam criteria but who do not have evidence of dMMR do not share the same cancer incidence as families with LS (ie, hereditary MMR deficiency). Relatives in such families were found to have a lower incidence of CRC than those in families with LS, and incidence was not increased for other cancers. These families should not be described or counselled as having LS. To facilitate distinguishing these entities, the designation of "familial CRC type X" was suggested by Lindor et al to describe this type of familial aggregation of CRC. [bib_ref] Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial..., Lindor [/bib_ref] In a prospective surveillance study of a high familial risk population [bib_ref] A prospective study of family history and the risk of colorectal cancer, Fuchs [/bib_ref] there was no significant difference in the prevalence of AAs in LS individuals versus FCC-X individuals. However on follow-up there were no incident cancers in the FCC-X group versus 4.4% CRC in Lynch patients, indicating lower risk of interval CRC in FCC-X despite equivalent AA risk. In a prospective pooled cohort study of 1585 patients from eight international centres 37 families were classified as FCC type X if they fulfilled the original Amsterdam criteria and late onset (LOFCC) if they fulfilled the Amsterdam criteria apart from not having a cancer diagnosed aged under 50. The results for FCC type X and LOFCC were very similar. At baseline, 22 prevalent asymptomatic CRCs were diagnosed, 120 (7.6%) individuals had high-risk adenomas and 225 (14.2%) simple adenomas. On follow-up high-risk adenomas were detected in 92 (8.7%) and multiple adenomas were detected in 20 (1.9%) individuals, from approximately 35 years of age onwards. Again the presence of AA at index colonoscopy was predictive of advanced neoplasia at subsequent procedures-33% of patients with an AA at index colonoscopy had an AA or cancer on follow-up. This study by Mesher et al 37 indicated patients at high familial CRC risk should be managed similarly with 5 yearly colonoscopies undertaken from between 30 and 40 years of age with more intensive surveillance in individuals developing multiple or high-risk adenomas. Amsterdam criteria families, where MMR testing of a CRC from an affected individual is not possible, may be offered surveillance as per LS. However such patients should be reviewed by a specialist service who may consider alternative testing strategies such as panel testing of affected individuals, or unaffected testing. ## Prevention and lifestyle modification in familial crc ## We recommend that individuals with ls should be advised that regular use of daily aspirin reduces crc risk. (GRADE of evidence: moderate; Strength of recommendation: strong) Consensus reached: 90% agreement. Long-term data from the CAPP2 RCT suggests that aspirin reduces this risk by approximately half as compared with placebo. [bib_ref] Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal..., Burn [/bib_ref] The benefits of regular aspirin intake take at least 3 to 5 years to become evident. Taking aspirin for less than 2 years' duration does not seem to confer any benefit in reducing the incidence of cancer, or increasing survival in patients with LS. We ## Recommend that people with ls should be offered research opportunities to take aspirin daily at different dosages. if they decline research participation they may be advised on their choices regarding dose of aspirin, risks and benefits of long-term aspirin use and ensure their medical practitioner is aware of their intake. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 90% agreement. There is uncertainty about the optimum dosage of aspirin to recommended to individuals with LS. There is some evidence that long-term intake of daily 600 mg aspirin can reduce the risk of all cancers including CRC in LS from the CAPP2 randomised control trial. [bib_ref] Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal..., Burn [/bib_ref] There is no other high quality evidence for any other dose of aspirin/ length of treatment but there are studies ongoing (CAPP3 trialwhich aim to identify optimum dosage. Evidence for the optimum dose will inform awareness and education among health professionals to mitigate the reluctance to prescribe higher doses of aspirin within primary care. [bib_ref] General practitioner attitudes towards prescribing aspirin to carriers of Lynch syndrome: findings..., Smith [/bib_ref] In the interim clinicians may consider 150 mg aspirin in the context of LS outside of a clinical trial, with 300 mg doses in those with a BMI above 25 kg/m 2 . ## There is insufficient evidence of the benefit of chemoprophylaxis in polyposis syndromes. (GRADE of evidence: moderate; Strength of recommendation: strong) Consensus reached: 100% agreement. Non-steroidal anti-inflammatory drugs (NSAIDs) have been the most commonly studied chemoprophylaxis agents in patients with FAP, predominantly for lower GI tract disease, with some RCTs. Aspirin and tiracoxib have been found to be ineffective, 51-53 although sulindac, celecoxib and rofecoxib have been demonstrated to reduce adenoma burden in the short term. [bib_ref] Sulindac causes regression of rectal polyps in familial adenomatous polyposis, Labayle [/bib_ref] [bib_ref] The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis, Steinbach [/bib_ref] [bib_ref] Randomized controlled trial of the effect of sulindac on duodenal and rectal..., Nugent [/bib_ref] [bib_ref] A randomized, double-blind, placebocontrolled trial of the effects of rofecoxib, a selective..., Higuchi [/bib_ref] A number of small series provide further support for these drugs and have also shown benefit from topical indomethacin. [bib_ref] Effect of indomethacin suppositories on rectal polyposis in patients with familial adenomatous..., Hirota [/bib_ref] However long-term cancer prevention as an end point has not been adequately addressed. In the largest cohort of 54 patients, published in abstract form, 10% developed cancer while on chemoprophylaxis.Other classes of agents have also been assessed, such as omega 3 fish oils, but again the results are only short term with reduction in polyp size and number as the main endpoint. [bib_ref] Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis, West [/bib_ref] Celecoxib and the combination of sulindac and erlotinib have been reported as being beneficial for those with FAP and advanced duodenal disease; this was a short-term study using polyp number and size as the primary endpoint. A cohort study reported outcomes of the use of Eviendep, which was observed to reduce polyp number and size. [bib_ref] Eviendep ® reduces number and size of duodenal polyps in familial adenomatous..., Calabrese [/bib_ref] However, no studies have demonstrated an effect on duodenal cancer prevention in FAP. Cyclooxygenase-2 (COX-2) expression may be increased in JPS. There exists a theoretical potential benefit in the use of selective COX-2 inhibitors in JPS or PJS, [bib_ref] Increased cyclooxygenase-2 expression in juvenile polyposis syndrome, Van Hattem [/bib_ref] [bib_ref] Cyclooxygenase-2 expression in polyps from a patient with juvenile polyposis syndrome with..., Kurland [/bib_ref] [bib_ref] Overexpression of cyclooxygenase 2 in hamartomatous polyps of Peutz-Jeghers syndrome, Mcgarrity [/bib_ref] but to date there are no trials demonstrating efficacy. ## We recommend that individuals at increased familial risk of crc should be strongly encouraged not to smoke, to maintain a normal bmi, to moderate their consumption of red and processed meat, and to exercise regularly. (GRADE of evidence: low; Strength of recommendation: moderate) Consensus reached: 81% agreement. Diet and lifestyle factors are well established as significant contributors to up to half of all CRCs. A systematic review of epidemiological studies investigating the associations between nutritional factors, FHCC and CRC risk [bib_ref] Do alcoholic beverages, obesity and other nutritional factors modify the risk of..., Fardet [/bib_ref] suggests that combinations of FHCC and higher consumption of alcoholic beverages, red or processed meat, or overweight/obesity increases the risk of CRC. There is evidence that LS individuals who smoke (particularly males with MLH1 mutations) have an increased risk of CRC. Data suggest current smokers are at significant increased risk of CRC irrespective of the age of initiation of smoking. Risk in former smokers decreased with each non-smoking year. [bib_ref] Tobacco use and increased colorectal cancer risk in patients with hereditary nonpolyposis..., Watson [/bib_ref] [bib_ref] Smoking and colorectal cancer in Lynch syndrome: results from the colon cancer..., Pande [/bib_ref] [bib_ref] Environmental factors and colorectal tumor risk in individuals with hereditary nonpolyposis colorectal..., Diergaarde [/bib_ref] [bib_ref] Smoking increases the risk for colorectal adenomas in patients with Lynch syndrome, Winkels [/bib_ref] CAPP2 study data from 29 month follow-up also indicate that overweight individuals with LS were more likely to develop CRC than those normal/underweight. [bib_ref] Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch..., Burn [/bib_ref] [bib_ref] Body mass index increases risk of colorectal adenomas in men with Lynch..., Botma [/bib_ref] [bib_ref] Body mass index in early adulthood and colorectal cancer risk for carriers..., Win [/bib_ref] [bib_ref] Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal..., Movahedi [/bib_ref] Though modifiable environmental risk factors such as weight and exercise 80 are common to both sporadic and familial CRC, individuals with familial risk may benefit from discussion about modifiable factors in order to potentially reduce their level of risk. There is emerging evidence of the benefit of targeted lifestyle modification in those with an FHCC. 83 ## Quality and advanced endoscopic imaging in colonoscopic surveillance ## We recommend that colonoscopy is the gold standard diagnostic and preventative method of surveillance for people with a hereditary risk of crc. ( ## We suggest that if the bowel preparation for colonoscopy is inadequate or if the examination is incomplete then a repeat colorectal surveillance procedure should be arranged within 3 months. (GRADE of evidence: moderate; Strength of recommendation: weak) Consensus reached: 95% agreement. ## We suggest high-quality, high-definition white light endoscopy as the preferred modality for colonoscopy surveillance. chromoendoscopy (virtual or dye-based) does not offer a clear advantage over high definition white light examination for colonoscopic surveillance, apart from in the context of determining the multiple polyp phenotype. (GRADE of evidence: moderate; Strength of recommendation: weak) Consensus reached: 89% agreement. High quality colonoscopy has been recognised as a core element of successful cancer prevention in sporadic patients. [bib_ref] UK key performance indicators and quality assurance standards for colonoscopy, Rees [/bib_ref] There are limited data that this may also be relevant to cancer prevention in LS. [bib_ref] Quality colonoscopy and risk of interval cancer in Lynch syndrome, Haanstra [/bib_ref] Therefore colonoscopic quality indicators in endoscopists performing surveillance in LS patients should at least reach if not exceed the KPIs required for sporadic colonoscopy, using validated measures, in particular caecal intubation rate, adenoma/polyp detection rate and, given that patients may require serial colonoscopic procedures, comfort score. Colonoscopy is less effective for cancer prevention if the procedure is not complete to the caecum or the bowel preparation is inadequate. Where caecal intubation is not achieved, a repeat examination with an expert colonoscopist is appropriate. Inadequate bowel preparation reduces adenoma and advanced adenoma detection rates. Inadequate preparation at initial colonoscopy led to a threefold increase in miss rate in adenomas 5 mm or smaller. [bib_ref] Surveillance of colonic polyps: are we getting it right?, Forsberg [/bib_ref] Therefore, repeat colonoscopy within 3 months seems appropriate for individuals at high familial risk. Advanced imaging techniques have been proposed to help reduce missed lesions, especially small and flat lesions. More non-polypoid lesions are found in LS compared with sporadic patients. [bib_ref] Nonpolypoid colorectal neoplasms: a challenge in endoscopic surveillance of patients with Lynch..., Rondagh [/bib_ref] Chromoendoscopy, both dye-based and virtual, was recommended in recent ESGE guidelines on colonoscopic surveillance in LS. 92 ## Guidelines Tandem studies with chromoendoscopy show a consistent benefit (online supplementary 1 GRADE table 2) 93-98 ; however, a study comparing a second pass with chromoendoscopy to a second white light pass did not show improved adenoma detection. [bib_ref] Missed adenomas during colonoscopic surveillance in individuals with Lynch syndrome (hereditary nonpolyposis..., Stoffel [/bib_ref] Meta-analysis of data in sporadic patients shows an OR for at least one neoplastic lesion of 1.53 (95% CI 1.31 to 1.79). [bib_ref] Chromoscopy versus conventional endoscopy for the detection of polyps in the colon..., Brown [/bib_ref] Real world cohort data comparing white light to chromoendoscopy provides some support for improved detection in high familial risk patients (39% LS) (15/24 (63%) adenomas with chromoendoscopy versus 15/77 (19%) white light endoscopy). [bib_ref] PWE-362 detection of neoplasia using dye spray chromoendoscopy in patients with a..., Mcgowan [/bib_ref] A recent large, multicentre, Spanish randomised parallel group study, using high definition endoscopes and with high adenoma-detecting endoscopists, did not demonstrate a significant increase in adenoma detection with chromoendoscopy in 256 Lynch patients (OR 1.34, 95% CI 0.79 to 2.28). [bib_ref] High definition white-light colonoscopy versus chromoendoscopy for surveillance of Lynch syndrome. A..., Sánchez [/bib_ref] A similar sized multi-centre parallel group RCT study in the Netherlands had similar results using chromoendoscopy in the proximal colon (overall adenoma detection rate (ADR) 33% vs 27% with white light endoscopy). [bib_ref] Effect of chromoendoscopy in the proximal colon on colorectal neoplasia detection in..., Haanstra [/bib_ref] At 2 year follow-up there was no difference in ADR between the two groups, but there were four cancers in the chromoendoscopy group versus one in the white light endoscopy group. Simply combining the results for ADR of these two studies gives a risk ratio of 1.23 (95% CI 0.94 to 1.60, p=0.14; Fisher exact, n=497; our calculation) suggesting a limited clinical benefit in terms of ADR for considerable extra effort, which may not translate into improved cancer prevention. Virtual chromoendoscopy, narrow band imaging (NBI, second generation, Olympus) and I-SCAN (Pentax) have shown some benefit in tandem studies [fig_ref] Table 1: Summary of surveillance recommendations Amsterdam criteria families where MMR testing is not... [/fig_ref] ; however, this improved detection is not consistent with meta-analysis data from sporadic patients, [bib_ref] Electronic imaging to enhance lesion detection at colonoscopy, Ket [/bib_ref] and NBI performed less well than chromoendoscopy in a cohort, tandem study. [bib_ref] Chromocolonoscopy detects more adenomas than white light colonoscopy or narrow band imaging..., Hüneburg [/bib_ref] In a study comparing different forms of colonoscopic imaging, chromoendoscopy was superior to white light colonoscopy, autofluorescence imaging, and narrow-band imaging for detection of diminutive colorectal lesions in adenomatous polyposis. [bib_ref] narrow-band imaging colonoscopy, and autofluorescence colonoscopy for detection of diminutive colorectal neoplasia..., Matsumoto [/bib_ref] Advanced colonoscopic imaging can assist in making a diagnosis of polyposis by revealing additional lesions required to meet diagnostic criteria: diagnoses of adenomatous polyposis may be missed if dye spray is not used, [bib_ref] Attenuated adenomatous polyposis coli: the role of ascertainment bias through failure to..., Wallace [/bib_ref] and there is similar evidence from the CONSCOP study that the identification of serrated polyps is enhanced through the use of pancolonic dye spray. [bib_ref] Feasibility and economic assessment of chromocolonoscopy for detection of proximal serrated neoplasia..., Hurt [/bib_ref] In summary, a high quality, high definition white light colonoscopic examination, by an endoscopist who meets all colonoscopy KPIs, seems adequate for LS and high familial risk patients, with the exception of those with multiple polyps where chromoendoscopy may help define the phenotype. ## Non-invasive surveillance methods for people with fhcc ## There is insufficient evidence to recommend other methods of surveillance for those with familial crc risk such as fit, mr or ct colonography (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 95% agreement. In meta-analysis of 12 published studies of patients at increased risk of CRC (predominantly familial risk), the average sensitivity of FIT for advanced neoplasia was 48% (95% CI 39% to 57%) and the average specificity was 93%. [bib_ref] Diagnostic accuracy of fecal immunochemical test in patients at increased risk for..., Katsoula [/bib_ref] A subgroup analysis of patients with familial risk only was performed, and the sensitivity for CRC was 86% and for advanced neoplasia 46%. Thus, although FIT may be close to equivalence to colonoscopy for the detection of CRC, AAs would be missed by surveillance with FIT alone. Patients with an FHCC no longer on colonoscopic surveillance should participate in national bowel cancer screening programmes designed for the average risk population. Some indirect evidence suggests that FIT or other forms of stool testing methods alongside colonoscopy may potentially be a useful adjunct in surveillance in patients after discharge from colonoscopic surveillance. [bib_ref] The impact of stratifying by family history in colorectal cancer screening programs, Goede [/bib_ref] Other methods such as colon capsule 108 or MR colonography 109 lack efficacy in this population. Although there is some evidence of the efficacy of CT colonography, 110 it is not clear how effective CT may be in the identification of serrated or non-polypoid lesions. Repeated CT scanning in particular may be inappropriate due to the risk of radiation damage to patients with inherited DNA repair defects. However, if total colonoscopy is not possible despite expert referral, low radiation-dose CT colonography with quality assurance 111 is the preferred modality, as it has similar test performance to colonoscopy for CRC. 110 ## Lynch syndrome ## We recommend that for all people when first diagnosed with crc, testing using immunohistochemistry (ihc) for mmr proteins or microsatellite instability is used to identify tumours with deficient dna mmr, and to guide further sequential testing for ls. (GRADE of evidence: strong; Strength of recommendation: strong) Consensus reached: 100% agreement. LS is a condition defined by the presence of pathogenic variants in the coding sequence or regulatory domains of the four MMR genes: MLH1, MSH2, MSH6 and PMS2. Patients with EPCAM mutations which embrace the regulatory domain of MSH2 should be managed as those with MSH2 pathogenic variants. Selection methods based on family history of cancer, or other clinical parameters, such as the Amsterdam or Bethesda criteria, were used historically to identify high-risk patients who may benefit from interventions and/or genetic testing; however, advances in constitutional testing in the past two decades have facilitated the accurate genetic diagnosis of LS. A comprehensive review performed by NICE of the clinical-and cost-effectiveness of universal diagnostic testing for LS was published in 2017.We recommend the use of colonoscopic biopsies as the preferred source material for tumour MMR testing. 114 ## Colonoscopic surveillance and ls ## We recommend that colonoscopic surveillance should be performed at a 2 yearly interval for all ls patients. (GRADE of evidence: moderate; Strength of recommendation: strong) Consensus reached: 85% agreement. Surveillance colonoscopy in LS does not completely eradicate the risk of CRC, with the well-recognised phenomenon of interval cancers related to multiple factors including adherence and timeliness of colonoscopy. However, the optimal interval for surveillance colonoscopy is yet to be established. The literature around colonoscopic surveillance is mixed with few studies reporting on recognised key performance indicators including adenoma detection rate, or caecal intubation rate or compliance with the screening interval. A study in the UK identified that hospital recall systems, clinician or patient related issues affect compliance with LS surveillance intervals. [bib_ref] Colonoscopy screening compliance and outcomes in patients with Lynch syndrome, Newton [/bib_ref] In this study variable colonoscopy quality indicators were highlighted with a caecal intubation rate was 92%, and approximately 10% had inadequate bowel preparation. In a retrospective, two centre Dutch study 31 interval CRCs were diagnosed in 29 patients with LS, within 2 years of previous colonoscopy, all of whom were MLH1 and MSH2 pathogenic variant carriers, and 84% were located in the proximal colon. [bib_ref] Quality colonoscopy and risk of interval cancer in Lynch syndrome, Haanstra [/bib_ref] In three of a total of five patients where colon examination was not achieved during the previous colonoscopy, the interval CRC was found in the unexamined proximal segment. In six of nine patients with a previous adenoma, the interval CRC was detected in the same colon segment, raising the possibility of incomplete endoscopic resection. There is some evidence that earlier tumour stage may be observed in those with more frequent colonoscopy. More recent prospective data have described cancer incidence and survival in LS in patients undergoing surveillance. [bib_ref] Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a..., Seppälä [/bib_ref] [bib_ref] Incidence of and survival after subsequent cancers in carriers of pathogenic MMR..., Møller [/bib_ref] [bib_ref] Cancer risk and survival in path_MMR carriers by gene and gender up..., Møller [/bib_ref] [bib_ref] Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological..., Møller [/bib_ref] The incidence of CRC was influenced by the LS-associated gene; cumulative CRC incidence at 70 years by gene was greater in those with MLH1 (46%) or MSH2 (35%) constitutional pathogenic variants compared with those with MSH6 (20%) or PMS2 (0%) pathogenic variants (although with wide confidence intervals). The prognosis from interval CRC was good, with a 5 year survival of 94% (90-98%), and a 10 year survival of 91% (84-95%). This concords with an earlier Dutch study which reported a non-significantly increased risk of interval CRC in those with MLH1 or MSH2 constitutional pathogenic variants. [bib_ref] One to 2-year surveillance intervals reduce risk of colorectal cancer in families..., Vasen [/bib_ref] In the prospective data published by Moller and colleagues, the interval between last surveillance colonoscopy and CRC was analysed; 100/145 (69%) CRCs were diagnosed >2 years after last colonoscopy (interval post colonoscopy range 0-125 months). [bib_ref] Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological..., Møller [/bib_ref] An observational study by Engel et al 123 compared prospective colonoscopic data from three countries with different LS surveillance policies (Germany: annual surveillance; Netherlands: 1-2 yearly surveillance; Finland: 2-3 yearly surveillance) and found no significant difference in cumulative CRC incidence or stage at detection among the countries. The study included data from 16 327 colonoscopic examinations of 2747 LS patients (MLH1, MSH2, MSH6 pathogenic variant carriers) over 23 309 personyears of cumulative observation time. The 10 year cumulative CRC incidence ranged from 4.1% to 18.4% for patients with low-and high-risk profiles, respectively, and was influenced by age, gender, LS gene, and prior detection of CRC or adenoma. The authors conclude that a 2 year surveillance interval might be appropriate, and short surveillance intervals may only be beneficial to LS patients with high-risk factors. The findings of this study should be interpreted with caution, however, as there are some limitations including unavailable data regarding key performance indicators and non-compliance with countryspecific surveillance protocols. The largest study to date has recently reported cancer risk estimates for PMS2 pathogenic variant carriers, 124 demonstrating a small increased risk of CRC (cumulative risk to age 80 years of 13% for males and 12% for females, compared with the general population risk of 6.6% and 4.7%, respectively). Based on this finding and data from the prospective LS database, the authors have suggested that extending the colonoscopic surveillance interval may be justified in PMS2 pathogenic variant carriers. However, most guidelines recommend surveillance colonoscopy between 1 and 2 yearly. [bib_ref] Guidelines for colorectal cancer screening and surveillance in moderate and high risk..., Cairns [/bib_ref] The data regarding differences between the LS-associated genes are not sufficiently robust such that the surveillance interval can be stratified by LS gene. A lower penetrance of CRC in those with an MSH6 pathogenic variant is likely to account for the lower risk of interval CRC on surveillance. The surveillance interval is determined by tumour biology and the accelerated pathway of carcinogenesis in LS. [bib_ref] Proximal adenomas in hereditary nonpolyposis colorectal cancer are prone to rapid malignant..., Rijcken [/bib_ref] There are no data to suggest that the speed of carcinogenesis in those with PMS2 or MSH6 constitutional pathogenic variants is different from those with MLH1 or MSH2 constitutional pathogenic variants; therefore until such data exist, the surveillance interval should be the same for all patients with LS, irrespective of the underlying LS-associated gene pathogenic variant. [bib_ref] What is the appropriate screening protocol in Lynch syndrome?, De Jong [/bib_ref] A number of other studies have confirmed that the risk of developing CRC before the age of 25 years is very low. [bib_ref] Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer), Hampel [/bib_ref] [bib_ref] Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact..., Hendriks [/bib_ref] [bib_ref] Cancer risks for mismatch repair gene mutation carriers: a population-based early onset..., Jenkins [/bib_ref] [bib_ref] Risk of colorectal and endometrial cancer for carriers of mutations of the..., Quehenberger [/bib_ref] It is largely based on these studies that most groups have recommended starting surveillance colonoscopy at the age of 20-25 years. [bib_ref] Guidelines for colorectal cancer screening and surveillance in moderate and high risk..., Cairns [/bib_ref] However, a meta-analysis of the data for MLH1 and MSH2 pathogenic variant carriers has questioned whether surveillance colonoscopy was justified before the age of 30 years. [bib_ref] Short-term risk of colorectal cancer in individuals with Lynch syndrome: a meta-analysis, Jenkins [/bib_ref] The US multi-society task force guidelines recommend starting surveillance colonoscopy at 20-25 years (or 2-5 years younger than youngest affected relative if diagnosed <25 years) but to consider starting at 30 and 35 years for MSH6 and PMS2 pathogenic variant carriers, respectively. [bib_ref] Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement..., Giardiello [/bib_ref] Ten Broeke et al described a series of 377 patients with constitutional PMS2 pathogenic variants. [bib_ref] Cancer risks for PMS2-associated Lynch syndrome, Ten Broeke [/bib_ref] They observed that the median age at first CRC was 52 years (26-86 years), and noted gender differences in CRC risk. The cumulative risk (%) in men and women up to the age of 69 years was 18.8% and 10.5%, respectively. They recommended that commencement of colonoscopic surveillance could be deferred. A nationwide French study of patients with LS supports a genotype-phenotype correlation. [bib_ref] Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes..., Bonadona [/bib_ref] There were no PMS2 pathogenic variant carriers in this cohort. Overall there was a cumulative CRC risk by 70 years of 38% in males and 31% in females. When analysed by genotype the cumulative CRC risks were 46% MLH1, 48% MSH2 and 12% MSH6. Furthermore, age (years) at CRC also varied by genotype: MLH1 45 , MSH2 44 , MSH6 54 . These data are supported by analyses of a prospective LS database. These reports observed that there was genotype specific penetrance. Furthermore, within each genotype the incidence of CRC was age dependent and CRC occurred as a stochastic event. In the report addressing first cancer incidence and survival in patients with LS receiving surveillance, Moller et al observed cumulative CRC cancer incidence to the age of 70 years was 46% MLH1, 35% MSH2, 20% MSH6 and 0% PMS2. Overall, there was no difference between gender. The most recent report from this prospective database [bib_ref] Cancer risk and survival in path_MMR carriers by gene and gender up..., Møller [/bib_ref] penetrance was confirmed; of note the number of PMS2 carriers in this cohort is small. Further studies are required to further stratify risk for MSH6 and PMS2 pathogenic variant carriers. Until such data are available, based on the current sparse literature it appears reasonable to defer initiation of surveillance for these patients. The current literature is sufficiently robust to recommend that MSH6 and PMS2 pathogenic variant carriers should have different ages of onset for colorectal surveillance (figure 2). ## Surgery in ls patients with crc ## We suggest that for ls patients with mlh1 or msh2 mutations who develop colon cancer or colonic neoplasia not amenable to endoscopic control, the decision to perform segmental versus total/near total colectomy should balance the risks of metachronous cancer, the functional consequences of surgery, the patient's age and patient's wishes. ( surgery This decision regarding which operation is preferable should be made on the basis of individual patient factors and preferences, with special emphasis on the risk of metachronous CRC, age and the preparedness of the patient to continue colonoscopic surveillance. High-quality patient information and shared decisionmaking between patient and surgeon will facilitate this decision. ## Risk of metachronous cancer Parry et al found the cumulative risk of metachronous CRC to be 16% at 10 years, 41% at 20 years and 62% at 30 years after segmental colectomy. In contrast none of 50 subjects who had extensive colectomy developed metachronous CRC. They calculated that the risk of metachronous CRC was reduced by 31% for every 10 cm of large bowel removed. Kalady et al reported 296 patients (253 with segmental colectomy and 43 with total colectomy/ileorectal anastomosis). Of the 253 segmental colectomy patients, 55 patients (25%) developed a second CRC at a median of 69 months after index surgery. Stages of the metachronous cancers were I-16, II-18, III-12, and IV-2. By comparison, four of 38 patients (11%) who underwent total colectomy developed subsequent high-risk adenomas and only three (8%) developed metachronous cancer. [bib_ref] Risk of colorectal adenoma and carcinoma after colectomy for colorectal cancer in..., Kalady [/bib_ref] A Finnish study reported the cumulative risk of subsequent CRC to be 20% within 10 years and 47% within 25 years after standard resection and 4% and 9% after extended surgery. [bib_ref] Subtotal colectomy for colon cancer reduces the need for subsequent surgery in..., Renkonen-Sinisalo [/bib_ref] A further study showed metachronous CRC in 6.3% of pathogenic variant carriers treated with total/subtotal colectomy compared with 27% treated by segmental colectomy. [bib_ref] Efficacy of proximal colectomy for surgical management of right-sided first colorectal cancer..., Hiatt [/bib_ref] In meta-analysis much of the excess risk of metachronous CRC appears to be in carriers of pathogenic variants in the MLH1 and MSH2 pathogenic carriers, with insufficient data to suggest excess risk in MSH6 or PMS2 variant carriers. 138 ## Survival from metachronous cancer Moller et al in an international collaborative study found the cumulative incidence of metachronous CRC was 36% from 40 to 70 years. Five and 10 year crude survival after colectomy for metachronous CRC was 94% and 91%, respectively, with no significant difference between the pathogenic variants of the different genes. [bib_ref] Incidence of and survival after subsequent cancers in carriers of pathogenic MMR..., Møller [/bib_ref] Natarajan et al found no significant difference in survival time between patients undergoing extended colectomy and limited resection in patients with LS. [bib_ref] Comparison of extended colectomy and limited resection in patients with Lynch syndrome, Natarajan [/bib_ref] The potential health effects in terms of life expectancy for patients undergoing subtotal colectomy or hemicolectomy for CRC were analysed. The 10 year risk of CRC after subtotal colectomy was 4% and after hemicolectomy was 16% and stages of CRCs detected within a 2 year surveillance interval were 32% Dukes' A, 54% Dukes' B, and 14% Dukes' C (derived from two cohort studies). The overall LE gain of subtotal colectomy compared with hemicolectomy at ages 27, 47, and 67 was 2.3, 1, and 0.3 years, respectively. [bib_ref] Decision analysis in the surgical treatment of colorectal cancer due to a..., De Vos Tot Nederveen Cappel [/bib_ref] The authors concluded that unless surveillance results improve, subtotal colectomy was the preferred treatment for CRC in LS in view of the difference in life expectancy and that for older patients, hemicolectomy may be an option as there was no appreciable difference in life expectancy is this age group. ## Functional consequences and qol In a Dutch study, no difference in global QoL was noted between 51 LS patients who underwent partial colectomy and 53 patients who underwent subtotal colectomy, although functional outcome (stool frequency and social impact) was worse after subtotal colectomy than after segmental colectomy. [bib_ref] Quality of life after surgery for colon cancer in patients with Lynch..., Haanstra [/bib_ref] Maeda et al constructed a state-transition (Markov) model to compare segmental colectomy and total abdominal colectomy with ileorectal anastomosis. [bib_ref] Decision model of segmental compared with total abdominal colectomy for colon cancer..., Maeda [/bib_ref] Quality-adjusted life years (QALYs) were calculated based on utility states for patients based on the colectomy they received. Multiple sensitivity analyses were planned to examine the impact of each assumption on model results. For young year-old) patients with LS, mean survival was slightly better with total colectomy than with segmental resection (34.8 vs 35.5 years). When QALYs were considered, the two strategies were approximately equivalent, with QALYs per patient of 21.5 for segmental colectomy and 21.2 for total colectomy. They suggested that with advancing age, segmental colectomy becomes a more favourable strategy. The decision regarding which operation is preferable should be made on the basis of individual patient factors and preferences, with special emphasis on the risk of metachronous CRC, age and the preparedness of the patient to continue colonoscopic surveillance. ## Patients presenting with rectal cancer A standard low anterior resection or abdominal perineal resection is a reasonable option to treat rectal cancers in LS patients, even though the residual colon is at high risk of metachronous neoplasia. A retrospective study of 79 LS patients with rectal cancer who had undergone proctectomy found a cumulative risk of metachronous colon cancer to be 19% at 10 years, 47% at 20 years, and 69% at 30 years after surgical resection. [bib_ref] Risk of metachronous colon cancer following surgery for rectal cancer in mismatch..., Win [/bib_ref] Kalady et al followed 50 HNPCC patients with a primary diagnosis of rectal cancer treated by proctectomy. Forty-eight high-risk adenomas developed in 13 patients (39.4%) and five patients (15.2%) developed metachronous adenocarcinoma at a median of 6 years (range 3.5-16) after proctectomy, including three at an advanced stage. Overall 17 of 33 patients (51.5%) developed high-risk adenoma or cancer after proctectomy. 144 ## Upper gi, pancreatic and small bowel risk management in ls ## We recommend that gastric, small bowel, or pancreatic surveillance in ls patients is only performed in the context of a clinical trial. [bib_ref] Cancer risk and survival in path_MMR carriers by gene and gender up..., Møller [/bib_ref] The risk of gastric carcinoma was reported to be the highest for MLH1 and MSH2 pathogenic variant carriers: 7.1% (95% CI 3.5% to 10.8%) for MLH1, 7.7% (95% CI 1.9% to 13.6%) for MSH2, and 5.3% (95% CI 0.0% to 13.1%) for MSH6. No gastric cancers were observed in PMS2 pathogenic variant carriers. The study also reported a 5 year overall survival rate of 61% (95% CI 33% to 81%) for LS-associated gastric cancer. This compares favourably with the prognosis in unselected patients with resectable gastric cancer, who have been reported to have an overall 5 year survival of 10-30%. [bib_ref] Gastric adenocarcinoma: review and considerations for future directions, Dicken [/bib_ref] A Finnish study reported the characteristics of 62 gastric cancers that occurred in 570 family members from the Finnish HNPCC registry. There was an overrepresentation of intestinal gastric cancers, which was found in 79% of cases, with only 13% of cases being diffuse gastric cancers. As the development of intestinal gastric cancers is thought to be closely associated with H. pylori-associated chronic gastritis, the authors investigated whether atrophic gastritis and H. pylori infection could be markers of gastric cancer risk in patients with LS. Twenty percent of the LS-associated gastric cancers were H. pylori positive. The median age at diagnosis was 56 years. [bib_ref] Gastric adenocarcinoma: review and considerations for future directions, Dicken [/bib_ref] Renkonen-Sinisalo et al assessed the diagnostic yield of upper endoscopy in a series of 73 MMR pathogenic variants carriers (median age 47 years). [bib_ref] No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal..., Renkonen-Sinisalo [/bib_ref] The authors found no early gastric cancers or premalignant lesions (diagnostic yield 0). A single screened-detected small bowel cancer was identified: an advanced stage duodenal cancer. No additional studies evaluating the benefit of gastric surveillance in LS were identified from the literature. The cumulative lifetime risk of gastric cancer is relatively low. Aspirin chemoprophylaxis may reduce the risk of all LS-associated cancers in patients with LS. In conclusion, there is no convincing evidence to support the utility of gastric surveillance in patients with LS. ## Guidelines small bowel cancer The cumulative lifetime risk of developing small bowel cancer has been estimated to be 4.2% in patients with constitutional MLH1 and MSH2 pathogenic variants. 149 Small bowel cancers have rarely been reported in patients with constitutional MSH6 and PMS2 pathogenic variants. A recent study has reported genespecific prospective cumulative cancer risks (up to the age of 75 years) for duodenal carcinoma in 3119 patients with LS. The risk of duodenal carcinoma was reported to be the highest for MLH1 pathogenic variant carriers (6.5%, 95% CI 1.7% to 10.2% for MLH1; 2.0%, 95% CI 0.1% to 4.0% for MSH2), and no small bowel cancers were observed in patients with constitutional MSH6 or PMS2 pathogenic variants. [bib_ref] Cancer risk and survival in path_MMR carriers by gene and gender up..., Møller [/bib_ref] LS-related small bowel carcinomas have an earlier onset compared with sporadic tumours with a median age of onset of 52 years (range 23-69 years). LS-related small bowel carcinomas most commonly occur in the duodenum (49%), and decrease in frequency from the jejunum (29%) to the ileum (12%). [bib_ref] HNPCC-associated small bowel cancer: clinical and molecular characteristics, Schulmann [/bib_ref] Patients with LS who develop small bowel cancers have been demonstrated to have a better prognosis compared with patients who develop sporadic tumours. Moller et al, in a recent study, reported a 5 year survival rate of 67% (95% CI 28% to 88%) in LS patients with small bowel cancers diagnosed below the age of 65. [bib_ref] Cancer risk and survival in path_MMR carriers by gene and gender up..., Møller [/bib_ref] This compares favourably with the 5 year survival of sporadic small bowel adenocarcinoma, which has been estimated to be 25-30%. [bib_ref] Current advance in small bowel tumors, Cheung [/bib_ref] Several studies have investigated the diagnostic yield of surveillance for small bowel cancers in patients with LS. In 2010 Saurin et al compared the use of CT enteroclysis and video-capsule endoscopy (VCE) in 35 asymptomatic patients with LS. [bib_ref] Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with..., Saurin [/bib_ref] Histologically confirmed small bowel tumours were identified in three patients (diagnostic yield of 8.6%): one jejunal adenocarcinoma (T3N0M0) and two adenomas with low-grade dysplasia. VCE identified all three tumours, but CT enteroclysis would have missed the two adenomas. [bib_ref] Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with..., Saurin [/bib_ref] In a Dutch study, Haanstra et al investigated the prevalence of small bowel tumours in 200 asymptomatic pathogenic variant carriers (aged 35-70 years) using VCE. [bib_ref] Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy, Haanstra [/bib_ref] Caecal visualisation was achieved in 95% of procedures. Histologically confirmed small bowel tumours were identified in two patients (diagnostic yield of 1%): one adenocarcinoma (TisN0Mx) and one adenoma, both located in the duodenum. In addition, another patient was diagnosed with a duodenal cancer (T2N0Mx) 7 months after a negative VCE (incidence of 1.5%). This suggests that VCE may miss some small bowel tumours. [bib_ref] Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy, Haanstra [/bib_ref] In a follow-up study, asymptomatic LS patients who underwent a VCE were invited to undergo a second VCE procedure 2 years later. A total of 155 (78%) of the initial 200 pathogenic variant carriers underwent a second VCE. Potentially significant lesions were identified in 17 patients (11%), which required further investigations: eight gastroduodenoscopies and nine balloon-assisted endoscopies were carried out, but no small bowel tumours were identified. [bib_ref] Incidence of small bowel neoplasia in Lynch syndrome assessed by video capsule..., Haanstra [/bib_ref] In the CAPP2 randomised trial, Burn et al examined the effect of aspirin in 861 patients with LS who were randomly assigned in a two-by-two factorial design to 600 mg of aspirin or aspirin placebo or 30 g of resistant starch or starch placebo, for up to 4 years. [bib_ref] Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal..., Burn [/bib_ref] The primary outcome was the incidence of new primary CRCs, but the incidence of all LS cancers was also examined. Following a re-analysis of the data at a mean follow-up of 55.7 months, for participants completing 2 years of intervention (258 aspirin; 250 aspirin placebo), per-protocol analysis yielded a hazard ratio (HR) of 0.45 (95% CI 0.26 to 0.79; p=0.005) for all LS-related cancers. The absolute lifetime risk of small bowel cancer in patients with LS is 4.2%; this risk is likely to be most significant for MLH1 pathogenic variant carriers. LS-related small bowel cancers have been demonstrated to have a better prognosis than sporadic small bowel cancers. Aspirin chemoprophylaxis has been demonstrated to significantly reduce the risk of all LS-associated cancers in patients with LS. Video capsule endoscopy has been used to successfully identify small bowel tumours in patients with LS. However, there have been a limited number of studies and the diagnostic yield has been variable (1-8.6%). VCE may have missed some cancers. No small bowel tumours were detected on follow-up surveillance after an interval of 2 years. In addition, a high false positive rate (11%) has been reported, resulting in asymptomatic patients requiring time consuming and invasive tests. ## Pancreatic cancer In a retrospective study, Kastrinos et al estimated pancreatic cancer risks in individuals (n=6342) from 147 families with constitutional MLH1, MSH2 and MSH6 pathogenic variants. [bib_ref] Risk of pancreatic cancer in families with Lynch syndrome, Kastrinos [/bib_ref] Forty-seven pancreatic cancer cases were reported in 31 families: 18 patients had a negative family history (38%). The cumulative risk for pancreatic cancer up to the age of 70 was reported to be 3.7% (95% CI 1.45% to 5.88%); this represented an 8.6-fold increased risk compared with the general population. Most of the pancreatic cases were observed in individuals from MSH2 families (31/47) and MLH1 families (13/47). Only three of the pancreatic cancers were diagnosed in the MSH6 families. The median age of pancreatic cancer diagnosis was 51.5 years (range . Prospective lifetime risks stratified by the MMR gene have now also been reported for pancreatic cancer. Moller et al reported a cumulative risk of pancreatic cancer (up to the age of 75) for MLH1 of 6.2% (95% CI 2.6% to 9.8%), for MSH2 of 0.5% (95% CI 0.0% to 1.5%) and for MSH6 of 1.4% (95% CI 0.0% to 4.2%). No pancreatic cancers were observed in PMS2 pathogenic variant carriers. The authors also calculated 5 year overall survival for the LS patients with pancreatic cancer. The poor prognosis of pancreatic cancer patients is well established, and none of the affected carriers was alive at 5 years. [bib_ref] Incidence of and survival after subsequent cancers in carriers of pathogenic MMR..., Møller [/bib_ref] Surveillance for pancreatic cancer has been recommended in high-risk groups (defined as >5%), including patients from familial pancreatic cancer pedigrees with an affected FDR, patients with PJS, and CDKN2A (P16), BRCA2 and MMR pathogenic variant carriers with at least one affected FDR. [bib_ref] International Cancer of the Pancreas Screening (CAPS) Consortium Summit on the management..., Canto [/bib_ref] The goal of screening is to identify and treat early stage pancreatic cancers (T1N0M0) and high-risk precursor lesions, high-grade pancreatic intraepithelial neoplasia (PanIN-3) and intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia. Signoretti et al conducted a systematic review and meta-analysis of 16 pancreatic surveillance studies in high-risk groups. [bib_ref] Results of surveillance in individuals at high-risk of pancreatic cancer: a systematic..., Signoretti [/bib_ref] A relatively low diagnostic yield of pancreatic cancers and relevant precursor lesions was reported (3.3%) using endoscopic ultrasound and MRI as first line screening tests. A significant proportion (25%) of the screen-detected cancers were also unresectable or metastatic. Some patients underwent surgery for precursor lesions and were not found to have high-risk precursor lesions. A significant morbidity (up to 40%) and mortality (0.5-6%) have been reported for the surgical treatment of suspicious pancreatic findings. [bib_ref] Incidence of small bowel neoplasia in Lynch syndrome assessed by video capsule..., Haanstra [/bib_ref] Pancreatic surveillance has not been demonstrated to reduce pancreatic-cancer specific mortality in patients with LS. The cumulative lifetime risk of pancreatic cancer is relatively low for MLH1 pathogenic variant carriers, and low (<5%) for MSH2, MSH6 and PMS2 pathogenic variant carriers. Aspirin chemoprophylaxis has also been demonstrated to significantly reduce the risk of all LS-associated cancers in patients with LS. The utility of pancreatic screening remains unproven, and there is a danger of overtreatment with patients undergoing surgery for benign or low-risk lesions. There is a significant morbidity and mortality associated with pancreatic surgery. ## Lynch-like syndrome ## We recommend that deficient mmr tumours without hypermethylation/braf pathogenic variant and no pathogenic constitutional pathogenic variant in mmr genes should undergo somatic tumour testing with a crc gene panel. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 100% agreement. ## We recommend that if double somatic mmr pathogenic variants are identified, manage proband and their fdrs based on the fhcc. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 95% agreement. ## We suggest that if no or one somatic pathogenic variant is identified, the proband and their fdrs should be managed as per ls. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 100% agreement. LLS describes a subgroup of patients with CRC or other LS-related tumours that manifest MMR deficiency (microsatellite instability (MSI) and/or loss of MMR protein expression) that is neither explained by somatic MLH1 promoter hypermethylation, BRAF pathogenic variant or a detectable pathogenic constitutional variant in an MMR gene or EPCAM LLS cases, and therefore cannot be readily assigned to either the sporadic or inherited MMR deficiency categories, respectively. [bib_ref] Differentiating Lynch-like from Lynch syndrome, Carethers [/bib_ref] [bib_ref] A practical approach to the evaluation of gastrointestinal tract carcinomas for Lynch..., Pai [/bib_ref] [bib_ref] Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with..., Buchanan [/bib_ref] Combining data from published studies, using current diagnostic approaches, an estimated 59% (95% CI 55% to 64%) of dMMR CRC cases are unexplained and categorised as LLS. [bib_ref] Role of tumour molecular and pathology features to estimate colorectal cancer risk..., Win [/bib_ref] ## Cancer risks Three studies have investigated CRC risks for patients with LLS and their relatives. Overbeek et al compared the characteristics of 76 families with a constitutional variant in a DNA MMR gene with those of 18 families with unexplained dMMR tumours. [bib_ref] Patients with an unexplained microsatellite instable tumour have a low risk of..., Overbeek [/bib_ref] Although the mean age of CRC onset of the index case was comparable at 44 years, a significantly higher proportion of the families with LS fulfilled the Amsterdam II criteria compared with the families with LLS (66% vs 11%; p<0.0001). Rodríguez-Soler et al were the first to quantify the risk of CRC for FDRs of CRC cases with LLS. [bib_ref] Risk of cancer in cases of suspected Lynch syndrome without germline mutation, Rodríguez-Soler [/bib_ref] This population-based study examined the risk of CRC in the FDRs of CRC cases with LLS, LS and sporadic pMMR tumours. The authors found the highest risk of CRC for the FDRs of the LS cases (standardised incidence ratio (SIR) for LS 6.04, 95% CI 3.58 to 9.5), an intermediate risk for the FDRs of LLS cases (SIR for LLS 2.12, 95% CI 1.16 to 3.56), and the lowest risks for the FDRs of sporadic pMMR CRC cases (SIR for sporadic 0.48, 95% CI 0.27 to 0.79; p<0.001). In a large family cohort study, Win et al subsequently confirmed that FDRs of LLS cases have a higher CRC risk compared FDRs of sporadic pMMR CRC cases, but a lower risk compared with FDRs of LS cases . [bib_ref] Role of tumour molecular and pathology features to estimate colorectal cancer risk..., Win [/bib_ref] Compared with FDRs of sporadic pMMR CRC cases, a higher risk of CRC was estimated for FDRs of LLS cases (HR 2.06, 95% CI 1.59 to 2.67), and an even higher risk for the FDRs of LS cases (HR 5.37, 95% CI 4.16 to 6.94). [bib_ref] Role of tumour molecular and pathology features to estimate colorectal cancer risk..., Win [/bib_ref] ## Potential aetiologies Studies have shown that up 70% of patients with LLS have double (biallelic) somatic pathogenic variants in the MMR genes. [bib_ref] Somatic mosaicism and double somatic hits can lead to MSI colorectal tumors, Sourrouille [/bib_ref] [bib_ref] Colon and endometrial cancers with mismatch repair deficiency can arise from somatic,..., Haraldsdottir [/bib_ref] [bib_ref] Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair..., Mensenkamp [/bib_ref] In a study of 25 LLS cases with unexplained immunohistochemical absence of the MLH1 or MSH2 protein, Mesenkamp et al identified biallelic somatic pathogenic variants (one pathogenic sequence variant and loss of heterozygosity) in 13 cases (52%; 8/18 in MLH1 and 5/7 in MSH2). [bib_ref] Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair..., Mensenkamp [/bib_ref] Other studies have subsequently confirmed the presence of a high proportion of biallelic somatic pathogenic variant LLS cases. In a study of 36 LLS cases, Geurts-Giele et al found double somatic pathogenic variants in 21 cases (58%; 16/21 in MLH1 and 5/12 in MSH2). [bib_ref] Somatic aberrations of mismatch repair genes as a cause of microsatellite-unstable cancers, Geurts-Giele [/bib_ref] In a study of 32 LLS cases, Haraldsdottir et al identified double somatic pathogenic variants in 22 cases (69%; seven for MLH1, 11 for MSH2, three for MSH6 and one for PMS2). [bib_ref] Colon and endometrial cancers with mismatch repair deficiency can arise from somatic,..., Haraldsdottir [/bib_ref] Biallelic somatic pathogenic variants may be in the form of point pathogenic variants coupled with loss of heterozygosity, or another point pathogenic variant. Double variant somatic pathogenic variants are likely to be in trans (one on each allele), and therefore if identified provide a potential explanation for the tumour MMR deficiency in patients with LLS. A recent study has shown that a significant proportion of LLS cases may also be explained by false positive screening results, caused by an incorrect interpretation of MMR immunohistochemistry (IHC) results. The authors found discordant findings on IHC and MSI in six out 32 LLS cases (19%). [bib_ref] Colon and endometrial cancers with mismatch repair deficiency can arise from somatic,..., Haraldsdottir [/bib_ref] However, there remains a possibility that some patients with LLS may actually have LS, due to constitutional pathogenic variants in the MMR genes that are not detected using current diagnostic methods, for example, pathogenic variants within regulatory/promoter regions and complex structural variants. [bib_ref] Differentiating Lynch-like from Lynch syndrome, Carethers [/bib_ref] Finally some patients with LLS may carry constitutional or somatic pathogenic variants in other genes, which may explain the deficient MMR tumour phenotype and/or occur in conjunction with somatic pathogenic variants in the MMR genes. [bib_ref] Biallelic MUTYH mutations can mimic Lynch syndrome, Morak [/bib_ref] [bib_ref] Germline variants in POLE are associated with early onset mismatch repair deficient..., Elsayed [/bib_ref] [bib_ref] Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers, Jansen [/bib_ref] Jasen et al investigated 62 LLS cases using gene panel sequencing including the POLE, POLD1 and MMR genes. The authors found somatic (n=7) or constitutional variants (n=2) in the POLE/POLD1 exonuclease domain in nine tumours (14.5%), which showed an ultramutated phenotype. Six of these cases also were found to carry somatic MMR variants. [bib_ref] Combined mismatch repair and POLE/POLD1 defects explain unresolved suspected Lynch syndrome cancers, Jansen [/bib_ref] In a study by Morak et al, MUTYH diagnostic testing was carried out in 85 patients with LLS and biallelic constitutional pathogenic variants were found in one patient (1.18%). [bib_ref] Biallelic MUTYH mutations can mimic Lynch syndrome, Morak [/bib_ref] Consequently, LLS cases have been found to have heterogeneous aetiologies, ranging from biallelic somatic pathogenic variants to unidentifiable constitutional pathogenic variants in MMR genes. This is likely to explain the intermediate cancer risks, which have been reported for the FDRs of LLS cases, and has implications for the clinical management of LLS families. Thus double somatic pathogenic variants in the MMR genes may explain up to 70% of LLS cases. Therefore, tumour sequencing of the DNA MMR genes should be undertaken in LLS cases, as this would help guide genetic counselling and the management recommendations for LLS cases and their FDRs [fig_ref] Guidelines figure 3: Management of Lynch-like syndrome [/fig_ref]. If double somatic pathogenic variants are identified, we would recommend that these patients and their FDRs be managed based on the FHCC, and not as LS. However, if no somatic pathogenic variants or only one somatic pathogenic variant or loss of heterozygosity of one allele is identified we would recommend that these cases and the FDRs be managed as potential LS cases and follow colorectal surveillance guidelines for LS. This is based on the possibility that these cases could have LS due to an unidentifiable constitutional pathogenic variant in an MMR gene. These recommendations are consistent with the NCCN (National Comprehensive Cancer Network) guidelines [bib_ref] NCCN guidelines insights: genetic/ familial high-risk assessment: colorectal, version 3, Gupta [/bib_ref] and may help reduce variability in practice in the UK. 171 ## Early onset crc ## We recommend that in patients under 30 years of age with dmmr crc, an ls constitutional panel test should be performed, followed by tumour testing for somatic testing if constitutional testing is negative. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 91% agreement. ## We recommend that in patients under 30 years of age with pmmr crc, a constitutional crc multiple gene panel test should be performed. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 100% agreement. Several studies have sought to define the prevalence and spectrum of constitutional cancer predisposition gene pathogenic variants among patients diagnosed with early-onset CRC (EOCRC), defined most commonly as CRC onset below age 50 years. [bib_ref] Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with..., Pearlman [/bib_ref] [bib_ref] High prevalence of hereditary cancer syndromes in adolescents and young adults with..., Mork [/bib_ref] [bib_ref] Germline genetic features of young individuals with colorectal cancer, Stoffel [/bib_ref] In a retrospective cohort of very young patients (age 35 or younger) with CRC referred for genetic evaluation, syndromespecific genetic testing guided by patient phenotype and family history, identified highly penetrant CRC syndromes in 35% of patients [bib_ref] Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with..., Pearlman [/bib_ref] A constitutional pathogenic variant in a high penetrance CRC gene was identified in 22% of patients with CRC diagnosed between 20-29 years (4/18): two MSH2 pathogenic variants in patients with dMMR tumours and two APC pathogenic variants in patients with pMMR tumours. [bib_ref] Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with..., Pearlman [/bib_ref] Of note, in those patients with a pathogenic variant identified in a high penetrance gene over the age of 30 years, all either had a significant family history, multiple primaries or exhibited dMMR on tumour testing. A recent retrospective evaluation of patients with early-onset CRC (aged <50) reported comparable findings. In this study, 430 patients with early-onset CRC were referred for genetic assessment at a single tertiary care cancer centre from 1998 until 2015. Of the 430 patients, 41 had an dMMR tumour (9.5%), 161 had an Microsatellite stable (MSS) tumour (37.3%), and 228 had tumours with an unknown MMR status (53%). Clinical constitutional sequencing in 315 patients, based on their personal and family history, identified cancer predisposition gene pathogenic variants in 79 patients (18% of entire cohort, 25% of patients who underwent clinical sequencing), although five were in genes not associated with CRC syndromes. Fifty-six patients had a pathogenic variant in a DNA MMR gene (25 MSH2, 24 MLH1, five MSH6 and two PMS2), 10 in APC, eight in MUTYH (seven biallelic pathogenic variants) and two in SMAD4. Three patients were found to carry pathogenic variants in other cancer predisposition genes (one TP53, one BRCA1 and one CHEK2). [bib_ref] Germline genetic features of young individuals with colorectal cancer, Stoffel [/bib_ref] In addition, 117 patients who had uninformative clinical evaluations underwent research-based next generation sequencing (NGS) using a multigene panel. This identified constitutional cancer predisposition pathogenic variants in six other patients (one PMS2, one MSH6, one MUTYH, one POLE, one APC and one TP53). In total, 85 patients (20%; 85/430) with early onset-CRC were found to carry a pathogenic variant in a constitutional cancer predisposition gene. However, only 79 were in genes associated with bowel cancer. LS was the most common genetic diagnosis (58/85; 68%). Seventeen patients with a constitutional MMR pathogenic variant had a dMMR tumour, 37 patients had a tumour with unknown MMR status and four (7%) patients had a pMMR tumour. 174 in conclusion ► The prevalence of cancer predisposition gene pathogenic variants in patients with early onset CRC (age <50) has been reported to range from approximately 15% to 20%. LS is the most common genetic diagnosis, accounts for up to 68% of cancer predisposition pathogenic variants in patients with early onset CRC (age <50 years), and the vast majority will have dMMR tumours. ► In patients with pMMR tumours, the most common genetic diagnosis is an adenomatous polyposis syndrome (FAP and MAP), and the prevalence of associated constitutional pathogenic variants has been reported to reach the 10% threshold for patients diagnosed with CRC below the age of 30. ► In patients with pMMR tumours between the age of 30 and 50 years at diagnosis of CRC, a genetic diagnosis may be suspected on the basis of FHCC or other clinical parameters. Altering the threshold for genetic testing in this patient cohort also needs to be balanced between clinical need and the ethical and logistical considerations of population testing. [bib_ref] New and recurrent colorectal cancers after resection: a systematic review and meta-analysis..., Fuccio [/bib_ref] The most plausible explanation is that many early, apparently metachronous cancers are actually due to prevalent cancers or advanced adenomas missed at the time of the primary CRC diagnosis. As a consequence, new guidelines (in development) for sporadic CRC may recommend that standard post-CRC colonoscopic surveillance cease after 3 years. ## Colonoscopic surveillance in eocrc Recently published, large, population-based cancer registry studies, including ones that specifically excluded patients with LS, recommend closer surveillance in high-risk populations, however. There have been no studies specifically assessing metachronous CRC risk or the role of colonoscopic surveillance in EOCRC patients. However, when patients with hereditary CRC syndromes are excluded from CRC cohorts there is no evidence that metachronous CRC risk is significantly different from the sporadic population. Nevertheless, it may not be appropriate to discharge EOCRC cases from surveillance after 3 years in the absence of published surveillance outcome data. Thus, it may be considered prudent to offer 5 yearly colonoscopic surveillance until they are eligible for national screening in patients where LS and polyposis have been excluded. ## We recommend a diagnosis of sps should be made in accordance with the new who 2019 criteria for sps. since causative gene pathogenic variants for sps have not been identified, a definitive diagnosis of sps should be phenotype-driven. (grade of evidence: moderate; strength of recommendation: strong) Consensus reached: 95% agreement. ## Other intestinal polyposis syndromes may present with serrated lesions. if (i) the patient is under 50 or (ii) there are multiple affected individuals within a kindred or (iii) there is dysplasia within any of the polyps, then other polyposis syndromes should be excluded by gene panel testing before making a definitive diagnosis of sps. (GRADE of evidence: very low; Strength of recommendation: weak) Consensus reached: 90% agreement. ## We recommend the cumulative number of serrated polyps from all endoscopic examinations should be used when applying the who 2019 diagnostic criteria for sps. we recommend the cumulative number of serrated polyps from all endoscopic examinations should be used when applying the who 2019 diagnostic criteria for sps. (GRADE of evidence: moderate; Strength of recommendation: strong) ## Guidelines Consensus reached: 94% agreement. SPS most probably comprises a phenotypically and genetically heterogeneous group of diseases. The phenotypic criteria for a diagnosis of SPS have recently been revised by the WHO in 2019 to include the following: (1) at least five serrated polyps proximal to the rectum, all >5 mm in size with at least two >10 mm in size; (2) at least 20 serrated polyps (of any size) with at least five located proximal to the rectum. 178 Fulfilment of either criterion is sufficient for a diagnosis of SPS. Importantly, the previous WHO 2010 criterion 2, which required the presence of just one serrated lesion in a patient who has an FDR with SPS, has been removed. Given that the prevalence of serrated lesions in the Western population may be up to 39%, most of which will be sporadic, the chances of a false positive diagnosis using this criterion were high. The prevalence of SPS in the West is generally considered to be around 1:3000 in screening populations. This may change as awareness of the condition among clinicians increases. Egoavil et al [bib_ref] Increased risk of colorectal cancer in patients with multiple serrated polyps and..., Egoavil [/bib_ref] found that patients with multiple serrated polyps but failing to fulfil the WHO criteria had a similar risk of CRC as those who did fulfil the criteria. Dovetailing with this to some degree (and possibly explaining this), Crowder et al 180 concluded that SPS was underdiagnosed due to failure to consider cumulative polyp numbers (rather than at a single episode). By evaluating "cumulative pathology" in a cohort of 927 consecutive patients undergoing colonoscopy, they found that up to 1.8% of patients with a serrated lesion at first colonoscopy eventually fulfilled the criteria for SPS. Patients with SPS have an overall lifetime risk of CRC of approximately 7-70% 181 and there is an increased risk in FDRs of patients with SPS. The risk of CRC thus may be reduced with appropriate management. There is an increased risk of CRC in FDRs of patients with SPS, but it does not follow a classical Mendelian pattern of inheritance. A single causative gene has not been identified and there is phenotypic overlap with some well characterised intestinal polyposis syndromes (MUTYHassociated polyposis, hereditary mixed polyposis syndrome, attenuated FAP). Most, but not all, of the tumours arising in SPS follow the serrated neoplasia pathway characterised by microsatellite instability (due to MLH1 promoter methylation) and BRAF pathogenic variant. This raises the possibility of accelerated tumorigenesis as well as phenotypic overlap with LS. Recently, constitutional truncating pathogenic variant in RNF43 pathogenic variant has been identified and shown to segregate with phenotype in one kindred with SPS. The same pathogenic variant was also identified in two patients in a separate study. In the absence of a single causative gene (and the possibility that some forms of SPS may be polygenic in nature), the diagnosis of SPS should be phenotype-driven. Given the overlap with other well-defined syndromes, these should be excluded in all patients in whom a diagnosis of SPS is made. A specific gene panel for SPS may include testing for RNF43 and GREM1; however the frequency of these pathogenic variants is too low to recommend routinely. 186 ## Colonoscopic surveillance in sps ## We recommend that patients with sps should have colonoscopic surveillance yearly once the colon has been cleared of all lesions >5 mm in size. if no polyps ≥10 mm in size are identified at subsequent surveillance examinations the interval can be extended to 2 yearly (GRADE of evidence: moderate; Strength of recommendation: strong) Consensus reached: 94% agreement. Colonoscopic surveillance is currently recommended following detection and resection for adenomas in the colorectum due to an increased risk of advanced adenomas and CRC in such patients; however, there is another major pathway to CRC "serrated pathway" which accounts for 15-30% of CRC and has serrated lesions as cancer precursors. SPS is common in bowel cancer screening programmes which use guaiac faecal occult blood test (gFOBT) or FIT as a screening test, with estimates of SPS prevalence ranging from 1:150 to 1:300. A recent Spanish FIT based cohort followed up all their patients with proximal serrated polyps, tripling the number of additional cases of SPS, for a final prevalence of 1:100. [bib_ref] Reassessment colonoscopy to diagnose serrated polyposis syndrome in a colorectal cancer screening..., Rivero-Sanchez [/bib_ref] Therefore, especially when using FIT in bowel cancer screening, colonoscopists should be alert to a diagnosis of SPS. The BSG position statement on serrated polyps in the colon and rectum recommended 1-2 yearly surveillance for patients meeting the WHO criteria for serrated polyposis syndrome. [bib_ref] British Society of Gastroenterology position statement on serrated polyps in the colon..., East [/bib_ref] This recommendation was on the basis that in early cohorts future risk of CRC was elevated as much as 7% at 5 years ; however in larger cohorts with rigorous surveillance performed every 1-2 years, with all lesions larger than 5 mm in size resected, at academic centres, the risk appeared much lower with CRC only diagnosed at 1.9 cases per 1000 years of patient follow-up. In a US study following up SPS patients which extended surveillance intervals for SPS patients to 2 years after colon clearance with no lesion ≥10 mm found at surveillance, no cancer developed or surgery was needed. [bib_ref] Endoscopic control of polyp burden and expansion of surveillance intervals in serrated..., Macphail [/bib_ref] A similar multicentre European study that individualised surveillance after colonic clearance to 1 or 2 year follow-up dependent on lesion size (≥10 mm), number and pathology also showed no difference in advanced neoplasia detection with a 2 year surveillance interval once the colon was cleared. [bib_ref] Personalised surveillance for serrated polyposis syndrome: results from a prospective 5-year international..., Bleijenberg [/bib_ref] No new data directly relevant to this area have been published since the BSG position statement. However, a study of patients with multiple serrated polyps and adenomas, not fulfilling the criteria for SPS, also noted that their risk for CRC was equivalent to patients who met the WHO definition of SPS, and that their FDRs had a comparable risk of CRC. 179 ## Colonoscopic surveillance in unaffected fdrs of patients with sps ## We recommend all fdrs of patients with sps on the basis of the new who 2019 sps criteria 1 or 2 should be offered an index colonoscopic screening examination at the age of 40 years or 10 years before the diagnosis of the index case. (GRADE of evidence: moderate; Strength of recommendation: strong) Consensus reached: 89% agreement. ## We suggest all fdrs of serrated polyposis patients have a surveillance examination every 5 years unless polyp burden indicates an examination is required earlier according to postpolypectomy surveillance guidelines. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 84% agreement. SPS may be a familial condition with between 1.3% and 7.7% of index cases having an FDR who meets the original WHO criteria 1 or 3 for SPS. A further 14.3%-24.4% of FDRs meet original WHO criterion two for SPS. Current guidelines recommend a one-off screening examination of all FDRs to detect these familial SPS cases; however, the majority of FDR will not meet the original WHO criteria for SPS after this initial examination. The risk of CRC for FDRs of SPS patients is estimated to be substantially elevated above that of the general population by three-to fivefold. This risk may also apply to those with multiple serrated polyps not meeting WHO criteria for SPS. It is unclear how this risk is distributed in the SPS FDR population. In three series the mean or median age at diagnosis for CRC in FDRs of SPS patients ranged from 55 to 62. CRC was very rare in those aged less than 40 years with the youngest case being aged 25. Authors have recommended a screening examination starting at 35 or between 40 and 50 for FDRs of SPS cases, or starting 5-10 years before the index case In a follow-up study of 78 patients, those who did not meet any WHO criteria for SPS seem to have low risk for subsequent polyp or advanced neoplasia development; however, those who meet WHO criteria 2 do seem to develop polyps with five of 14 patients developing three or more adenomas and two others of the 14 developing a serrated lesion ≥10 mm in size. [bib_ref] Serrated polyposis: prospective study of firstdegree relatives, Oquiñena [/bib_ref] High rates of polyps in patients who met WHO 2 criteria were also seen by Hazewinkel et al. [bib_ref] Yield of screening colonoscopy in firstdegree relatives of patients with serrated polyposis..., Hazewinkel [/bib_ref] Therefore a significant proportion of WHO 2 SPS patients would meet criteria for 3 yearly surveillance according to current guidelines. No cancers developed. No data are available to look at the colonoscopic yield in FDRs of index patients who meet WHO criteria 2, that is, a second degree relative of a patient with SPS WHO 1 or 3, although the risk of CRC in second degree relatives of index cases of SPS is only slightly elevated (SIR 1.38, 95% CI 1.01 to 1.91). [bib_ref] Cancer risks for relatives of patients with serrated polyposis, Win [/bib_ref] The WHO definition of SPS has recently changed with criteria 2 abandoned completely so that FDRs with serrated polyps are not considered to meet the definition for SPS. Therefore a blanket recommendation for colonoscopic surveillance for FDRs of SPS every 5 years based on the three-to fivefold increase in SIR of CRC is suggested from age 40 or 10 years before the diagnosis for the index case, with more frequent surveillance in line with sporadic recommendations if additional polyps are detected. FDRs of patients with multiple serrated polyps (MSP, 10 or more polyps in total of which 50% are serrated) but who do not meet the 2019 WHO criteria for SPS might be considered for similar surveillance approaches for FDRs. The risk of CRC in FDRs of SPS patients is sufficiently elevated that they should be offered colonoscopic screening and regular surveillance. ## Multiple colorectal adenomas ## We suggest an individualised approach to germline testing of patients with mcra (defined as having 10 or more metachronous adenomas). consider this testing for: ► patients under 60 years of age with lifetime total of ≥10 adenomas;or ► Patients from 60 years of age with lifetime total of: -≥20 adenomas, or -≥10 adenomas and an FHCC or polyposis (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 91% agreement. ## We suggest that patients with a finding of 10 or more polyps (adenomas or serrated lesions) should, at their next colonoscopy, have a high-quality colonoscopic assessment with pancolonic dye spray in order to accurately define the multiple polyp phenotype. (GRADE of evidence: very low; Strength of recommendation: weak) Consensus reached: 89% agreement. We suggest that the endoscopic management of patients with 10 or more metachronous adenomas, without MUTYH or APC gene mutations, should be individualised according to phenotype. (GRADE of evidence: very low; Strength of recommendation: weak) Consensus reached: 91% agreement. ## We suggest annual colonoscopic surveillance for patients with 10 or more metachronous adenomas after the colon has been cleared of all lesions >5mm in size. if no polyps 10mm or greater in size are identified at subsequent surveillance examinations the interval can be extended to 2 yearly. (GRADE of evidence: very low; Strength of recommendation: weak) Consensus reached: 80% agreement. Patients with multiple adenomas but without classical familial adenomatous polyposis are frequently encountered in clinical practice. Approximately 1.1% of patients undergoing colonoscopy in the English bowel cancer screening programme have 10 or more adenomas. [bib_ref] OWE-25 patients with multiple adenomas in bowel cancer screening program are not..., Alexander [/bib_ref] There is an association of adenoma multiplicity with metachronous advanced adenoma and/or CRC risk, with the degree of risk correlating with increasing adenoma number and size. With less than three adenomas as reference, Cubiella et al (n=5401) reported a statistically increased risk for AN when three or four adenomas (14.8%), and also when five to nine adenomas (18.4%), were present at index colonoscopy. [bib_ref] Incidence of advanced neoplasia during surveillance in high-and intermediate-risk groups of the..., Cubiella [/bib_ref] In the largest study to date of individuals with 10-19 adenomas, 172 3789 patients with 10 or more colorectal polyps underwent constitutional testing of the prevalence of pathogenic variants with a 17-gene panel. The diagnostic yield of pathogenic variants remained above 5% in all ages and cohorts, despite a decrease with age. In the multiple adenoma cohort, the yield was higher in those patients with a personal or family history of cancer. In 1342 patients with 10-19 adenomas, 7.8% had a pathogenic variant in one of the panel genes, with 2.2% in "traditional"' polyposis predisposition genes, and 2.8% in MMR genes. Thus an unbiased multi-gene panel test approach may be associated with a higher diagnostic yield. In a study of 7225 individuals with MCRA and oligopolyposis, pathogenic variants in APC or common European founder pathogenic biallelic variants in MUTYH were identified in 87/970 (9%) individuals with 10-19 adenomas and 559/3253 (17%) individuals with 20-99 adenomas. [bib_ref] Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple..., Grover [/bib_ref] There was an incremental increase in the odds of a pathogenic variant with an increasing number of adenomas and earlier age at adenoma diagnosis, particularly under the age of 50 years. In addition to APC and MUTYH there is an evolving range of other multiple adenoma susceptibility genes including NTHL1, GREM1, POLE, POLD1 and MSH3. Spier et al in 2015 demonstrated POLE pathogenic variants in 1.5% of individuals with greater than 20 synchronous or 40 metachronous adenomas although this percentage increased with a family history. [bib_ref] Frequency and phenotypic spectrum of germline mutations in POLE and seven other..., Spier [/bib_ref] There is also some evidence of polygenic risk contributing to this attenuated polyposis phenotype. [bib_ref] Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype,..., Cheng [/bib_ref] In summary, it is advisable to consider a diagnosis of a highly penetrant syndrome in patients with multiple adenomas. A nuanced approach to patient selection for constitutive testing should incorporate patient age and personal and family history. With regard to colonoscopic surveillance in the multiple adenoma patient population, the GDG suggests constitutional gene testing to rule out known hereditary syndromes. Subsequently an individualised approach should be taken depending on adenoma size and number, with the goal of clearance of colorectal adenomas >5 mm in size. However, surgical resection should be considered where surveillance is not feasible. ## Guidelines In patients with 10-99 adenomas without APC or MUTYH pathogenic variants, the clinical phenotype is similar to that of attenuated polyposis, with both an upper GI (21% with duodenal adenomas) and colorectal phenotype. [bib_ref] Clinical characteristics of multiple colorectal adenoma patients without germline APC or MYH..., Tieu [/bib_ref] In a study of 83 patients also of 10-99 adenomas without APC or MUTYH pathogenic variants from the UK and Holland, the upper GI phenotype was reported in a minority of patients (9.6%), all of whom had Spigelman I or II disease (ie, early stage). [bib_ref] Duodenal adenomas in patients with multiple colorectal adenomas without germline APC or..., Kallenberg [/bib_ref] For FDRs of MCRA patients, clinicians may consider a colonoscopic assessment of risk at the time of referral, and/or a repeat assessment at age 50 years. This is in order that patients who may be at risk of high penetrance cancer predisposition syndromes may be effectively identified (for example, the children of individuals with unidentified mosaic pathogenic variants of the APC gene 206 ). However the GDG did not reach consensus on this recommendation, and recommend that multicentre outcome data in these patients be collected and published to help guide future recommendations. ## Familial adenomatous polyposis FAP is defined by the presence of pathogenic variants in the APC gene with a prevalence of about 1/8500. It is a dominantly inherited multisystem cancer predisposition syndrome with a characteristic phenotype characterised by colorectal and upper GI polyposis. ## Colorectal surveillance in fap ## We recommend that colonic surveillance should normally commence at the age of 12-14 years in those confirmed to have fap on predictive genetic testing. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 100% agreement. ## We suggest that for those with fap, intervals between surveillance colonoscopy may be individualised depending on colonic phenotype every 1-3 years. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 94% agreement. ## We suggest that colonoscopy screening is performed for individuals who have an fdr with a clinical diagnosis of fap (ie, "at-risk") and in whom an apc mutation has not been identified, starting at the age of 12-14 years, and should continue on 5 yearly surveillance until either a clinical diagnosis is made and they are then managed as fap, or they reach the age at which they can enrol in national screening. (GRADE of evidence: very low; Strength of recommendation: weak) Consensus reached: 95% agreement. Current international guidelines recommend starting colonoscopy surveillance or screening at the age of 12-14 years, after diagnostic genetic testing has been performed in at-risk children. There are no new data to recommend any change to this recommendation of age at which to start. The risk of CRC under the age of 20 years is very small and under 15 years extremely rare. [bib_ref] Guidelines for the clinical management of familial adenomatous polyposis (FAP), Vasen [/bib_ref] In patients with FAP-related symptoms such as rectal bleeding, diarrhoea or mucous discharge should lead to a colonoscopy at any age, particularly in those with a constitutional pathogenic variant at codon 1309, which is associated with a greater risk of a more severe colonic phenotype. Colonoscopic surveillance has been shown to lead to a reduction in CRC and CRC-associated mortality. Data detailing the results of polyposis registries have shown that in symptomatic patients the incidence of CRC was 50-70% compared with 3-10% in those that were identified by registry initiated surveillance. [bib_ref] Clinical features in familial polyposis coli. Results of the Danish polyposis register, Bülow [/bib_ref] [bib_ref] Finnish Registry for familial adenomatosis coli, Järvinen [/bib_ref] [bib_ref] The value of screening and central registration of families with familial adenomatous..., Vasen [/bib_ref] Surveillance and prophylactic intervention has reduced CRC associated mortality. Colonoscopic surveillance enables assessment of adenoma burden and distribution, which can guide the timing of and type of prophylactic surgery required. Previous guidelines recommended the use of flexible sigmoidoscopy. However, most endoscopic procedures are performed under general anaesthesia in children and young teenagers; therefore a full colonoscopy is recommended in an affected patient, to better determine their phenotype, as polyp distribution is not uniform and the rectum and sigmoid may be normal despite the presence of more proximal adenomas. It is not recommended therefore for flexible sigmoidoscopy to be used routinely in screening/surveillance in FAP. Current guidelines advocate annual endoscopic assessment. There is no evidence for accelerated carcinogenesis in FAP and the rather scant data that are available do not indicate a rapid increase in polyp number in teenagers/young adults. [bib_ref] Natural history of colonic polyposis in young patients with familial adenomatous polyposis, Sarvepalli [/bib_ref] Therefore it does not seem logical to mandate an annual assessment for all affected patients, particularly given that there is significant variability in colonic phenotype. Those with an attenuated phenotype (<100 adenomas) may not require such frequent colonoscopic surveillance as those with a classical phenotype (>100 adenomas). In addition, if an individual only has adenomas of 1-2 mm their surveillance could perhaps be longer than those with larger polyps, for example, 8-9 mm. Personalising surveillance interval according to phenotype, 1-3 yearly would appear safe as long as families are not lost to follow-up and this would concord with current paediatric guidelines. [bib_ref] Management of familial adenomatous polyposis in children and adolescents: position paper from..., Hyer [/bib_ref] Extending the interval, however, should be for those with an attenuated phenotype, in the setting of good quality colonoscopy with robust systems in place to ensure appropriate recall. There are a few patients with a particularly attenuated phenotype. In this group, primary endoscopic management by surveillance and polypectomy may be considered either to defer surgery or possibly to avoid the need for surgery altogether. However, there are no robust data to support this approach. At risk patients, where predictive genetic testing is not possible, should be screened by colonoscopy every 5 years from the age of 12-14 years. If adenomas are identified, the patient should undergo repeat colonoscopy at a frequency depending on the colonic phenotype as described above. If no phenotype has been observed by the age of 50 years, FAP is unlikely and so the patient could be discharged from routine colonoscopic screening to have continued screening under the auspices of the national bowel cancer screening programme. ## Upper gi surveillance in patients affected with fap ## We recommend upper gi surveillance for fap patients starting at the age of 25 years. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 90% agreement. ## We suggest that for those considered at risk, where predictive genetic testing is not possible, screening with upper gi endoscopy is not routinely recommended but should be started if/ when a clinical diagnosis of fap is made based on colorectal phenotype. (GRADE of evidence: very low; Strength of recommendation: weak) Consensus reached: 89% agreement. Lifetime risk of duodenal polyposis approaches 100% in FAP. [bib_ref] Duodenal adenomatosis in familial adenomatous polyposis, Bulow [/bib_ref] The absolute lifetime risk of developing duodenal cancer in FAP is estimated to be around 5%. [bib_ref] Decision analysis in the management of duodenal adenomatosis in familial adenomatous polyposis, Vasen [/bib_ref] Because of this, surveillance has been recommended and survival benefit for those diagnosed with duodenal cancer by surveillance compared with those who presented symptomatically has been demonstrated. [bib_ref] Duodenal surveillance improves the prognosis after duodenal cancer in familial adenomatous polyposis, Bülow [/bib_ref] The Spigelman classification [fig_ref] Table 3: Staging the duodenum and ampulla and recommended OGD surveillance intervals [/fig_ref] is the system that is most widely used for staging non-ampullary duodenal disease 218 2; it has been shown to correlate with cancer risk [bib_ref] Duodenal cancer in patients with familial adenomatous polyposis (FAP): results of a..., Groves [/bib_ref] and is recommended to determine surveillance intervals. [bib_ref] Guidelines for the clinical management of familial adenomatous polyposis (FAP), Vasen [/bib_ref] There is debate about how to incorporate ampullary disease in this classification system. A staging system for ampullary disease has been proposed, 220 which in one series correlated to the development of ampullary cancer. [bib_ref] Features of duodenal cancer in patients with familial adenomatous polyposis, Latchford [/bib_ref] A surveillance interval determined by the combination of these staging systems may be the most helpful and reliably replicated clinical means of managing duodenal surveillance (see [fig_ref] Guidelines figure 1: Management of people with a family history of colorectal cancer [/fig_ref]. A duodenoscope is required to reliably assess and/or biopsy the periampullary region and ampulla itself. Although there are reports of chromoendoscopy increasing duodenal adenoma detection, its utility in clinical practice is not established. It may increase the number of adenomas detected but there remains no evidence that dye spray increases the pick-up of larger, more clinically meaningful lesions. [bib_ref] The impact of chromoendoscopy for surveillance of the duodenum in patients with..., Hurley [/bib_ref] There are no data to suggest that it alters the need for endoscopic or surgical intervention. The concern is that it may increase the pick-up of small lesions and may artificially "upstage" the duodenal disease but without reflecting a higher cancer risk, compared with white light endoscopy. Recent data suggest that it is polyp size and the presence of high-grade dysplasia that are the most important predictors of cancer risk, polyp multiplicity. [bib_ref] Spigelman stage IV duodenal polyposis does not precede most duodenal cancer cases..., Thiruvengadam [/bib_ref] It should be noted that the Spigelman classification system was developed and validated using white light endoscopy, without high definition. The role of endoscopic therapy in the duodenum and ampullary is not well established. It has an acceptable safety profile ; however, there are no long-term data to demonstrate it reduces cancer risk or indeed prevents or delays the need for prophylactic surgery. Nevertheless, it is widely performed in centres dealing with a large cohorts of patients with FAP. It would be most prudent for patients being considered for endoscopic therapy for duodenal disease to be referred to their local specialist centre, so that assessment and work up to decide as to the appropriateness of endoscopic and surgical intervention can be performed. The data regarding endoscopic management of ampullary disease are rather scant. However, it appears to be less safe with risk of haemorrhage, pancreatitis and perforation, morbidity rates up to 45% 225 and with high rates of recurrence, up to 58%. [bib_ref] Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous..., Ma [/bib_ref] It cannot be routinely recommended. Referral to a specialist hepato-pancreatico-biliary (HPB) centre should be made for those in whom endoscopic ampullectomy is being considered. Gastric lesions are also common in adult patients with FAP. Fundic gland polyps (FGPs) are seen in up to 80% of patients with FAP 228 and although there is some debate they are likely to be an entirely benign entity without malignant potential. Gastric adenomas are being seen more commonly, as indeed is gastric cancer. Although historically gastric cancer risk was not thought to be elevated in patients with FAP, there are reports that gastric adenomas and cancer are becoming an important clinical problem. There are no data published regarding outcomes of endoscopic therapy for gastric adenomas in FAP. Referral to a specialist centre for assessment and management seems prudent given the lack of evidence and absence of consensus guidelines. ## Congenital hypertrophy retinal pigmentation epithelium ## We suggest that patients with congenital hypertrophy retinal pigmentation epithelium (chrpe) be referred for a specialist ophthalmic review. patients with bilateral and multiple chrpe lesions should be referred for screening for fap and considered for genetic testing and colonoscopy. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 100% agreement. Up to two thirds of patients with FAP have CHRPE identified at ophthalmoscopy, [bib_ref] Genotype-phenotype correlation between position of constitutional APC gene mutation and CHRPE expression..., Wallis [/bib_ref] compared with a prevalence in the general population of 1-4%. CHRPE lesions associated with FAP are most often multiple, bilateral (in 86% of cases) and oval or pisciform in shape. Multiple retinal lesions have a very high specificity as a phenotypic marker for FAP. [bib_ref] Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome, Traboulsi [/bib_ref] Referral for a specialist ophthalmic review will assist in characterising those with lesions which need to be considered for screening for FAP. Such patients should be referred to a specialist centre for consideration of screening for FAP by genetic testing and thereafter colonoscopy, age 12-14 years, or at time of diagnosis if diagnosed at an older age. ## Fap and surgery ## We recommend that for patients with fap who are undergoing colonoscopic surveillance, relative indications for surgery are polyps >10 mm in diameter, high grade dysplasia within polyps and a significant increase in polyp burden between screening examinations. (GRADE of evidence: low; Strength of recommendation: strong) Consensus reached: 82% agreement. For most patients the choice of surgery will be between total colectomy with ileorectal anastomosis (IRA) and proctocolectomy and ileal pouch anal anastomosis (IPAA). The choice of surgery will depend on rectal polyp number, size and presence of high-grade dysplasia, genotype and the functional consequences of the surgical procedure. IPAA should also be considered Guidelines for those patients who are likely to be poorly compliant with follow-up surveillance. Total proctocolectomy with end ileostomy can be considered for patients with poor sphincter function, incontinence, distal rectal cancer, cancers requiring radiation, or for those who desire to avoid the functional consequences of an ileoanal pouch. In patients with FAP, colon cancer will inevitably develop if the colon is not removed. Total colectomy will prevent colon cancer in FAP patients. Prophylactic surgery can usually be planned at a time which is suitable to the patient, based on the risk of cancer as assessed colonoscopically. The timing and choice of surgical procedure should take into account the educational, social, family planning and emotional development of the patient and their reliability for attending follow-up evaluations. Indications for surgery include polyps >10 mm diameter, polyps with high-grade dysplasia, and marked increases in polyp number between examinations. Symptoms from polyps should be rare in those undergoing regular screening and surgery should be performed before symptoms from polyps develop. Total colectomy with ileorectal anastomosis (TAC-IRA) can be offered to patients with relative rectal sparing (<20 polyps) if all rectal adenomas are <5 mm in diameter and any polyps >5 mm can be endoscopically removed. However, flexibility with regard to a threshold polyp number should be employed with the advent of high-definition or chromo-endoscopic techniques. The decision to retain the rectum is made based on future rectal cancer risk, polyposis phenotype in the rectum, functional considerations and the genotype. Bülow et al evaluated 776 patients who had IRA, including 576 before the ileoanal pouch era, and 200 after the ileoanal pouch became available in these centres. [bib_ref] Colectomy and ileorectal anastomosis is still an option for selected patients with..., Bülow [/bib_ref] The cumulative risk of rectal cancer by Kaplan-Meier analysis was 10% in the prepouch era versus 2% in the pouch era. A cohort study from Church et al of 213 patients with FAP included 165 patients who had rectal-sparing surgery, with 128 of these having <20 polyps and 37 having >20 polyps. [bib_ref] Risk of rectal cancer in patients after colectomy and ileorectal anastomosis for..., Church [/bib_ref] The rectal cancer incidence was 1.6% in the patients with <20 polyps, compared with 10.8% in the patients with >20 polyps. Predicting future rectal excision may also aid decision making about choice of surgery. A study from St Marks hospital of 427 patients who underwent IRA found that by the age of 60 years, half of the patients retained their rectum. Rectal polyp count exceeding 20, APC pathogenic variant codon 1250-1450, colonic polyp count ≥500 and age <25 years at the time of surgery were independent predictors of progressive rectal disease. [bib_ref] Risk factors for secondary proctectomy in patients with familial adenomatous polyposis, Sinha [/bib_ref] Church et al also found rectal polyp count >20 to predict future rectal excision. [bib_ref] Predicting polyposis severity by proctoscopy: how reliable is it?, Church [/bib_ref] Genotype can also be utilised specifically when discussing surgical options. A study of four national polyposis registries included 475 polyposis patients with a previous colectomy. Cumulative risks of secondary proctectomy 20 years after primary colectomy were 10%, 39% and 61% in the attenuated, intermediate and severe genotype groups, respectively (p<0.05, groups compared separately). [bib_ref] Genotype predicting phenotype in familial adenomatous polyposis: a practical application to the..., Nieuwenhuis [/bib_ref] Patients with a severe genotype have a high-risk of rectal excision after primary colectomy and may be better directed to proctocolectomy with IPAA. Influence of genotype on survival has also been reported by Newton et al. [bib_ref] Genotype-phenotype correlation in colorectal polyposis, Newton [/bib_ref] For patients undergoing IRA, 1-3 flexible sigmoidoscopies are required as per FAP patients with intact colons. There have been no randomised trials comparing the functional outcome of IRA versus IPAA. The study by Aziz et al provides a fair summary of the literature. [bib_ref] Meta-analysis of observational studies of ileorectal versus ileal pouch-anal anastomosis for familial..., Aziz [/bib_ref] They performed a meta-analysis on 12 non-randomized studies published between 1991 and 2003 and containing over 1000 patients (47% IRA vs 53% IPAA). Bowel frequency, nocturnal defaecation and use of incontinence pads were significantly less in the ileorectal group, although faecal urgency was reduced with the ileal pouch. There was no significant difference between the techniques in terms of sexual dysfunction, dietary restriction or postoperative complications. The fecundity of women with FAP before operation and after colectomy with ileorectal anastomosis has been reported to be similar to that of the general population. However, fecundity dropped to 54 per cent following proctocolectomy with ileal pouch-anal anastomosis. It is recommended that the significant reduction in female fecundity after IPAA should be communicated to young women with FAP before surgery. [bib_ref] Female fecundity before and after operation for familial adenomatous polyposis, Kø O [/bib_ref] The risk of developing postoperative fertility problems is not associated significantly with the type of surgery, indication for surgery, complications or other comorbid conditions. Postoperative fertility problems appear to be more common among women who had their first surgical procedure at a younger age. [bib_ref] Female fertility after colorectal surgery for familial adenomatous polyposis: a nationwide cross-sectional..., Nieuwenhuis [/bib_ref] Indications for rectal excision following IRA include: the development of rectal cancer, polyps >10 mm diameter, polyps with high-grade dysplasia, and marked increases in polyp number between examinations. When conversion of an IRA to IPAA is required, functional outcomes appear similar to primary IPAA procedures. Complication rates and pouch failure rates are reported to be similar, but conversion to IPAA will not be possible in a small percentage of patients. [bib_ref] Comparison of outcomes of ileal pouchanal anastomosis for familial adenomatous polyposis with..., Von Roon [/bib_ref] Proctocolectomy with IPAA is the treatment of choice in the presence of: rectal cancer, a large rectal polyp burden (>20 synchronous adenomas, adenoma with high-grade dysplasia, large (>10 mm) adenomas) or a severe phenotype (>1000 synchronous adenomas). ## Risk of neoplasia and cancer in the pouch There is a very small risk of adenocarcinoma after an IPAA. Most cancers develop in residual rectal or in the anal transitional zone (ATZ) mucosa. Cancer can also develop within the ileal component of the pouch. Currently nearly all pouches are constructed with the use of stapling devices which results in the ATZ mucosa being preserved. Von Roon reported on 206 patients with a median follow-up of 10.3 years. [bib_ref] Mucosectomy with handsewn anastomosis reduces the risk of adenoma formation in the..., Von Roon [/bib_ref] The risk of adenoma of the IPAA at 10 years was 51% after stapled IPAA; no patient developed cancer. van Duijvendijk et al reported the risk of developing a polyp of the IPAA after 7 years was 31% after stapled IPAA. [bib_ref] Cumulative risk of developing polyps or malignancy at the ileal pouch-anal anastomosis..., Van Duijvendijk [/bib_ref] Of 212 patients followed up in the Dutch polyposis registry, the cumulative risk of developing an adenoma in the pouch at 10 year follow-up was 45%. Twenty-five patients (11.8%) developed an adenoma with advanced pathology and four (1.9%) developed a carcinoma. The cumulative risk of developing a pouch carcinoma at 10 year follow-up was 1%. [bib_ref] Risk of developing adenomas and carcinomas in the ileal pouch in patients..., Friederich [/bib_ref] A 2013 review of 24 studies reporting 92 pouch-related cancers found that 23 of 92 cancers (25%) developed in the pouch mucosa and 69 (75%) in the ATZ. [bib_ref] Adenocarcinomas after prophylactic surgery for familial adenomatous polyposis, Smith [/bib_ref] A Mayo clinic study on 117 patients showed a median time to development of dysplasia was 149 months. Adenocarcinoma developed in one patient after 284 months. Risk of dysplasia at 10, 20 and 25 years was 17%, 45% and 69%, respectively. [bib_ref] Risk of neoplastic change in ileal pouches in familial adenomatous polyposis, Boostrom [/bib_ref] Thus, although the risk of severe mucosal dysplasia and cancer is low, annual endoscopic surveillance of any remaining rectal mucosa, ATZ mucosa and ileal pouch are recommended for life. ## Fap and desmoid disease We suggest that FAP patients should be counselled about the risk of post-operative desmoid disease formation. In individuals with APC pathogenic variants in the desmoid region 3' to codon 1399, abdominal surgery was associated with a 65% risk of developing mesenteric desmoids. [bib_ref] Desmoid tumours in patients with familial adenomatous polyposis and desmoid region adenomatous..., Speake [/bib_ref] As desmoids can cause significant complications and pose a low risk of death, genotypes predictive of desmoid formation and family history of desmoids should be determined for all patients before colectomy. Identification of at-risk patients will enable appropriate counselling and consent before surgery and allow informed decision about the timing of surgery. This decision should sensibly balance the risk of malignancy with the risk of mesenteric desmoid disease. Some desmoid tumours spontaneously stop growing, some regress and others remorselessly increase in size. In a small proportion, this increase may be rapid and uncontrollable. There are no proven predictors of growth pattern. The distinction between intra-and extra-abdominal desmoids is important. Abdominal wall desmoids cause pain (variable) and mass effect. Intra-abdominal lesions, in addition, are at risk of causing secondary effects: ureteric and small bowel obstruction, fistula formation or small bowel ischaemia. The quality of data on which to make decisions about treatment of abdominal wall and intra-abdominal desmoid disease is limited and largely consists of small, non-controlled studies. As such, the treatment of patients with desmoid tumours remains controversial. For abdominal wall lesions, there is an expanding role of percutaneous ablative treatments and in some institutions ablation has become the primary treatment. [bib_ref] Expanding role of percutaneous ablative and consolidative treatments for musculoskeletal tumours, Kurup [/bib_ref] Church et al 251 combined symptoms (pain, restriction, hospitalisation and sensation of a mass) with size and growth rate in a proposed staging system for intra-abdominal desmoid disease. Decisions about treatment are partly based on size and symptoms, but are more often determined by secondary effects of the desmoid on the urinary and GI tract. Following diagnosis, if no secondary effects are present, serial imaging with CT or MRI scanning every 6-12 months depending on growth rate is reasonable. Radiological screening at 12 months following surgery for those who are at high-risk of desmoid development might be appropriate. If there is concern about the size or growth rate of desmoid disease, first line treatment should be with high-dose selective oestrogen receptor modulators and sulindac, according to the regime outlined by Quast et al. [bib_ref] Long-term outcome of sporadic and FAP-associated desmoid tumors treated with high-dose selective..., Quast [/bib_ref] In this observational series all desmoid patients treated and followed at their institution had completed at least 1 year of treatment. [bib_ref] Long-term outcome of sporadic and FAP-associated desmoid tumors treated with high-dose selective..., Quast [/bib_ref] Response was defined as stable size or regression of desmoid size between two CT or MRI scans. Of the 134 patients included, half had a confirmed diagnosis of FAP. Eighty-five per cent of patients showed regression or had stable desmoid size. The mean time to reach at least stable size was 14.9±9.1 months. After regression or stabilisation, medication was tapered in 60% of the treated patients with only one long-term recurrence after >10 years. In patients with progressive intra-abdominal desmoid disease that does not respond to this treatment, chemotherapy (eg, doxorubicine and dacarbazine or methotrexate and vinblastine) or radiation therapy is indicated. Surgery should be reserved for secondary effects of the desmoid disease. ## Mutyh-associated polyposis colorectal surveillance in map ## We recommend that colorectal surveillance is commenced in map starting at the age of 18-20 years. if surgery is not undertaken then annual surveillance is suggested. ( MAP is a recessively inherited cancer and polyposis predisposition syndrome caused by pathogenic variants in the MUTYH base-excision repair gene, with significant phenotypic overlap with FAP. It is classically said to be associated with a more attenuated phenotype than FAP but there is significant phenotypic variation. Past guidelines have suggested that colonoscopy should commence at the age of 18-20 years, on the basis that CRC in MAP is rare below the age of 30 years 207 and be performed up to 2 yearly, as the colonic phenotype is usually more attenuated. This attenuated phenotype also lead the authors to comment that endoscopic management may suffice if there is an attenuated phenotype. CRC in MAP is more likely to be right sided and synchronous. A cumulative CRC risk of 63% at 60 years has been reported. [bib_ref] Evidence for accelerated colorectal adenoma-carcinoma progression in MUTYH-associated polyposis?, Nieuwenhuis [/bib_ref] The median age of CRC seems dependent on the underlying genotype. [bib_ref] Clinical Implications of the colorectal cancer risk associated with MUTYH mutation, Lubbe [/bib_ref] MAP accounts for up to 29% of those patients with 10-100 adenomas but also up to 29% of those with a classical phenotype (100-1000 adenomas). Biallelic pathogenic variants have also been reported in patients with <10 adenomas and also in patients with CRC but no adenomas. [bib_ref] Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer..., Croitoru [/bib_ref] [bib_ref] Germline susceptibility to colorectal cancer due to base-excision repair gene defects, Farrington [/bib_ref] [bib_ref] Contribution of bi-allelic germline MUTYH mutations to early-onset and familial colorectal cancer..., Knopperts [/bib_ref] There are further data to suggest that CRC risk in MAP may not correlate to adenoma number. [bib_ref] Evidence for accelerated colorectal adenoma-carcinoma progression in MUTYH-associated polyposis?, Nieuwenhuis [/bib_ref] Colonoscopy surveillance may not be effective in MAP and it has been postulated that there may be accelerated carcinogenesis. Nieuwenhuis and colleagues reported that of those who presented with a polyposis phenotype but without CRC, 9% Guidelines developed CRC during 5 years of surveillance. If the presentation was with CRC, then they observed a 5 year metachronous cancer risk of 11%. [bib_ref] Evidence for accelerated colorectal adenoma-carcinoma progression in MUTYH-associated polyposis?, Nieuwenhuis [/bib_ref] In light of these data, annual colonoscopy would appear appropriate if colonoscopy surveillance is pursued, but it appears that surgery may be the more appropriate management strategy, balanced against age, co-morbidity and expected functional outcome. ## Upper gi surveillance in patients affected with map We suggest that upper GI surveillance should be considered in MAP, starting at the age of 35 years. We recommend that the surveillance interval is determined as outlined for FAP. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 94% agreement. The data regarding the upper GI tract phenotype in MAP is far less extensive than in FAP. It is generally suggested that the two conditions should be managed in a similar manner. Duodenal adenomas have been reported in 17-34% of those with MAP. The median age at which duodenal adenomas are diagnosed has been reported as 50 years. [bib_ref] Frequency and features of duodenal adenomas in patients with MUTYH-associated polyposis, Walton [/bib_ref] The lifetime risk of developing duodenal cancer is estimated to be around 4%. [bib_ref] Expanded extracolonic tumor spectrum in MUTYH-associated polyposis, Vogt [/bib_ref] Two patients were diagnosed with duodenal or ampullary cancer in one series, age 83 and 63 years, respectively; both were diagnosed at index upper GI endoscopy but no cancer arose in patients who were on a surveillance programme. [bib_ref] Frequency and features of duodenal adenomas in patients with MUTYH-associated polyposis, Walton [/bib_ref] Polyps appear to progress through the development of villous features and increasing size in this series, rather than progression in number or dysplasia. [bib_ref] Frequency and features of duodenal adenomas in patients with MUTYH-associated polyposis, Walton [/bib_ref] Certainly the phenotype does appear to be different and polyp multiplicity in MAP does not seem to be observed in the same manner as it is in FAP. There appears to be scientific evidence to suggest that MAP duodenal polyps may behave differently to those in FAP. A higher burden of somatic pathogenic variants in MAP duodenal adenomas is reported, compared with FAP, despite a lower Spigelman stage disease. It is postulated that this may reflect an increased cancer risk in the context of apparently less severe benign disease 264 ; however, long-term data to support this hypothesis are lacking. Because of the reduced frequency of duodenal adenomas, compared with FAP and the later onset of duodenal adenomas, it has been suggested that starting upper GI endoscopic surveillance could be deferred until the age of 35 years. [bib_ref] Frequency and features of duodenal adenomas in patients with MUTYH-associated polyposis, Walton [/bib_ref] In the absence of more robust data, determining surveillance intervals according to duodenal and ampullary staging, as has been recommended in FAP, appears to be a pragmatic approach. There are few data regarding gastric lesions in MAP. FGPs have been reported in 6% of a cohort with MAP and gastric adenomas in 3%. [bib_ref] Expanded extracolonic tumor spectrum in MUTYH-associated polyposis, Vogt [/bib_ref] This would suggest that gastric polyposis is seen less commonly than in FAP. In the same series gastric cancer was observed but the incidence was not statistically different to the risk for the general population. Further data regarding the gastric phenotype are required to determine risk and how best to manage such lesions. ## Peutz-jeghers syndrome PJS is an autosomal dominant genetic disorder characterised by the development of benign hamartomatous polyps in the GI tract and hyperpigmented macules on the lips and oral mucosa (which fade with age). The prevalence of PJS is between 1/8300 and 1/29 000 and most patients have pathogenic variants in the STK11 (also called LKB1) gene. Diagnostic criteria [bib_ref] Management of Peutz-Jeghers syndrome in children and adolescents: a position paper from..., Latchford [/bib_ref] : A diagnosis of PJS in an individual may be made when any one of the following is present: ► Two or more histologically confirmed PJ polyps ► Any number of PJ polyps detected in one individual who has a family history of PJS in a close relative ► Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in a close relative ► Any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation ► A pathogenic variant in STK11. ## The risk of gi tract cancer in pjs GI tract carcinogenesis in PJS is controversial. The malignant potential of the PJS polyp is unclear. A hamartoma-adenomacarcinoma sequence has been proposed but robust supporting data are lacking. There are data suggesting that the PJS polyp is non-neoplastic, including descriptions of polyclonality and the rarity of dysplasia in PJS polyps. [bib_ref] Peutz-Jeghers syndrome: intriguing suggestion of gastrointestinal cancer prevention from surveillance, Latchford [/bib_ref] It is widely accepted that there is an increased risk of malignancy in PJS. However, the risk is difficult to quantify, with the majority of the literature being small cohort studies with inherent bias, potentially leading to overestimation of risk. A metaanalysis has been performed by Hearle et al creating a cohort of 419 patients with PJS. [bib_ref] Frequency and spectrum of cancers in the Peutz-Jeghers syndrome, Hearle [/bib_ref] This offers the most comprehensive data for cancer risk with a luminal GI cancer risk of 1%, 9%, 15%, 33% and 57% at 30, 40, 50, 60 and 70 years, respectively. More recent data, although from a smaller cohort, support the proposition that GI cancers are less of a clinical problem and that pancreatic and breast cancers are the most commonly diagnosed malignancies in PJS. [bib_ref] Peutz-Jeghers syndrome: intriguing suggestion of gastrointestinal cancer prevention from surveillance, Latchford [/bib_ref] ## Gi surveillance and pjs ## We suggest that in an asymptomatic patient with pjs, gi surveillance by upper gi endoscopy, colonoscopy and vce commence at the age of 8 years. we recommend that small bowel surveillance should continue 3 yearly. if baseline colonoscopy and ogd are normal, then they can be safely deferred until the age of 18 years; however, if polyps are found at baseline examination, then they should be repeated 3 yearly. earlier investigation of the gi tract should be performed in symptomatic patients. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 82% agreement. Small bowel polyps resulting in intussusception is the major clinical problem affecting children with PJS. The cumulative intussusception risk is estimated at 50-68% during childhood, with 15-30% requiring surgery before the age of 10 years with a median age of the first intussusception of 10-16 years. These data include patients who preceded routine small bowel surveillance. They also combine patients with an established diagnosis of PJS undergoing surveillance, with those not under surveillance in whom the diagnosis of PJS was made at presentation with an intussusception. The recommendation to start small bowel surveillance at the age of 8 years, and earlier if symptomatic, is based on these data. [bib_ref] Peutz-Jeghers syndrome: a systematic review and recommendations for management, Beggs [/bib_ref] Gastroscopy and colonoscopy are the preferred investigation to assess the upper GI tract and colon, respectively. Barium follow through has been replaced by VCE and MRI enterography, both of which are better tolerated by patients, have a similar accuracy in detecting clinically significant polyps (>1 cm) and avoid the need for repeated ionising radiation. [bib_ref] A prospective trial comparing wireless capsule endoscopy and barium contrast series for..., Mata [/bib_ref] [bib_ref] Radiological work-up in Peutz-Jeghers syndrome, Kurugoglu [/bib_ref] [bib_ref] Video capsule endoscopy in Peutz-Jeghers syndrome: a blinded comparison with barium follow-through..., Brown [/bib_ref] [bib_ref] Comparison of capsule endoscopy and magnetic resonance imaging for the detection of..., Caspari [/bib_ref] [bib_ref] Surveillance of patients affected by Peutz-Jeghers syndrome: diagnostic value of MR enterography..., Maccioni [/bib_ref] [bib_ref] A prospective study of MR enterography versus capsule endoscopy for the surveillance..., Gupta [/bib_ref] VCE and MR enterography may be complimentary. While VCE may be better at detecting smaller polyps, MRI enterography is better at localisation and accurate sizing. Double balloon enteroscopy (DBE) should not recommended as a surveillance tool as it is technically challenging, limited by size of the abdomen and requires both oral and rectal approaches; therefore a general anaesthetic is required to reliably visualise the whole length of the small bowel. The main role of DBE is therapeutic, for targeted polypectomy. ## Role of endoscopic polypectomy in pjs ## We suggest elective polypectomy to prevent polyp related complications. small bowel polyps >1.5-2 cm in size (or smaller if symptomatic) should be considered for elective resection to prevent intussusception. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 88% agreement. Polypectomy at surveillance is recommended in PJS. It is not clear whether this approach modifies cancer risk and indeed, given the lack of dysplasia in PJS polyps, it is unlikely to do so. The main role for polypectomy therefore is to prevent polyp-related complications. Prevention of anaemia and bleeding, however, is difficult to quantify and there are no data regarding this. Intussusception is the most important clinical problem in children with PJS, with an accumulative risk of 50-68% in childhood. Existing guidelines suggest intervening in small bowel polyps which are 1.5-2 cm, earlier if symptomatic. [bib_ref] Peutz-Jeghers syndrome: a systematic review and recommendations for management, Beggs [/bib_ref] This is supported by data which report a median polyp size of 35 mm (15-60 mm) in cases of confirmed intussusception. [bib_ref] High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to..., Van Lier [/bib_ref] In addition, in a cohort in whom routine surveillance was performed, with intervention planned as outlined above, no patient required emergency surgery for intussusception during 683 patient-years follow-up. [bib_ref] Peutz-Jeghers syndrome: intriguing suggestion of gastrointestinal cancer prevention from surveillance, Latchford [/bib_ref] Options to remove a PJS polyp include endoscopy, surgery or combined approaches. There are no data to state that one modality is superior to another and choice will be dependent on patient (eg, age, past abdominal surgery), polyp factors (size, location and multiplicity) and local availability of techniques. For those who undergo surgery for small bowel polyps, intraoperative enteroscopy and a "clean sweep" is recommended and has been demonstrated to reduce the need for subsequent laparotomy. [bib_ref] Benefits of 'clean sweep' in Peutz-Jeghers patients, Oncel [/bib_ref] Polyp clearance by intraoperative enteroscopy in the PJS may be effective in the long term. juveniLe POLyPOsis syndrOme JPS is an autosomal dominant condition characterised by predisposition to hamartomatous polyps in the GI tract. The prevalence is between 1/100 000 and 1/160 000, with the following diagnostic criteria [bib_ref] Management of juvenile polyposis syndrome in children and adolescents, Cohen [/bib_ref] : ► >5 juvenile polyps in the colon or rectum ► Juvenile polyps in other parts of the GI tract ► Any number of juvenile polyps and a positive family history ► A pathogenic variant in SMAD4 or BMPR1A. About 40% of families have mutations in SMAD4 and a further 40% in BMPR1A. Some patients have large chromosomal deletions encompassing both PTEN and BMPR1A genes. There is a requirement to develop an evidence base for the personalised management of JPS-related cancers, which is beyond the scope of this guideline. ## Jps and colorectal surveillance We suggest colonoscopic surveillance should commence from the age of 15 years or earlier if symptomatic. The surveillance interval should be 1-3 yearly, personalised according to colorectal phenotype. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 85% agreement. The polyps in JPS are thought to have the potential for malignant transformation with dysplasia present in 8% of resected polyps in one series. [bib_ref] Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome, Latchford [/bib_ref] The risk of CRC is ill-defined, being based on small series, with inherent bias. Such cohorts have reported CRC in 14-22% of patients with a reported lifetime CRC risk of 39-68%. [bib_ref] Juvenile polyposis--a precancerous condition, Jass [/bib_ref] 282 CRC in childhood is not a clinically significant problem. The mean age of CRC in two of the larger studies was 44 years. The risk of CRC is undoubtedly elevated, and the current consensus is that colonoscopic surveillance is required, with the aim of preventing or detecting early cancers. Colonoscopy and polypectomy also has the potential to prevent polyp-related morbidity (bleeding, anaemia or abdominal pain). There are few data regarding the outcomes of surveillance in JPS. In one of the largest cohorts, colonoscopy was safe. Two patients developed CRC on surveillance-one in the setting of carpeting of polyps, and the other arose following what was almost certainly an incomplete colonoscopy in the mid 1970s. [bib_ref] Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome, Latchford [/bib_ref] For those with a confirmed genetic diagnosis of JPS, or individuals with a clinical diagnosis of JPS in whom molecular genetic test results were uninformative, colonoscopic surveillance can be delayed until the age of 15 years if asymptomatic. There are no data to guide the most appropriate interval for colonoscopy surveillance in JPS. There are no data to support accelerated carcinogenesis in JPS. A personalised approach with the surveillance interval (1-3 yearly) based on individual colonic phenotype appears to be a pragmatic approach and is in line with recent paediatric polyposis guidelines. [bib_ref] Management of juvenile polyposis syndrome in children and adolescents, Cohen [/bib_ref] Colonic resection may be considered for those with a polyp burden not manageable endoscopically. For those unaffected individuals from families with a clinical but not molecular diagnosis, 5 yearly colonoscopy would seem adequate. If normal, the interval to be reviewed if a JPS phenotype is found or other sporadic polyps are identified. ## Upper gi surveillance and jps ## We suggest that for those with a confirmed clinical or genetic diagnosis, upper gi endoscopic surveillance should start at the age of 18 years for smad4 pathogenic variant carriers and the age of 25 years for bmpr1a pathogenic variant carriers and those without an identified mutation. the surveillance interval should be 1-3 yearly, personalised according to upper gi tract phenotype. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 83% agreement. ## We suggest that for those with an fdr with a clinical diagnosis of jps and in whom a mutation has not been identified, screening of the upper gi tract is not required routinely but should be initiated if/when a clinical diagnosis is made on the basis of colonic phenotype. it may however be considered if there is a family history suggestive of hereditary haemorrhagic telangiectasia (hht), even in the absence of colonic polyps. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 83% agreement. Upper GI endoscopy is not required in those unaffected individuals in whom the diagnosis in the family is clinical without a confirmed molecular diagnosis. It is clear that the colon is the site most likely to be affected in JPS and therefore any upper GI tract assessment can be deferred until a colonic phenotype of JPS has been established in that individual. There is a paucity of data evaluating the upper tract in JPS. Historical series report the incidence of gastric polyps between 65% and 83% and duodenal polyps between 14% and 33%. More recently, 28/41 patients had neither macroscopic nor microscopic features of upper GI tract polyps and 13/41 had confirmed histological upper GI tract involvement at a median age of 33 years. [bib_ref] Upper tract juvenile polyps in juvenile polyposis patients: dysplasia and malignancy are..., Ma [/bib_ref] In this cohort five patients underwent Guidelines OGD before the age of 15 years and three had changes consistent with JPS, but none had dysplasia. In another series, gastroduodenal polyps were seen in 37%; in this cohort none of the six patients who had upper GI endoscopy before the age of 18 years had gastroduodenal polyps. [bib_ref] Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome, Latchford [/bib_ref] Due to limited data, it is difficult to determine the exact lifetime risk of gastric cancer in JPS. There were two gastric cancers in a cohort of 44 patients with JPS (median age 56 years) [bib_ref] Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome, Latchford [/bib_ref] and a further two (age not specified) in a cohort of 56 patients who appear to have been mostly JPS but some of whom had phenotypic features overlapping with Cowden syndrome. [bib_ref] Analysis of genetic and phenotypic heterogeneity in juvenile polyposis, Woodford-Richens [/bib_ref] In another series, 3/42 patients had either high grade dysplasia or cancer in the stomach [bib_ref] Upper tract juvenile polyps in juvenile polyposis patients: dysplasia and malignancy are..., Ma [/bib_ref] and a further two patients had prophylactic gastrectomy for benign gastric polyp burden. The risk of severe gastric polyposis and gastric cancer phenotype appears to be increased in patients with SMAD4 pathogenic variants. All patients with advanced gastric polyposis were SMAD4 pathogenic variant carriers in one cohort. Aretz et al reported a significantly higher risk of gastric polyposis in SMAD4 pathogenic variant carriers (73% vs 8%; p<0.001) and again all cases of gastric cancer in this cohort occurred in patients with SMAD4 pathogenic variants. [bib_ref] High proportion of large genomic deletions and a genotype phenotype update in..., Aretz [/bib_ref] Current published guidelines for the age at which to start upper GI surveillance ranges from 12 years 261 to 25 years of age. [bib_ref] Guidelines for colorectal cancer screening and surveillance in moderate and high risk..., Cairns [/bib_ref] Given the emerging genotype-phenotype association and the lack of significant pathology being found in childhood, it is recommended that those with a SMAD4 mutation undergo upper GI tract surveillance 1-3 yearly from the age of 18 years, and those with a BMPR1A mutation from 25 years of age. ## Additional investigations required in patients with a smad4 mutation ## We suggest that patients with a smad4 pathogenic variant should be evaluated for haemorrhagic telangiectasia (hht), and that those at risk of, or with a confirmed diagnosis of hht are best managed in conjunction with a specialist hht centre. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 90% agreement. The coexistence of JPS and HHT was reported early in the 1980s. [bib_ref] Generalized juvenile polyposis with pulmonary arteriovenous malformations and hypertrophic osteoarthropathy, Baert [/bib_ref] It is now recognised that this is due to SMAD4 mutations. Up to 76% of patients with JPS due to SMAD4 mutations have features of HHT. [bib_ref] Appreciating the broad clinical features of Smad4 mutation carriers: a multicenter chart..., Wain [/bib_ref] Thoracic aortic disease and mitral valve dysfunction have also been reported. Aortopathy has been described in 38% of patients with a SMAD4 mutation, irrespective of the JPS phenotype. [bib_ref] Prevalence of thoracic aortopathy in patients with juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia..., Heald [/bib_ref] Patients may lack overt clinical symptoms of HHT but are at risk of asymptomatic arteriovenous malformation (AVMs) which can result in life threatening complications. Patients with a SMAD4 pathogenic variant are probably best managed in conjunction with a specialist centre with experience in evaluating and managing HHT patients. The recent British Thoracic Society guidelines on pulmonary AVMs may act as a useful resource. [bib_ref] British Thoracic Society clinical statement on pulmonary arteriovenous malformations, Shovlin [/bib_ref] PTEN-hamartoma syndrome overlap and additional investigations indicated in a patient with microdeletions involving BMPR1A ## Patients with jps and a microdeletion involving bmpr1a and pten are at risk of the clinical manifestations of both jps and pten-hamartoma tumour syndrome (phts). we suggest that they should be referred to their local genetics centre for further advice and to coordinate their surveillance needs. (GRADE of evidence: low; Strength of recommendation: weak) Consensus reached: 89% agreement. PHTS encompasses four major clinically distinct syndromes associated with constitutional pathogenic variants in the tumour suppressor PTEN. These are associated with macrocephaly, dysmorphism, developmental delay and an increased risk of extra-intestinal cancers and possibly intestinal cancers. BMPR1A is located in the same chromosomal region as PTEN and deletions involving both genes have been reported. Microdeletions involving both genes have important clinical implications. There are numerous case reports suggesting that if the pathogenic variant (microdeletion) is found in both genes, these patients may present with a severe form of JPS with onset in early childhood and may also have an increased risk of the extra-intestinal manifestations of PHTS. [bib_ref] Variable phenotypes associated with 10q23 microdeletions involving the PTEN and BMPR1A genes, Menko [/bib_ref] [bib_ref] Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis..., Delnatte [/bib_ref] [bib_ref] Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23, Dahdaleh [/bib_ref] [fig] Guidelines figure 1: Management of people with a family history of colorectal cancer. BSG, British Society of Gastroenterology; CRC, colorectal cancer; FHCC, family history of colorectal cancer; FDR, first degree relative; MMR, mismatch repair. [/fig] [fig] Guidelines figure 3: Management of Lynch-like syndrome. CRC, colorectal cancer; FDRs, first degree relatives; FHCC, family history of colorectal cancer, MMR, mismatch repair. [/fig] [fig] ►: At least 5 serrated lesions/polyps proximal to the rectum all being ≥ 5 mm in size, with 2 or more ≥ 10 mm in size Criterion 2 More than 20 serrated lesions/polyps of any size distributed throughout the large bowel, with at least 5 proximal to the rectum Any histological subtype of serrated lesion/polyp (hyperplastic polyp, sessile serrated lesion without or with dysplasia, traditional serrated adenoma, and unclassified serrated adenoma) is included in the final polyp count. The polyp count is cumulative over multiple colonoscopies diagnosis [/fig] [table] Table 1: Summary of surveillance recommendations Amsterdam criteria families where MMR testing is not possible may be offered surveillance as per Lynch syndrome families and/or additional constitutional testing. CRC, colorectal cancer; FDR, first degree relative; MMR, mismatch repair. We recommend that patients with a moderate familial CRC risk should have a one-off colonoscopy at age 55 years. [/table] [table] Table 2: Molecular testing strategies in hereditary colorectal cancer (CRC) We suggest that in high-risk families (a cluster of 3× FDRs with CRC across >1 generation) a 5 yearly colonoscopy should be performed from age 40 years until age 75 years. (GRADE of evidence: moderate; Strength of recommendation: weak) Prevention and lifestyle modification in familial CrC ► We recommend that individuals with LS should be advised that regular use of daily aspirin reduces CRC risk. (GRADE of evidence: moderate; Strength of recommendation: strong) ► We suggest that people with LS should be offered research opportunities to take aspirin daily at different dosages. If they decline research participation they may be advised on their choices regarding dose of aspirin, risks and benefits of long-term aspirin use and ensure their medical practitioner is aware of their intake. (GRADE of evidence: low; Strength of recommendation: weak) ► There is insufficient evidence of the benefit of chemo-We suggest high-quality, high-definition white light endoscopy as the preferred modality for colonoscopy surveillance. Chromoendoscopy (virtual or dye-based) does not offer a clear advantage over high definition white light examination for colonoscopic surveillance, apart from in the context of determining the multiple polyp phenotype. (GRADE of evidence: moderate; Strength of recommendation: weak) ► We suggest a repeat colonoscopy performed by an expert endoscopist is indicated in the event of a previously failed colonoscopy, with efforts made to both improve patient experience and to ensure procedure completion, given the advantages of colonoscopic surveillance. If colonoscopy is not possible then consider CT colonography. (GRADE of evidence: low; Strength of recommendation: weak) ► We suggest that if the bowel preparation for colonoscopy is inadequate or if the examination is incomplete then a repeat colorectal surveillance procedure should be arranged within 3 months. (GRADE of evidence: low; Strength of recommendation: weak) ► There is insufficient evidence to recommend other methods of surveillance for those with familial CRC risk such as FIT We suggest that for LS patients with MLH1 or MSH2 mutations who develop colon cancer or colonic neoplasia not amenable to endoscopic control, the decision to perform segmental versus total/near total colectomy should balance the risks of metachronous cancer, the functional consequences of surgery, the patient's age and patient's wishes. We recommend screening for Helicobacter pylori in patients with LS and subsequent eradication therapy if indicated. (GRADE of evidence: low; Strength of recommendation: strong) We recommend that if double somatic MMR pathogenic variants are identified, manage proband and their FDRs based on the FHCC. (GRADE of evidence: low; Strength of recommendation: strong) ► We suggest that if no or one somatic mutations are identified, the proband and their FDRs should be managed as per LS. (GRADE of evidence: low; Strength of recommendation: weak) We recommend all FDRs of patients with SPS on the basis of the new WHO 2019 SPS criteria, one or two should be offered an index colonoscopic screening examination at age 40 years or 10 years before the diagnosis of the index case. (GRADE of evidence: moderate; Strength of recommendation: strong) ► We suggest all FDRs of SPS patients have a surveillance exam-We suggest that for those considered at risk, where predictive genetic testing is not possible, screening with upper GI endoscopy is not routinely recommended but should be started if/when a clinical diagnosis of FAP is made based on colorectal phenotype. (GRADE of evidence: very low; Strength of recommendation: weak) ► We suggest that patients with congenital hypertrophy [/table] [table] 67: of 193; 23 LS, 22 pathogenic variant-negative LS, 16 FAP, two constitutional MMR deficiency (CMMRD), two MAP, and one Li-Fraumeni syndrome). LS (23.3%; including patients with unexplained MMR deficiency, variants of uncertain significance, and incomplete LS investigations) and FAP (8.3%) were the most commonly identified CRC syndromes 173 In a prospective cohort, panel testing of 25 cancer predisposition genes (APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53) was performed in 450 patients diagnosed with early-onset CRC (aged <50). Forty-eight patients (10.7%) had dMMR tumours and 402 (89.3%) had pMMR tumours. Sixteen percent of patients (72 of 450) were found to have a pathogenic variant in at least one cancer predisposition gene. 172 Of the 48 patients with dMMR tumours, 40 patients (83.3%) had at least one constitutional pathogenic variant: 37 patient had LS (13 MLH1, 16 MSH2, one MSH2/monoallelic MUTYH, two MSH6, five PMS2), one patient had the low penetrant APC c.3920T>A, p.I1307K variant and a PMS2 variant of uncertain significance, and two patients had biallelic MUTYH pathogenic variants. Of the 402 patients with pMMR tumours, 32 (8%) had at least one constitutional pathogenic variant in a cancer predisposition gene: nine (2.2%) patients had pathogenic variants in high penetrant CRC predisposition genes (five APC, one APC/PMS2, two biallelic MUTYH pathogenic variants), 13 patients had pathogenic variants in genes not traditionally linked with CRC susceptibility (three ATM, one TM/CHEK2, two BRCA1, four BRCA2, one CDKN2A and two PALB2), three patients had the low penetrant APC c.3920T>A, p.I1307K variant, and seven patients had monoallelic MUTYH pathogenic variants. [/table] [table] Table 3: Staging the duodenum and ampulla and recommended OGD surveillance intervals [/table]	None	https://gut.bmj.com/content/gutjnl/69/3/411.full.pdf	Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual’s lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.
c09d5e5a682faf4e757922a4ddfb3f3a8d8c3cd0	pubmed	Public health issues and health rendezvous for migrants from conflict zones in Ukraine: A French practice guideline	Public health issues and health rendezvous for migrants from conflict zones in Ukraine: A French practice guideline # Introduction In its referral of 15 March 2022, the Directorate General for Health (Direction Générale de la santé, DGS) of the French Ministry of Health asked the High Council for Public Health (Haut Conseil de la santé publique, HCSP) to update its statement of 6 May 2015on the medical examination of migrants arriving from foreign countries, by issuing recommendations adapted to the health situation of people leaving conflict zones in Ukraine. Several million people have left Ukraine since Russia's military actions began on 24 February 2022. With the continuation of the conflict, the arrival of migrants in European countries could continue to be intensified. The DGS wishes to have the HCSP's recommendations on public health actions to be applied for all Ukrainian migrants, whatever their age: identification of health issues, monitoring of major pathologies, screenings as a key priority, vaccinations according to a specified schedule, establishment of traceability procedures (and action to be taken)when they cannot be fully documented, all of these in line with the recommendations of European Centre for Disease Prevention and Control (ECDC) and World Health Organization (WHO) regional office for Europe (Ukraine is part of the WHO European region but is not the European Union). It is likewise of prime importance to call upon the respective fields of expertise of the French Infectious Diseases Society (Société de pathologie infectieuse de langue franç aise, SPILF), the French Public Health Society (Société franç aise de santé publique, SFSP) and the High Authority for Health (Haute Autorité de santé, HAS). # Methodology To respond to this referral, the HCSP has set up an ad hoc working group involving experts who may or may not be members. Literature data were analyzed and experts and representatives from the national public health agency (Santé publique France, SPF), DGS, HAS and SPILF were interviewed. Practical guidelines were developed by the working group. Several meetings were held between 16 and 23 March 2022. Since relevant publications were few and far between, a rigorous methodology such as systematic review of the literature could not be applied. The present guidelines are therefore an expert statement based on available evidence, which has been published online in French by the HCSP. ## Recommendations The experts took into consideration the following aspects below. ## The international situation and the arrival of migrants from ukraine on french soil Even though the French government provides figures on the arrival of people from Ukraine, it is currently difficult to identify the demographic structure and arrival mode (flows, means of transport, dispersion in the French departments, private or public reception structures, etc.). In addition, many individuals have welcomed at a distance from organized support and information on access to rights and care. While unquantified information is often given on the ages of the migrants (young women, children, elderly), their health conditions (illness, disability) are less frequently indicated. In 2019, according to official figures, Ukraine had a population of 43,994,000, of whom 2,184,000 were children under the age of 5 (5%) and 7,012,000 were under 15 (15.9%). People aged 65 and over represented 16.5% of the population. It is important to note that while Ukrainian is the official language, Russian is spoken by a substantial part of the population, especially in the southern and eastern regions. In the current conflict (Russian army offensive), men have been invited or forced to stay in Ukraine to join the army. According to the United Nations refugee agency (UNHCR), as of 15 March 2022a large part of the population, 3,063,095 people, was displaced and more than half of them were in Poland. Migrant women who enter the EU/EEA from Ukraine may be vulnerable to certain infectious diseases, particularly due to their temporary living conditions and their situation while moving. The "temporary protection" system instituted by the European authorities and introduced in France for people from Ukraine (see below), allows them to benefit from the same level of protection as the host country's population in terms of prevention and control measures for infectious diseases, including those that can be prevented by routine vaccination. However, they may be subject to specific risks due to increased incidence of various infectious diseases in their country of origin, disrupted living conditions prior to and during displacement, and possible sequelae of trauma. Other obstacles to accessing health care in France include inadequately availability of appropriate resources in the host territories and the language barrier. 3.2. The 6 May 2015 HCSP recommendations concerning the health check-up of migrants arriving from foreign countriesIt is recommended that a "health rendezvous" be systematically organized for all newly arrived migrants within at most 4 months after arrival and that it be separated from any control function. Subject to medical confidentiality, this appointment is designed to provide information, prevention, screening, guidance, and integration into the mainstream healthcare system. It is intended for people arriving through family immigration, workers, asylum seekers, students, and schoolchildren, whatever their geographical origin, including from countries outside the European Union. In addition to systematically provided information (healthcare system access, organization, and operation, care coverage, women's health, health and protection of minors), it includes systematic screening and others tests adapted to the migrants' situation. This French ministerial directive specifies that the purposes of the "Health Rendezvous" are (a) to manage chronic noncommunicable diseases; (b) to detect vulnerabilities caused by the migration process, particularly psycho-trauma and sexual violence; (c) to screen for diseases that are more prevalent in the countries of origin; (d) to consider the exacerbated fragility associated with some situations, particularly among pregnant women and children; (e) to compensate for a lack of knowledge of the healthcare system and administrative procedures, as well as a lack of proficiency in the French language. The directive is also aimed at constructing health pathways adapted to the concerned territories by coordinating the local offer and guaranteeing access to a "health rendezvous". In this context, the transmission of information to newly arrived migrants is of major importance in access to care. With this in mind, it is necessary to have a map of the medical and medico-social structures and other services mobilized throughout France for the care of migrants and to make them known to professionals. Mapping consists in an operational directory of resources, to which access is limited for the time being to users registered with regional ehealth development support groups or regulation platforms. Other information tools for health professionals and individuals should be made available on shared workspace, one of them being the updated version of the bilingual health booklet drawn up by the NGO Comede (Committee for the health of exiles) and the French national public health agency (SPF); further information is available on the French health insurance website and the SPF websites. ## Special conditions for migrants from ukraine Having arrived in France, people from Ukraine have the right to stay in France for 90 days without going through administrative procedures. On March 4, 2022, the Council of the European Union decided to apply Directive 2001/55/EC to Ukrainian nationals (and their rights holders), refugees and stateless persons, as well as third-country nationals who were residing in Ukraine before February 24, 2022, as holders of a long-stay resident permit, and who are unable to return to their country of origin. On the other hand, Ukrainian nationals who were legally resident in France before February 24, 2022 cannot benefit the above provisions. This Vaccine-preventable diseases of particular importance in the context, prevalence and coverage in Ukraine. status is effective for one year, allowing its beneficiary to obtain a residence permit (in France, a temporary residence permit under temporary protection does not award refugee status), to have the right to work and to enjoy untrammelled access to social rights (health insurance and supplementary coverage with no waiting period, family support, etc.). While it is not compulsory to apply for asylum to be granted this status, the person who wishes to do so continues to benefit from temporary protection while their asylum application is being examined. To apply for temporary protection, it is necessary to contact a state representative at the departmental level (in France, the prefecture). Reception centers have been organized in some regions to facilitate access to the right to residence, which usually includes rights to health insurance coverage by the national health insurance scheme. The regional health agencies (Agences régionales de la santé, ARS) have been asked to provide support on arrival, in terms of both psychological care and general medicine. Provision to the national health insurance agency of a certified copy of the resident permit leads to affiliation to both basic and complementary health insurance (Complémentaire Santé Solidaire, CSS), free of charge and without either a prerequisite concerning activity or residence, or the three-month waiting period applied to asylum seekers. French nationals repatriated from Ukraine or Russia likewise benefit from full coverage. Once a valid identity document has been provided, registration with a national directory registration number (NIR = Numéro d'Immatriculation au Répertoire de l'INSEE) and a health insurance card (Carte vitale), or a provisional registration number (Numéro d'Immatriculation d'Attente) will be issued. For children, several situations are possible: - they are accompanied by their parents or legal guardians: - if an identity document attesting to the link with the legal representatives is available: certificate as a beneficiary, - if an identity document proving the link is not available, form S3705 to be completed for registration as a beneficiary; - they are not accompanied by their legal representatives but are referred to families: registration as an ADCA beneficiary is possible (ascendant, descendant, collateral or allied, ACDA); - they are not accompanied or accommodated by relatives: care by the child welfare services (Aide Sociale à l'Enfance). As Ukraine is at war and much of the population has witnessed the fighting or bombardment and been uprooted or separated from their families, the risk of psychological trauma and its repercussions in terms of short or long-term mental health (anxiety, post-traumatic stress disorder and mood disorders) are likely to be at the forefront of care needs. In this context, medical-psychological emergency units (Cellules d'urgence médico-psychologique, CUMP) have been activated, and mobile psychiatry security teams (Equipes mobiles psychiatrie précarité, EMPP) and medical-psychological centers (Centres medico-psychologiques, CMP) remain closely involved. In addition, in the MINSANTE 2022-22 ministerial document on the organization of care for migrants arriving from Ukraine, the French Ministry of Solidarity and Health indicates that as mentioned in MINSANTE 2022-21, the care system must take into account the Covid-19 risk by organizing (a) Covid-19 screening, particularly in the case of collective accommodation; (b) Covid-19 (primary and booster) vaccination; (c) verification of childhood vaccinations (in particular MMR and BCG), and organization of booster vaccinations in line with the vaccination calendar; (d) prevention of tuberculosis by remaining alert to any signs of the disease, with when necessary; (e) organization of care and treatment for other chronic diseases, when necessary; (f) organization of specialized consultations, and provision of medical and psychological care, with follow-up for those in need. The expected presence of many women and children to be is underlined. Attention has been given to the risk of rabies risk for any migrants arriving with a pet and the importance of anti-rabies vaccination for these animals for (coverage in Ukraine is low). An information document in Ukrainian is available online. The need for professional health care translating is recalled and the challenges of its organization are underlined. The need to involve prefectures, local authorities, NGOs and the regional unions of health professionals likely to be the first contact for people who have arrived by their own means is likewise highlighted. ## Vaccination status of people from ukraine The prevalence and coverage of vaccine-preventable diseases in Ukraine are detailed in . The Ukrainian immunization scheduleis different from the one used in France and should be made available and consulted when assessing vaccine status. The relevant information is detailed in [fig_ref] Table 2: Vaccination schedule in Ukraine [/fig_ref] and Supplementary files 1, 2 and 3. For people arriving from Ukraine but originally coming from another country (students), the vaccination schedule and the vaccination coverage of that country are also available on the WHO website. With epidemiological findings in mind and in the absence of documented evidence of previous vaccination, the ECDCrecommends prioritizing the vaccinations against Covid-19, MMR, DTP-IPV/dTp-IPV and HiB; and suggests consideration of the vaccinations against HBV, meningococcal, pneumococcal, chickenpox, influenza and tuberculosis. 3.6. The SPILF/HAS guidelines on catch-up vaccination for newcomer migrants, in the event of unknown, incomplete or incompletely known vaccination statusGeneral rules for catch-up vaccination have been established and highlight the following points: - any previous vaccinations without proof of vaccination are disregarded; - the absence of danger in administering vaccines to a person who may already be immune to this disease, enabling the indication for catch-up vaccination in case of unknown status; - a minor infection or low-grade fever should not delay catch-up vaccination. Febrile illness (> 38 - ) or a moderate or severe acute infection does not contraindicate vaccination but may lead to a delay of a few days; - definitive medical contraindications to vaccination are extremely rare (severe allergy from a previous injection of a particular vaccine). However, in the context of Covid-19 vaccination, certain adverse effects of Covid-19 vaccines, such as myocarditis in young subjects, should be considered. ## Epidemiology of communicable and non-communicable diseases in ukraine The epidemiology of communicable infectious diseases is summarized here and has been detailed in the ECDC report "Prevention and control of infectious diseases in the context of Russia's aggression towards Ukraine". ## The epidemiological situation in ukraine of the sars-cov-2 pandemic According to the ECDC, since the start of the Covid-19 pandemic and up until 2 March 2022, a total of 4,849,022 confirmed SARS-CoV-2 infections and 106,239 Covid-19 deaths had been recorded in Ukraine. The emergence of the Omicron variant of concern resulted in the fourth and largest wave of SARS-CoV-2 transmission in the country, which recorded its highest 7-day average daily case rate of 35,978 cases on 10 February 2022. Although the number of sequences submitted to the GISAID-EpiCoV database in recent weeks has been very limited, the available sequence data indicate that Omicron is currently the main circulating variant. Two-dose vaccination coverage is low among the Ukrainian population (35.6%) and booster shots as of February 16, 2022were almost non-existent (1.7%). It was 79.1% at the end of 2021 among health professionals, 30.6% for those aged 60 and over, and vaccine hesitancy is common although lower than in France. Vaccine uptake is uniformly low in the adult age groups, including the over-60s, who are most at risk of severe disease. As of August 2021, nearly 56% of Ukrainians were hesitant about vaccination against Covid-19 [bib_ref] COVID-19 pandemic in Ukraine, Wikipedia [/bib_ref]. Vaccination intention may subsequently have improved in view of the number of deaths recorded in Russia. SARS-CoV-2 is therefore likely to be actively circulating among migrants from Ukraine and if they have risk factors, they are unlikely to be effectively protected against the risk of infection and severe forms. Moreover, the vulnerability of migrant populations is linked to basic medical conditions and more specifically to migratory flows (promiscuity, confinement), which increase the risk of exposure to infectious agents. The ECDC report specifies general recommendations for vaccination against Covid-19 and indicates the need to comply with host country guidelines. In addition, to facilitate border crossings, some border countries (e.g. Poland, Romania and Slovakia) have reduced travel restrictions related to Covid-19. Covid-19 screening tests are fully covered for migrants from Ukraine until 31st May 2022. ## Other vaccine-preventable diseases [12] People arriving from Ukraine, especially children, may be more vulnerable to vaccine-preventable diseases; polio and measles should be considered priority diseases for monitoring and surveillance. The main warning signs are: - the low diphtheria vaccination coverage reported by WHO for some regions (19-81%); - the occurrence of two recent cases of poliovirus, derived from a type 2 vaccine (PVVC2), and the low uptake of the mass immunization campaign (22%) suggest that polio immunization is the preferred option; - the significant risk of a measles outbreak, given that vaccination coverage is insufficient and has been declining for some years in some Ukrainian regions.. It should be borne in mind that rabies is still endemic in wild animals, as well as in dogs and cats in Ukraine. In this context, the vaccination of pets should be checked and completed if necessary. In the event of a bite, advice from the nearest rabies center is called for. ## Tuberculosis Tuberculosis (TB) remains a major public health problem and a priority communicable disease in Ukraine. According to the 2021 European TB Surveillance and Monitoring Annual Report, based on 2019 data, Ukraine reported the second highest number of TB cases , with an incidence of 65 cases per 100,000 and a mortality rate of 7.3 deaths per 100,000. Ukraine is one of the 10 countries in the world with the highest burden of drug-resistant tuberculosis (DR-TB), and in 2019, Ukraine reported 27% of new cases of DR-TB (4,490 cases, 70% of which were male). Ukraine also has the second highest prevalence of HIV/TB co-infection (26%) in the World Health Organization (WHO) European Region (7800 cases in 2019). ## Other chronic infectious diseases Chronic infectious diseases (HIV, chronic hepatitis B or C) may be undiagnosed and require continuous treatment, which may have been interrupted during the transit weeks. ## Hiv. According to the ECDC, HIV remains a public health issue and a priority communicable disease in Ukraine. According to the Annual European HIV Surveillance Report 2021, based on 2020 data, Ukraine reported 15,658 new HIV diagnoses. In 2020, the HIV diagnosis rate for Ukraine was the second highest in the WHO European Region (37.5 per 100,000 population), while the EU rate was 3.3 per 100,000 population. In 2020, an estimated 257,000 people in Ukraine were living with HIV. The number of HIV diagnoses in Ukraine is particularly high among injecting drug users (IDUs) and was increasing between 2018 and 2020. IDUs represented a 38% share of all new diagnoses in 2020. In that year, an estimated 146,000 people in Ukraine living with HIV were receiving antiretroviral drugs (57% treatment coverage), while in the EU, treatment coverage is estimated at 82%.. ## Hcv. Ukraine is an intermediate endemic area for hepatitis C. Intravenous drug use is widespread and contributes to the persistence of HIV and hepatitis C epidemics. It is estimated that between 2.5% and 5% of the Ukrainian population is living with chronic hepatitis C, which is higher than in the European Union, where prevalence is estimated at 1.5%. This high prevalence is partly explained by infections linked to intravenous drug use. Infections are also reported in children through vertical transmission. 3.7.5. Non-communicable diseases 3.7.5.1. Chronic diseases. In 2016, according to the WHO, 9.1% of Ukrainians were diabetic, 51.7% were overweight and 21.7% obese. By comparison, in France in 2016, prevalence of diabetes, overweight and obesity was 8%, 64.1% and 25.7% respectively. Hypertension (BP > 16/9) affected 34.8% of the population and 11.1% had BP > 16/10. However, hypertension is not regularly monitored. A heart attack history was reported by 14% of the population (6.5% among 18-29-year-olds). ## Addictions. Tobacco use affects 33.9% of Ukrainians. Twothirds of men and half of women drink alcohol and almost one in five (19.7%) drink more than 6 glasses on a single occasion. Intravenous drug use is widespread and has contributed to the HIV and hepatitis C epidemics. ## Vaccination against covid-19 in ukraine ## Vaccines available and used in ukraine The vaccines used in Ukraine or that may have been received by the Ukrainian population in Russia are mainly: mRNA-1273 (Spikevax-Moderna), BNT162b2 (Comirnaty-Pfizer-BioNTech), Ad26.COV2.S (Janssen-Johnson&Johnson), ChAdOx1-S (Vaxzevria-AstraZeneca-Oxford), ChAdOx1 nCoV-19 (Covishield) and Sinovac/CoronaVact [bib_ref] Covid-19: Ukraine conflict calls Russia's vaccine diplomacy into question, Tinari [/bib_ref]. In addition, the Russian adenoviral vaccine Gam-COVID-Vac (Sputnik V) could be received by part of the Ukrainian population. The vaccines used were either purchased by the Ukrainian government through the Covax program or supplied by Russia. In January 2022, UNICEF sent 999,000 doses. ## Certificate of vaccination against covid-19 The EU digital Covid-19 certificate with QR code is available in Ukraine, but only a minority of the population has been vaccinated, and not all of those vaccinated have received the QR code. In addition, many people have fled Ukraine without taking their medical documents with them. Aside from the digital certificate, their certificates are not written in French or English. ## Nationwide covid-19 vaccination recommendations ## Vaccination schemes in france The schemes are specified in DGS-Urgent No. 2022-28which is based on the regulatory texts and statements of the HAS and the Conseil d'orientation de la stratégie vaccinale (COSV). ## Primary vaccination schedule A full primary vaccination schedule is still required, i.e.: - a two-dose primary immunization schedule, regardless of the vaccine used, respecting the spacing between injections specific to each vaccine (Supplementary file 4); - a single-dose primary vaccination schedule if infection occurs before or after the first injection. ## Recall schemes The validity of the doses and history of infection is recalled in Supplementary file 4 in accordance with the COSV notice [32]. ## Validity and finalization of vaccination schedules for those vaccinated abroad [33] People who have received two doses of an EMA-recognized vaccine (Comirnaty, Spikevax, Vaxzevria or one dose of Janssen) or an "EMA-like" vaccine (Covishield, R-Covi and Fiocruz, whose composition and manufacturing process are similar to those of the Vaxzevria vaccine) abroad, benefit from a complete vaccination scheme recognized by France. People who have received a single dose of a vaccine not recognized by the EMA but which has obtained the WHO Emergency Use Listing (EUL) label (Sinopharm (Beijing Institute of Biological Products or BIBP), Sinovac and COVAXIN) must receive two doses of an mRNA vaccine in France, at least 4 weeks after their last injection, in order to complete their vaccination schedule and thereby obtain the health pass. Persons who have received two or more doses of these vaccines must receive a dose of mRNA vaccine in France, at least 4 weeks after their last injection, to complete their vaccination schedule and consequently obtain a health pass. People who have received one or more doses of a vaccine not recognized by the EMA and who have not obtained the WHO EU label must receive two doses of an mRNA vaccine in France, at least 4 weeks after their last injection, to complete their initial vaccination schedule and thereby obtain their vaccination certificate (for more information, see DGS-Urgent n - 2021 125 of December 07, 2021). ## Considering The following have been considered: - the language barrier; - the likelihood of several waves of arrivals of migrants from Ukraine of different health status; - the possible arrival of sick people from Ukrainian hospitals; - the need to ensure access to information, care and prevention for migrants from Ukraine, and for the elderly, pregnant women, and children in particular; - the prevalence of certain communicable diseases in Ukraine; - the difficulty of having a traceable medical history; - low vaccination coverage for various contagious diseases (Covid-19, poliomyelitis, tuberculosis, measles, etc.); - the risk of suspended monitoring of chronic illnesses for some of the displaced persons; - the expected psychological consequences of conflict and exile; - the need to organize a "health rendezvous" as soon as possible after the arrival of migrants in French territory; - the importance of health pathway traceability in host countries; - the need to inform foster caregivers about care needs and health risks. ## The experts recommend The experts recommend the following: - that all the recommendations from the different institutions, learned societies and agencies and the applications planned by the host structures be made available on a single website; - that information on access to care throughout the host countries be provided and coordinated; - that medical and social support (opening of social rights and access to care) be provided; - that computerization of medical data ensuring their traceability be achieved as soon as feasible; - that the "health rendezvous" detailed in the 2015 recommendations and recently updated be implemented; - that there be a single digital portal for accessing information (including documents translated into bilingual French -Russian, French -Ukrainian) (Supplementary file 5); - that professional interpreting and/or health facilitators be put into work, and that if they are not available, digital translation tools be used; - that host families be provided with practical and understandable information on the risks of infection and on the orientation and care of the persons accommodated; - that teaching of the French language be initiated for all age groups. 3.11.1. Concerning initial (immediate) reception, upon arrival in the country - Emergency care: detecting signs suggestive of a communicable infectious disease (cough, fever and/or diarrhea); assessing immediate needs (violence experienced, imperiled mental health); identifying conditions requiring uninterrupted medication (diabetes, anticoagulant, contraception, etc.); compensating for the loss of medical devices (glasses, hearing aids, etc.); ensure access to sanitary towels and infant formula. - Organizing pregnancy monitoring for pregnant women. - Organizing immediate care for infants in a maternal and child protection center (PMI), with a special focus on tuberculosis prevention (screening and BCG vaccine). - Grouping together the relevant administrative regularization procedures (temporary residence permit in the context of temporary protection, health coverage, accommodation) for migrants, ideally in a single place and via a simplified and coherent pathway, with the help of social support operators. - Raising awareness of physical and mental health issues among professionals in reception facilities and among people receiving persons arriving from Ukraine. 3.11.2. Concerning the measures to be implemented as a matter of priority - Catch-up on vaccinations against Covid-19 (see details in §3.9), and the main communicable diseases, particularly diphtheria, Contents of the "Health Rendezvous". General clinical examination by a physician including systematic detailed interview with Search for a history of physical and mental violence and their consequences on health (after-effects of abuse, depression, post-traumatic syndrome, etc.); Search for situations of sexual vulnerability Search for sleep disorders, anxiety syndrome, mood disorders and/or post-traumatic stress disorder Full clinical examination with blood pressure measurement Collection of the patient' personal (known) medical history, particularly allergies, and consumption of tobacco, alcohol and drugs, especially intravenous drugs, and the search for current treatment Assessment and updating of immunization status In complex situations, this assessment may be entrusted to referral structures or professionals Tuberculosis screening Tuberculosis screening is the task of Tuberculosis centers (Centres de lutte anti-tuberculeuse, CLAT). The CLAT's mission is to refer people with the disease to a care facility, to organize any screening among family and friends, and to arrange distance visits for people who are not infected. For young children, CLATs may entail a specialized hospital consultation Expert statement on the modalities of tuberculosis screening Screen for TB disease by looking for suggestive symptoms and performing a routine chest X-ray as soon as possible in accordance with the ECDC recommendations on screening for TB in migrantsScreening tetanus, polio and measles (MMR) (according to current recommendations). - Priority must be given to children for entry into school, effective from the moment of their arrival on French territory. Screening and "health rendezvous" should not be prerequisites for admission to school. - Screen for symptoms that may suggest Covid-19, influenza or tuberculosis and perform an early chest x-ray to detect TB disease. - Screen for the risk of post-traumatic stress disorder, suicidal risk, and possible violence and organize early psychological support. Remain vigilant for early signs of decompensation of psychological disorders that may be due to the context or to discontinuation of a drug treatment. 3.11.2.1. Concerning vaccination in general. - Provide health professionals with a translation of the Ukrainian vaccination schedules and booklets. - Provide clear and understandable information on the purpose of vaccination and the entire course of medical, social and preventive care. - Provide and disseminate translated documents with crosstranslations concerning vaccine recommendations in France. - Consider possible reluctance to vaccinate, cultural or religious beliefs or social representations. - Carry out a catch-up vaccination (for all ages) as soon as possible after entering the country and within an optimal period of 4 months after arrival on the occasion of the "health Rendezvous", referring to the HAS/SPILF recommendations on catch-up vaccination in case of unknown or incompletely known vaccination status. - Ensure verification and catch-up vaccination against COVID 19, including booster shots, in conjunction with other prevention activities. - Document a history of Covid-19 (RT-PCR or antigenic test results, or serology with anti-N antibodies) and vaccination history (proof of vaccination, type of vaccine, dates, or notion of vaccination without proof in cases of positive SARS-CoV-2 serology): - for migrants with a documented history of infection and/or vaccination, apply the recommendations in force on the national territory (according to paragraph 3.9); - for migrants for whom no information is available, or with a history of vaccination with a vaccine not recognized in France (or by the European Union), or in the absence of proof of vaccination, propose that a TROD SARS-CoV-2 be performed: -in case of positivity, administer a single dose of mRNA vaccine, -in case of negativity, or refusal of TROD, propose a complete vaccination scheme. - In all cases, schedule the necessary booster shots according to the vaccination schedule in force in France. - Make sure that all those involved in vaccination against Covid-19 be able to update the health/vaccination pass, thereby attesting to the vaccinations received abroad. 3.11.2.3. The HCSP confirms the following points from its 2015 recommendations on the reception of newcomers, whatever their origin, and recommends. - Vigilance in the management and continuity of rights and care after the initial period has been completed. - A "Health Rendezvous" should be organized within four months of entry into the country, during which the following information is systematically provided: - the principles of health care in France: universal access to health care, medical confidentiality, equal rights, especially between men and women, consent to care, free choice of doctor, - the operating rules of public service ensured by health professionals of both sexes with the same missions, - the terms of coverage of care (health insurance, complementary health insurance, etc.), - perinatal monitoring (maternal and child protection service -PMI), the integrity of the body, access to contraception, the right to abortion, prevention of intra-family violence, screening for gynecological cancers, etc., - health and protection of children and minors: compulsory vaccinations, recommended visits, PMI, child protection service, school health service, etc. - In addition to the booklet already available in Russian and French, a bilingual health document from Comede NGO and National Public Health Aging in Ukrainian and French should be accessible, on easily identifiable websites. - The medical contents of the "health rendezvous" must be in conformity the nationwide system of reference, as detailed in . - At the end of this "health rendezvous", a document ensuring health pathway traceability is issued, mentioning the examinations performed and the person's vaccination status. Development of digital health space should be prioritized. - The data collected and anonymized during this "health rendezvous" may be used for epidemiological purposes. - Above and beyond the assistance provided in accessing care, particular attention should be paid to the absence of any discrimination related to gender, sexual orientation and origin. Drawn up on the basis of the knowledge available at the date of publication of this statement, these recommendations may change as overall knowledge and epidemiological data are updated. Statement written by a group of experts, members or nonmembers of the High Council for Public Health. # Ethical statement The authors have no conflict of interest to declare in relation to the manuscript. The work received institutional support from the French High Council for Public Health (Haut Conseil de la santé publique, HCSP) and the French Infectious Diseases Society (Société de pathologie infectieuse de langue franç aise, SPILF). # Funding The work received institutional support from the French High Council for Public Health (Haut Conseil de la santé publique, HCSP) and the French Infectious Diseases Society (Société de pathologie infectieuse de langue franç aise, SPILF). # Disclosure of interest The authors declare that they have no competing interest. [fig] •: For people with unknown vaccination status or incomplete vaccinations, priority should be given to catching up with the dT-IPV/dTP-IPV/DTP-IPV/DTP-IPV-Hib according to age, and MMR for people aged at least 1 year and born after 1980. The coadministration of these vaccines is possible within the limits of the person's acceptability and the number of 4 injections per visit. [/fig] [table] Table 2: Vaccination schedule in Ukraine. [/table]	None	None	None
8496461116ea112b3ae6843e42ff63783b0406ac	pubmed	Clinical care of children and adolescents with COVID‐19: recommendations from the National COVID‐19 Clinical Evidence Taskforce	Clinical care of children and adolescents with COVID‐19: recommendations from the National COVID‐19 Clinical Evidence Taskforce [bib_ref] Virus expert says COVID will "not go away" and could be around..., Murdock [/bib_ref] [bib_ref] Weekly updates of national living evidence-based guidelines: Methods for the Australian Living..., Tendal [/bib_ref] ## Covid-19 in children and adolescents Initial reports on the incidence of COVID-19 in China noted a limited number of severe cases and hospitalisations in children. [bib_ref] Epidemiology of COVID-19 among children in China, Dong [/bib_ref] Larger international cohorts have confirmed that, in general, children have a much less severe acute form of the disease compared with adults, especially older adults. [bib_ref] Clinical characteristics of children and young people admitted to hospital with covid-19..., Swann [/bib_ref] [bib_ref] COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study, Götzinger [/bib_ref] However, SARS-CoV-2 infection can cause severe respiratory complications in children, especially in neonates and infants. [bib_ref] Clinical characteristics of children and young people admitted to hospital with covid-19..., Swann [/bib_ref] [bib_ref] COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study, Götzinger [/bib_ref] Other groups who appear disproportionately affected include children from minority ethnic groups in the United Kingdom and the United States 5,7 and children with comorbidities. [bib_ref] Clinical characteristics of children and young people admitted to hospital with covid-19..., Swann [/bib_ref] A review of COVID-19 mortality in children (> 8700 deaths worldwide as of May 2021)showed larger fatality rates in lower and middle-income countries compared with higher income countries. The prevalence and severity of the disease for children and adolescents is likely to increase with the emergence of SARS-CoV-2 variants that affect younger people, such as the Delta strain. [bib_ref] COVID-19 in children: time for a new strategy, Mclaws [/bib_ref] In early 2020, in addition to descriptions of acute COVID-19 in children, researchers in France 10 and the UK [bib_ref] Kawasaki-like disease: emerging complication during the COVID-19 pandemic, Viner [/bib_ref] reported a sudden increase in cases of apparent Kawasaki disease, including atypical presentations. This increase in paediatric inflammatory syndromes, later reported in the US and elsewhere, has now been recognised as temporally and causally associated with SARS-CoV-2 infection. [bib_ref] Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of..., Ouldali [/bib_ref] It has been termed paediatric inflammatory multisystem syndrome (PIMS-TS) or multisystem inflammatory syndrome in children (MIS-C).Although it has certain similarities with Kawasaki disease, differences in epidemiology and clinical features have cemented its current status as a distinct syndrome. [bib_ref] COVID-19-associated multisystem inflammatory syndrome in children -United States, Godfred-Cato [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus..., Abrams [/bib_ref] The Australian response: the formation of a national taskforce The Australian Living Evidence Consortium is a world leader in the development of living guidelines. [bib_ref] Breathing life into Australian diabetes clinical guidelines, White [/bib_ref] In March 2020, during the first wave of infection in Australia, the National COVID- [bib_ref] Weekly updates of national living evidence-based guidelines: Methods for the Australian Living..., Tendal [/bib_ref] Clinical Evidence Taskforce was established to produce living recommendations on the clinical care of people with COVID-19 in Australia, bringing together representatives from the peak health professional bodies whose members are providing clinical care to people with COVID-19. The Taskforce employs over 20 dedicated staff and involves more than 250 experts across all spheres of health care (average 360 volunteer hours per week). To develop recommendations specific to paediatric COVID-19 care, the Taskforce established a Paediatric and Adolescent Care (PAC) Panel. This Panel currently comprises 15 paediatric experts (53% women) from New South Wales, Victoria, Queensland, South Australia, Western Australia and the Northern Territory, including an Indigenous representative supported by the National Aboriginal Community Controlled Health Organisation, and representation from urban, rural and remote areas. # Methods The living guidelines have been developed according to the Australian National Health and Medical Research Council (NHMRC) standards, including the use of Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The Taskforce uses the MAGICapp platform (https://magic evide nce.org/) and its Evidence to Decision framework. [bib_ref] GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to..., Alonso-Coello [/bib_ref] The guidelines were first approved by the NHMRC on 23 November 2020. Complete guideline methods are available online. [bib_ref] Weekly updates of national living evidence-based guidelines: Methods for the Australian Living..., Tendal [/bib_ref] No primary data from human subjects were collected and, therefore, formal ethics approval was not sought. ## Methodology issues specific to children and adolescents Specific challenges to the provision of reliable guidance for the management of children and adolescents arise from the fact that this population is not routinely included in clinical trials. [bib_ref] Clinical trials in children, Caldwell [/bib_ref] Given the paucity of paediatric data, it was decided to include trial evidence from the adult population when considering paediatric recommendations. The PAC Panel noted that clinicians providing care for children and adolescents are familiar with this approach, including reviewing literature for safety and pharmacokinetic data in children, and extrapolating efficacy data from adult populations. Importantly, the resultant recommendations emphasise that rigorous clinical trials in paediatric populations are needed to establish strong evidence for interventions. [bib_ref] A call for pediatric COVID-19 clinical trials, Campbell [/bib_ref] As the guidelines used GRADE 23 methods, the Panel downgraded the certainty of the evidence for the outcomes of interest by one step (due to serious indirectness) if the studies being considered did not include children or adolescents. When no trial evidence in adults was available, the Panel decided to produce consensus recommendations based on best practice, data from similar conditions or treatments, and expert consensus. As living guidelines, these recommendations are updated as new evidence, either from adults or children and adolescents, becomes available. The Taskforce's evidence team conducts daily searches for relevant population, intervention, comparison and outcomes (PICO) questions, constructed by and reviewed with the relevant panels meeting regularly to consider their findings. For the development of PIMS-TS-specific recommendations, the Taskforce convened an expert advisory group to provide additional expertise to the PAC Panel. Experts in Kawasaki disease and related conditions advised the panel on this novel syndrome. As there was no evidence from clinical trials available for this condition, the Panel considered additional sources, including international, peer-reviewed guidelines and large, multicentre cohort studies reporting on PIMS-TS or MIS-C. The Panel then formulated consensus recommendations pending new, higher quality evidence, which will be reviewed as it becomes available. ## Consumer input The Taskforce, in collaboration with the Consumers Health Forum of Australia, convened a consumer panel beginning in June 2020, including members who were parents (including of children with health care needs) and/or involved in child advocacy, but no children or adolescents. This panel reviewed all PAC Panel recommendations, provided feedback and advised on the preferences and values of children, adolescents and their families and carers when formulating recommendations for the care of children and adolescents. ## Pregnancy and perinatal care For those recommendations involving newborn care and pregnancy and perinatal health care, collaborative discussions were held between the PAC Panel and the Pregnancy and Perinatal Care Panel to reach consensus. Recommendations for pregnancy and perinatal care have been recently published. 24 ## Governance and review Draft recommendations from the PAC Panel are reviewed and approved sequentially by the National Guidelines Leadership Group and the Steering Committee, which include representatives from the 32 Australian stakeholder organisations endorsing the guidelines.The structure of the National COVID-19 Clinical Evidence Taskforce is shown in the online Supporting Information (figure 1). ## Recommendations ## Overarching principles The overarching principles are detailed in the online Supporting Information (table 1). In general, our recommendations are aimed towards children under 16 years of age. The decision to apply paediatric or adult recommendations should be guided by consideration of the physical and developmental maturity of individual patients. The term "child" also includes infants and neonates unless otherwise specified. The following recommendations are current as of 20 August 2021; any updates since publication are available at https://covid 19evi dence.net.au/. ## Definition of disease severity Box 1 provides the definitions of COVID-19 severity in children and adolescents (consensus recommendation). Cardiorespiratory and vital parameters must be considered within the normal age-appropriate ranges for neonates and children, and/or any pre-existing illness. ## Disease-modifying treatments for covid-19 Disease-modifying treatment recommendations for children and adolescents are shown in Box 2 and in the online Supporting Information , and the supporting evidence is summarised below. ## Corticosteroids Evidence informing these recommendations comes from a recent meta-analysis 28 of seven randomised controlled trials of patients with critical COVID-19; 29-36 one study of patients with moderate, severe and critical COVID-19;and one study of patients with severe COVID- Evidence indicates that corticosteroids reduce deaths in adult patients with critical or severe COVID-19, but may increase deaths in adult patients with moderate COVID-19. Although these trials did not include children, due to a reduction in death along with no important resource implications and the likely acceptability of these drugs, we recommend considering using corticosteroids in children and adolescents with COVID-19 who are receiving oxygen, including mechanically ventilated children. ## Remdesivir Evidence supporting this recommendation comes from four randomised controlled trials that compared remdesivir with standard care in over 7300 adults hospitalised with COVID-19. [bib_ref] Remdesivir for the treatment of COVID-19 -preliminary report, Beigel [/bib_ref] [bib_ref] Effect of remdesivir vs standard care on clinical status at 11 days..., Spinner [/bib_ref] [bib_ref] Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, Wang [/bib_ref] Given the absence of children or adolescents in any of these trials, as well as concerns about how applicable this evidence is for the paediatric population (low certainty of the evidence due to serious indirectness), the PAC Panel considered that the potential benefits of remdesivir may not outweigh the harms, and that more research is needed in children and adolescents. ## Tocilizumab The evidence supporting the use of tocilizumab comes from ten randomised trials that compared tocilizumab with standard care in 6570 adults hospitalised with COVID-19. The majority of data are from the RECOVERY trial, which included 4116 adults hospitalised with moderate to critical COVID- Evidence indicates that tocilizumab probably reduces the risk of death in hospitalised adults who require supplemental oxygen, as well as reducing the need for invasive mechanical ventilation and admission to the intensive care unit. Given this evidence, the previous experience on using tocilizumab in children plus the absence of trials in children and adolescents, the PAC Panel formulated a conditional recommendation supporting the use of tocilizumab in children and adolescents. ## Treatments not recommended (strong recommendations against) and/or only recommended in trials The Taskforce has issued a further 45 recommendations on a wide range of disease-modifying treatments (Box 2 and online Supporting Information, table 2). Full evidence summaries are available at https://app.magic app.org/#/guide line/L4Q5A n/ secti on/L0OPkj. A dose of 6 mg daily is recommended in adults. The RECOVERY trial protocol recommended a dose of 0.15 mg/kg/day to a maximum of 6 mg/day for children, but it is not stated whether any children were included in the trial. If dexamethasone is not available, an acceptable alternative regimen would be: - hydrocortisone: intravenous or intramuscular 1 mg/kg dose every 6 hours for up to 10 days (to a maximum dose of 50 mg every 6 hours); - methylprednisolone may also be an acceptable alternative, but the most appropriate dosage is uncertain In the RECOVERY trial, 29% of patients received a second dose 12-24 hours after the first dose, although results were not reported separately for this population. The decision to administer a second dose of tocilizumab should take into consideration the availability of tocilizumab In addition, the RECOVERY and REMAP-CAP trials have demonstrated a significant benefit when using corticosteroids in conjunction with tocilizumab in adults. Use of combined tocilizumab and corticosteroids should be considered in children and adolescents hospitalised with COVID-19 who require oxygen; however, the optimal sequencing of tocilizumab and corticosteroid use is unclear in all populations As tocilizumab inhibits the production of CRP, a reduction in CRP should not be used as a marker of clinical improvement ## Remdesivir Use of remdesivir for children or adolescents with COVID-19 outside a trial setting should not be routinely considered (GRADE: low certainty; conditional recommendation against) - If treatment is considered -in exceptional circumstances -it should be in consultation with a clinical reference group, such as the ANZPID COVID-19 Clinical Reference Group (https://www.asid.net.au/group s/anzpid). Informed consent from parents or caregivers should also be obtained. Currently, there is no direct evidence for the use of remdesivir in children or adolescents. Information about the patients and the intervention (dosages, duration) in the trials used for this recommendation can be found in the "practical info tab" at https://app.magic app.org/#/guide line/L4Q5A n/rec/jz9PeE. Trials of remdesivir in children and adolescents are currently being conducted, this recommendation will be updated once new evidence is available - Due to antagonism observed in vitro, concomitant use of remdesivir with chloroquine or hydroxychloroquine is not recommended in vitro 27 ## Other treatments not recommended Do not use aspirin, azithromycin, colchicine, convalescent plasma, hydroxychloroquine, hydroxychloroquine plus azithromycin, interferonβ-1a, lopinavir-ritonavir or interferonβ-1a plus lopinavir-ritonavir, for the treatment of COVID-19 (GRADE: high certainty; strong recommendation)* - This recommendation applies to adults, children and adolescents, pregnant and breastfeeding women, older people living with frailty, and those receiving palliative care. Use of these drugs may still be considered in the context of randomised trials with appropriate ethics approval, such as combination therapies that include these drugs - Rationale: the panel considered that, although none of these trials included children, given the absence of benefit in the adult population, there is no evidence that will point to a dissimilar effect in children. Hence, although indirect evidence, it was decided to recommend against these treatments, consistent with adult recommendations ## Other treatments recommendations: venous thromboembolism prophylaxis In the adult population, there has been concern of an increased risk for venous thromboembolism. [bib_ref] Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort..., Wichmann [/bib_ref] Paediatric guidelines published in the US in 2020 recommended a modified approach to thromboprophylaxis in children. [bib_ref] Consensus-based clinical recommendations and research priorities for anticoagulant thromboprophylaxis in children hospitalized..., Goldenberg [/bib_ref] The PAC Panel currently considers that the evidence is insufficient to modify well established protocols of thromboprophylaxis in children and adolescents (Box 2 and online Supporting Information, table 2). ## Respiratory support in neonates, children and adolescents The paediatric population is particularly vulnerable to respiratory failure due to viral infection. [bib_ref] Viral infection in the development and progression of pediatric acute respiratory distress..., Nye [/bib_ref] At the commencement of the COVID-19 pandemic, the roles of many established and evidence-based critical care respiratory support approaches were questioned due to the risk of infection of staff, patients and carers from aerosol generation. The Taskforce evaluated a diverse range of respiratory therapies, including non-invasive ventilation, management of the deteriorating child (including intubation and approaches to intubation), prone positioning, mechanical ventilation strategies and the use of high frequency oscillatory ventilation and extracorporeal membrane oxygenation. The Taskforce has formulated ten recommendations on the management of respiratory support in children and adolescents (Box 3). There is currently no primary evidence on the benefits and harms of any of the respiratory support approaches in children and adolescents with COVID-19. Therefore, the PAC Panel relied on consensus and previous experience to issue these recommendations, noting that many of these therapies have established evidence, or are considered best practice, in other conditions with similar pathophysiology to COVID-19, or are designed for disease processes that are known complications of COVID-19 (such as acute respiratory distress syndrome). Recommendations for the use of neuromuscular blockers and videolaryngoscopy were adapted from the evidence used in recommendations for adults, with specific commentary to reflect the equity, access and training limitations for these therapies in children. ## Respiratory support in neonates, children and adolescents ## Type of respiratory support Non-invasive respiratory support - High flow nasal oxygen and other modes of non-invasive ventilation ► Consider using high flow nasal oxygen or non-invasive ventilation* therapy for neonates, children and adolescents with hypoxaemia or respiratory distress associated with COVID-19 and not responding to low flow oxygen. Due to the potential for aerosol generation, use non-invasive ventilation with caution and pay strict attention to staff safety, including the use of appropriate personal protective equipment (Consensus recommendation) [formula] - [/formula] ## Management of children with pims-ts* recommendation remarks rationale IVIg plus corticosteroids Consider using IVIg (2 g/kg per dose) in combination with methylprednisolone in children and adolescents who meet PIMS-TS criteria (Conditional recommendation) IVIg should be considered for all children with complete or incomplete Kawasaki disease, irrespective of whether it may be related to COVID-19. Depending on the age and the phenotype expression of PIMS-TS, combination therapy of IVIg and corticosteroids should be considered as a first line therapy. [bib_ref] Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of..., Ouldali [/bib_ref] [bib_ref] Treatment of multisystem inflammatory syndrome in children, Mcardle [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children -initial therapy and outcomes, Son [/bib_ref] This is particularly relevant for older children with myocardial dysfunction, as opposed to younger children with a more Kawasaki disease-like phenotype Three Observational studies on the management of PIMS-TS have been identified: [bib_ref] Association of intravenous immunoglobulins plus methylprednisolone vs immunoglobulins alone with course of..., Ouldali [/bib_ref] [bib_ref] Treatment of multisystem inflammatory syndrome in children, Mcardle [/bib_ref] [bib_ref] Multisystem inflammatory syndrome in children -initial therapy and outcomes, Son [/bib_ref] - An international observational cohort study 47 compared treatment of IVIg plus glucocorticoids with IVIg alone and glucocorticoids alone in children with multisystem inflammatory syndrome after suspected COVID-19 infection. The primary outcomes were a composite of inotropic support or mechanical ventilation (invasive or non-invasive) by day 2 or later or death, and reduction in disease severity. The study found that IVIg plus steroids compared with IVIg alone made no difference in the receipt of inotropic or ventilatory support or death (n = 410; OR, 0.77; 95% CI, 0. ## Paediatric inflammatory multisystem syndrome The panel reviewed all available definitions and reached consensus on endorsing the provisional case definition for PIMS-TS from the UK Royal College of Paediatrics and Child Health,but also reviewed published articles using other common definitions, including MIS-C in the US. [bib_ref] Emergence of Kawasaki disease related to SARS-CoV-2 infection in an epicentre of..., Ouldali [/bib_ref] This approach was considered suitable for reviewing global evidence and translating it to an Australian context. The panel also noted the initial definition and advice produced in the Australian context by the Paediatric Active Enhanced Disease Surveillance (PAEDS) network and the Royal Australasian College of Physicians.The defining features of PIMS-TS are summarised in the online Supporting Information .The recommendations for PIMS-TS management are informed by an ongoing living systematic review and evidence surveillance that includes observational studies, systematic reviews and metaanalyses as well as international guidance. Box 4 provides specific recommendations for the management and treatment of PIMS-TS. # Discussion Developing paediatric evidence-based recommendations during a global pandemic has proven difficult and has produced unique challenges compared with other population groups. Traditionally, children have been excluded from clinical trials and this has remained the case for many COVID-19 therapies. [bib_ref] Roehr CC, den Boer MC. Inclusion of children and pregnant women in..., Malhotra [/bib_ref] The Taskforce needed to rely on trial data from adults to formulate recommendations for children, with the well known limitations and risks of extrapolation this brings. [bib_ref] Children are not just small adults: the urgent need for high-quality trial..., Klassen [/bib_ref] The need to consider certain paediatric subpopulations separately, such as neonates and adolescents, amplified this problem. Pragmatic adaptive trials such as RECOVERYand WHO Solidarity 38 have proven to be successful methods of providing timely evidence; these trial designs could be applied to children and adolescents. Where high quality trial data do not exist, robust observational data are needed. Several established, and newly formed, prospective, multinational collaborations focusing on paediatric populations are providing rapid and useful information, especially when managing less frequent conditions such as PIMS-TS. In the Australian context, this includes initiatives such as the PAEDS network and the Australian and New Zealand Paediatric Infectious Diseases Group of the Australasian Society of Infectious Diseases. Balancing the importance of providing the best therapy to a patient against the risks that it may pose to health care workers has been problematic during the COVID-19 pandemic. This was particularly relevant for the development of respiratory recommendations for children and adolescents. Non-invasive therapies were well established before the COVID-19 pandemic and were based on a sound evidence base in paediatric critical care. Due to the high aerosol-generating potential of non-invasive therapies, this was questioned at the start of the pandemic, despite the higher morbidity profile associated with invasive therapies. These considerations, together with the lower total oxygen flow rates delivered to children compared with adults, were important in the recommendation to use non-invasive ventilation and high flow cannulae when appropriate infection control measures could be applied. Another important consideration is that dedicated paediatric critical care, especially invasive respiratory support, is highly centralised in Australia. This creates greater inequity in resource allocation (equipment and airway expertise) in rural and remote areas compared with adult populations. Although it is not the primary objective of the Taskforce, concerns were raised by the PAC Panel regarding the impact that COVID-19 measures could have on wellbeing and psychosocial and developmental factors in children and adolescents, such as closures of schools and childcare services.The potential impact of emerging aspects of the COVID-19 pandemic, such as "long COVID-19" and SARS-CoV-2-specific vaccinations, also need to be considered in children and adolescents. Development and psychosocial wellbeing of children affected by COVID-19 should be included as outcome measures in future research. # Conclusion The Taskforce has successfully produced timely, evidencebased living guidelines for Australian clinicians (and beyond) managing COVID-19 in children and adolescents. The strength of diverse representative voices with the inclusion of different Australian health care and consumer stakeholders has enabled a values-driven and evidence-based approach. The evidence landscape is changing rapidly, and the guidelines will continue to adapt to this change. We encourage those who care for infants, children and adolescents affected by COVID-19 to keep up-to-date at https://covid 19evi dence.net.au/. Aspirin and other antithrombotic agents Children who are treated for PIMS-TS with IVIg or other agents should also be prescribed low-dose aspirin (3-5 mg/kg once daily for at least 6 weeks) (Consensus recommendation) Additional measures to be considered to prevent venous thrombosis associated with PIMS-TS include anticoagulation therapy and compression stockings (in children older than 12 years of age) Aspirin is used as an antithrombotic to prevent coronary artery thrombosis in Kawasaki disease [bib_ref] Aspirin dose and prevention of coronary abnormalities in Kawasaki disease, Dallaire [/bib_ref] COVID-19 = coronavirus disease 2019; IL = interleukin; IVIg = intravenous immunoglobulin; OR = odds ratio; RR = risk ratio; TNF = tumour necrosis factor. * Children and adolescents who have suspected or confirmed PIMS-TS should be managed by and discussed with a multidisciplinary team. Because of the potential for rapid deterioration, early consultation with experts and consideration of early transfer to a paediatric hospital with intensive care facilities to manage children are recommended for patients with suspected or confirmed PIMS-TS (Consensus recommendation [table] 1: Definitions of disease severity for children and adolescents with acute coronavirus disease 2019 (COVID-19)* Requires advanced modes of support to maintain oxygenation: ► high flow nasal oxygen at > 2 L/kg/ min, § OR ► non-invasive ventilation, OR ► intubation and mechanical ventilation, OR ► extracorporeal membrane oxygenation MET = medical emergency team; SpO 2 = peripheral oxygen saturation. * Depending on the physical size and/or developmental status of the patient, either the paediatric or adult severity grading can be applied. † Oxygen saturation targets should be modified for patients with cyanotic heart disease. ‡ Temperature instability should be considered an abnormal vital sign in infants. Fever is common in children and does not contribute to determination of illness severity in isolation. § Infants and neonates < 4 kg may be managed on high flow nasal cannula oxygen at 2-8 L/min irrespective of weight. Comorbidities (eg, preterm infants, oncology, immunosuppressed etc) may increase the risk of more severe disease. ◆ Corticosteroids Consider using dexamethasone daily intravenously or orally for up to 10 days (or acceptable alternative regimen) in children and adolescents with acute COVID-19 who are receiving oxygen (including mechanically ventilated patients) (GRADE: low certainty; conditional recommendation) [/table]	None	http://minerva-access.unimelb.edu.au/bitstreams/b2d28149-2dcc-53c1-b140-1fcdc9134f9a/download	The epidemiology and clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection are different in children and adolescents compared with adults. Although coronavirus disease 2019 (COVID‐19) appears to be less common in children, with milder disease overall, severe complications may occur, including paediatric inflammatory multisystem syndrome (PIMS‐TS). Recognising the distinct needs of this population, the National COVID‐19 Clinical Evidence Taskforce formed a Paediatric and Adolescent Care Panel to provide living guidelines for Australian clinicians to manage children and adolescents with COVID‐19 and COVID‐19 complications. Living guidelines mean that these evidence‐based recommendations are updated in near real time to give reliable, contemporaneous advice to Australian clinicians providing paediatric care.
30f7c12bf52805bd0b7e93ed3244319668b8b836	pubmed	Women's sexual/reproductive health and access challenges amid COVID-19 pandemic	Women's sexual/reproductive health and access challenges amid COVID-19 pandemic A B S T R A C TChallenges to women's health in the context of COVID-19 is based on their unique experience shaped by sex/gender. This paper provides clinical practice-, research-, and policy-related commentary on key COVID-19 pandemic factors impinging on women's sexual/reproductive health (SRH) and care access, particularly in the context of pregnancy, childbirth, sexual/gender variations, and concurrent chronic conditions. Women tend to have less severe outcomes from COVID-19 than men but certain sub-groups are more vulnerable than others. Yet few United States studies have disaggregated the data accordingly. Forming a basis for wellinformed policy generation, needed is more research specific to COVID-19 vulnerability/risk factors and outcomes for groups of women by age, race and socioeconomic and cultural determinants. Access to SRH-related clinical services has been diminished during the pandemic, making a priority for restoring/preserving inclusive SRH care for women, for example, family planning, healthy pregnancies, age-related disease screening and treatment, and health/wellness promotion.Important concerns include severity of the disease, morbidity in pregnant and postpartum women, increased risk to the fetus, virus transmission to fetus or newborn, and impact of lack care access. Uncertainty in current knowledge is heavily related to lack of sex specific data. 2020). Sex as a biological variable in biomedical research is established, but COVID-19 data in the United States (U.S.) includes few reports of disaggregated data analyzed by sex. Analysis of data by sex and where appropriate by gender sub-groups is needed to build a more comprehensive, clinical knowledge base [bib_ref] Sex differences in immune responses, Klein [/bib_ref] [bib_ref] Sex differences in immune responses to infectious diseases, Fischer [/bib_ref] [bib_ref] Sex differences in immune responses that underlie COVID-19 disease outcomes, Takahashi [/bib_ref] to inform clinical care and further research. # Sex-related covid-19 severity Sex and gender differences related to viral infection susceptibility, disease manifestation and trajectory are not completely clear. Fewer women than men have severe COVID-19 outcomes (i.e., lower rates of hospitalization, admissions to intensive care and fatalities) [bib_ref] Sex-based differences in severity and mortality in COVID-19, Alwani [/bib_ref] [bib_ref] Biological sex impacts COVID-19 outcomes, Klein [/bib_ref] [bib_ref] Considering how biological sex impacts immune responses and COVID-19 outcomes, Scully [/bib_ref]. Of the 15% of COVID-19 patients with severe manifestations, women are seen to have earlier and greater antibody responses than men and constitute about one-third of patients admitted to ICUs, requiring mechanical ventilation or dying (Mauvais-Jarvis, [bib_ref] Estradiol, progesterone, immunomodulation, and COVID-19 outcomes, Mauvais-Jarvis [/bib_ref]. The relative risk of dying from COVID-19 is higher in men across all age groups until the range of 60 to 69 years [bib_ref] Sex-based differences in severity and mortality in COVID-19, Alwani [/bib_ref]. One limitation is that U.S. sources have been slow to disaggregate by sex, age, or race so that most data are from other countries. Evidence is emerging regarding a wide range of symptoms such as dyspnea, extreme fatigue, tachycardia, and mental fog that persist beyond the acute phase of COVID-19 (longer than 3Àweeks), referred to as "LongÀCOVID" or "Chronic COVID Syndrome." As yet poorly understood, women appear disproportionately affected (14.9% as compared to 9.5% men). Factors that are seen to increase the odds, such as the presence of pre-existing asthma conditions more prevalent in women, [bib_ref] Sex-based differences in severity and mortality in COVID-19, Alwani [/bib_ref] warrant much more study. Not outlined comprehensively for this paper, but key areas of COVID-19 sex differences are basic viral mechanisms, comorbid conditions, and sex hormone influences. For example, as part of basic mechanisms, angiotensin-converting enzyme 2 (ACE2) acting as a SARS-CoV2 receptor and transmembrane protease serine 2 (TMPRSS2) as a facilitator for cell attachment and entry are observed to correlate with disease severity and TRMPRSS2 expression is observed higher in bronchial epithelial cells in males. Co-morbid conditions such as chronic obstructive pulmonary disease, diabetes, cerebrovascular disease, cancer and hypertension are associated with worse COVID-19 outcomes and more men have these conditions . Sex hormone (estrogen, progesterone, testosterone) receptors are prevalent on most immune system cells with complex and varied modulation effects not yet completely understood. However, their potential as a basis for interventions has been raised . In summary, data show greater numbers of men exhibit the most negative Covid-19 trajectories but for those women with severe COVID-19, more may experience long range consequences, similar to other chronic fatiguing conditions more prevalent in women, (e.g., chronic fatigue syndrome, fibromyalgia). More investigation of the factors underlying sex and gender differences in COVID-19 severity using a sexand gender-informed approach [bib_ref] Sex and gender differences in health: what the COVID-19 Pandemic can teach..., Spagnolo [/bib_ref] is needed. ## Women's sexual and reproductive health amid covid-19 During the current pandemic, myriad sexual and reproductive health (SRH) factors have been documented on a global scale, for example, the WHO response (WHO, 2020). Lessons learned from past epidemics suggest gender inequalities are common globally across a range of SRH issues. Important research areas include disease influence in pregnant and postpartum women; increased risk or demise of the fetus; virus transmission from infected women, pregnant or not; and access to relevant health care services [bib_ref] Sexual and reproductive health (SRH): A key issue in the emergency response..., Tang [/bib_ref]. Health care delivery factors include access to SRH services and supplies during restricted activities and quarantine plus diversion of essential health care workers from SRH services to emergency screening and care of COVID patients. Early impacts of the COVID-19 pandemic demonstrated women had increased worry about ability to pay for (27%) and obtain contraception and other SRH services (28%) [bib_ref] The sexual and reproductive health of adolescents and young adults during the..., Lindberg [/bib_ref] ; worry is fueled by losing income and/or health insurance due to restaurant or retail business closures. ## Pregnancy and childbirth Ongoing COVID-19 pregnancy and childbirth factors range from prevalence, symptoms experienced, comorbidities, birth-related vertical transmission, and transmission in breast milk. Pregnant women are particularly susceptible to infectious diseases, and previous evidence showed viral infections may negatively affect pregnancy outcomes [bib_ref] Respiratory disease in pregnancy, Mehta [/bib_ref]. In a review of 11 studies of pregnant women (N = 9,032) with COVID-19 in China, pregnant women exhibited significantly milder symptoms of fever (28% pregnant women: 83% nonpregnant women), cough (51%:82%), and dyspnea (21%:31%). These data concur with findings of a previous study in China , but may, in part, be due to the younger age of the pregnant patients compared to the N u r s O u t l o o k 7 0 ( 2 0 2 2 ) 2 3 8 À2 4 6 nonpregnant group. Scarce data can be found about COVID infections in early pregnancy, likely biased by the absence of tests performed [bib_ref] Effects of COVID-19 infection during pregnancy and neonatal prognosis: what is the..., De Sousa [/bib_ref]. Early data were unclear as to whether pregnant women have increased risk of severe complications from COVID-19, but a large study from the CDC indicated increased risk. Among the 450,000 studied, admission to an intensive care unit, invasive ventilation, extracorporeal membrane oxygenation, and death were all more likely among pregnant compared to non-pregnant women of similar reproductive age [bib_ref] CDC COVID-19 response pregnancy and infant linked outcomes team Update: Characteristics of..., Zambrano [/bib_ref] [bib_ref] Risk for stillbirth among women with and without COVID-19 at delivery hospitalization-United..., Desisto [/bib_ref]. Of note is the death rate was disproportionately high among non-Hispanic Black individuals. Evidence is scant for the effects of COVID-19 infection on outcomes with normal or complicated pregnancies. Compared to a global preterm delivery rate of between 5% and18% (WHO, 2020), a review of 11 studies of pregnant women with COVID-19 (N = 9,032) showed a preterm delivery rate of 29% [bib_ref] Clinical manifestations and perinatal outcomes of pregnant women with COVID-19: A systematic..., Yee [/bib_ref]. This COVID-19 preterm delivery rate is similar to rates reported for other corona virus outbreaks, for example, with severe acute respiratory syndrome (20%) and Middle East respiratory syndrome (32%). In a review paper of pregnant women with COVID-19, the pregnancy comorbidities of gestational diabetes and fetal distress didn't influence outcomes of the pregnant women or their newborns. The main COVID-19 symptoms were fever (53%, n = 363), cough (42%, n = 290), dyspnea (12%, n = 83) and (12%, n = 83) tested positive but were asymptomatic [bib_ref] Effects of COVID-19 infection during pregnancy and neonatal prognosis: what is the..., De Sousa [/bib_ref]. Higher rates of hospital admissions for preeclampsia in pregnant women with COVID-19 have been reported [bib_ref] Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic..., Mascio [/bib_ref] but data remain insufficient for establishing a clear relationship. Moreover, a COVID-19 diagnosis documented during delivery hospitalization was associated with an increased risk for stillbirth in the U.S., with a stronger association during the period of Delta variant predominance [bib_ref] Risk for stillbirth among women with and without COVID-19 at delivery hospitalization-United..., Desisto [/bib_ref]. Unsettled questions are whether women who get COVID-19 during pregnancy pass on the disease and immunity to their newborns prior to or at the time of delivery. An ongoing controversy is whether mother to fetus in utero transmission of the COVID-19 virus (i.e., vertical transmission) occurs. Prior corona virus infection observations did not provide definitive evidence about vertical transmission; however, influenza and respiratory syncytial viral vertical transmission has been reported [bib_ref] Detection of respiratory syncytial virus (RSV) at birth in a newborn with..., Manti [/bib_ref] [bib_ref] Pandemic (H1N1) 2009 in neonates, Takahashi [/bib_ref]. Findings from a few case studies failed to provide evidence for intrauterine transmission from pregnant women with COVID pneumonia in the third trimester [bib_ref] Severe COVID-19 during pregnancy and possible vertical transmission, Alzamora [/bib_ref] [bib_ref] Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine..., Chen [/bib_ref] , and a metaanalysis supported the lack of evidence (Di [bib_ref] Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic..., Mascio [/bib_ref]. Although scientists say vertical transmission of COVID-19 can occur, the exact risk and mechanism is uncertain. Apparently, the presence of the virus on the placental surface does not always indicate placental infection; viral infection of placental cells does not necessarily mean transmission to the fetus; and when fetal infection does occur, responses are varied and infection does not always mean fetal damage [bib_ref] Tobacco use among adults by sexual orientation: Findings from the population assessment..., Wastnedge [/bib_ref]. In Pennsylvania, of 1,500 women who gave birth from April to August, 2020, 83 tested positive for COVID-19 antibodies. After birth, 73 of their babies had cord blood positive tests for COVID-19 antibodies [bib_ref] Evidence builds that pregnant woman pass COVID antibodies to newborns. The New..., Caron [/bib_ref]. Women who tested positive for COVID-19 earlier in their pregnancy appeared to transfer more antibodies to their babies than those who tested positive closer to delivery. Whether the virus is transmitted through breast milk also remains uncertain and potentially confounded by transmission to baby in other ways, for example, from mothers or hospital personnel during postpartum care. One case showed COVID-19 viral RNA detection in the milk of one pregnant woman and a subsequent COVID-19 positive test for the baby, despite the mother following safety precautions during breastfeeding (surgical mask, washing hands etc.). Other limited data are suggestive that COVID-19 from infected mothers is not transmitted through breast milk [bib_ref] Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine..., Chen [/bib_ref]. Current guidelines advocate mothers continue breastfeeding even if they test positive in the postpartum period. Hand washing and basic hygiene should be followed and women with confirmed COVID-19 should wear a medical grade mask when breastfeeding [bib_ref] National Institutes of Health Office of Research on Women's Health (NIHORWH). (2020)...., Mullins [/bib_ref]. At delivery and postpartum sites, medical team members should wear the recommended protective gear [bib_ref] Effects of COVID-19 infection during pregnancy and neonatal prognosis: what is the..., De Sousa [/bib_ref]. Nearly all vaccines are viewed as safe to be given in pregnancy since generally benefits outweigh potential risks [bib_ref] Pregnancy, postpartum care, and COVID-19 vaccination in 2021, Rasmussen [/bib_ref]. Pregnant women traditionally have been omitted from clinical trials resulting in lack of scientific data on safety of drugs and vaccines for women and their unborn children. Since vaccines are generally considered to be low risk even without rigorous clinical trial data, immunization of pregnant women has been encouraged for influenza and other diseases since the 1960s. Similarly, there is limited evidence about the effects of vaccination on lactating women [bib_ref] COVID-19 vaccination in pregnant and lactating women, Adhikari [/bib_ref]. Nevertheless, the vaccine lipid of mRNA vaccines is unlikely to enter the blood stream, reach breast tissue and even so, transfer into milk. If present in breast milk, it would be digested by the child and unlikely to have biological effects (Academy of Breastfeeding Medicine, 2021). The American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine, and the CDC support making COVID-19 vaccine available to pregnant and lactating women . Emerging data show higher pre-term delivery rates and possible stillbirths in pregnant women with COVID-19 but limited clarity on vertical and breastfeeding transmissions. More research is needed in these areas to inform effective clinical screening, treatment protocols and policy considerations. Risk/ benefit data regarding the effect of vaccines during pregnancy should underpin public health advocacy of vaccines for protecting pregnant women and their newborns. ## Sexual and gender variation groups Investigation into the COVID-19-related health impact on sex and gender variation (SGV) individuals is meager but shows disproportionate impact from the pandemic. Given the complex intersect of sex, sexual orientation, gender identity, and sexual partner behaviors, integrating evidence across studies is challenged by the variations in group and sub-group distinctions. Generally, subgroups include Lesbian, Gay, Bisexual, Transgender, Two-Spirit, Queer, Intersex, and Asexual (LGBT2SQIA+). Although lack of subgroup data disaggregation obscures insights into specifically women's health, some data have emerged during the pandemic for cisgender SGV women (e.g., lesbian or bisexual women, women who have sex with women or identify as other than completely heterosexual). Compared to cisgender heterosexual counterparts, SGV women have pre-existing vulnerabilities and environmental risks that are compounded in context of the COVID-19 pandemic [bib_ref] Sexual and gender minority health vulnerabilities during the COVID-19 health crisis, Gibb [/bib_ref]. Discussed here are: (a) excess prevalence of certain chronic physical and mental health conditions, (b) engagement in healthjeopardizing behaviors such as hazardous substance use, and (c) high stress-related pressures. Superimposed on exposure to COVID-19 for SGV women are accentuated susceptibility for asthma, other respiratory diseases, urinary tract infections, Hepatitis B and C, and perhaps cancer, and heart disease diagnoses [bib_ref] Minority stress and physical health among sexual minorities, Lick [/bib_ref] [bib_ref] Systematic review and meta-analysis of diabetes mellitus, cardiovascular and respiratory condition epidemiology..., Meads [/bib_ref] , as well as depressive mood, anxiety, and suicidal ideation [bib_ref] Mental health in sexual minority and transgender women, Schulman [/bib_ref]. Compared to heterosexual cisgender persons, SGV groups show less robust infectious disease defense markers (systemic inflammation levels, day-to-day cortisol variation and cortisol reactivity), cardiovascular functioning, and allostatic load biomarkers (physiological indicators of cumulative burden of chronic stress and life events) [bib_ref] Sexual and gender minority health vulnerabilities during the COVID-19 health crisis, Gibb [/bib_ref]. Oppressive social circumstances vs conditions inherent to individuals is implied as the problem source. Known to be associated with COVID-19 disease severity (Centers for Disease Control, 2021), a further vulnerability to negative COVID-19 impact for SGV women is heightened rates of hazardous substance use, i.e., alcohol, other drug use, and tobacco. A scoping review of alcohol and other drug use showed SGV women as more likely than heterosexual women to drink, drink heavily, and experience alcohol-related problems and alcohol-use disorders (Hughes, Veldhuis, Drabble, & Wilsnack, 2020), likely contributing to liver, and heart diseases. Supported by less research than for alcohol use, more SGV women engage in drug misuse, including marijuana (now legal in many states) and have diagnosed drug use disorders [bib_ref] Understanding alcohol and marijuana use among sexual minority women during the covid-19..., Bochicchio [/bib_ref] [bib_ref] Research on alcohol and other drug (AOD) use among sexual minority women:..., Hughes [/bib_ref]. Relative to tobacco use, one study showed that women identifying as lesbian or bisexual and reporting attractions to same-sex or both-sexes when compared to fully heterosexual women reported higher use for six tobacco products and were highest out of all SGV subgroups studied (including men) for cigarette and e-cigarette use (Wheldon, Kaufman, Kasza & Moser, 2018). High stress is linked to poorer health status within minority populations, including SGV groups. It is seen to embody stigma, systemic discrimination, other forms of structural violence and marginalization and typified by disparities in access to vital resources such as educational and employment opportunities, wealth, housing, health care, social support, and political power [bib_ref] Sexual and gender minority health vulnerabilities during the COVID-19 health crisis, Gibb [/bib_ref]. In general, more SGV individuals are likely to report economic insecurity plus limited access to social capital, social and health education, supportive community resources, and culturally congruent and sensitive health care. The COVID-19 restricted commerce, movement, and gatherings heightened social isolation, and job loss, among other issues. SGV groups report greater psychological stress associated with social distancing than heterosexuals [bib_ref] Introduction to special issue: impacts of the covid-19 pandemic on LGBTQ+ health..., Drabble [/bib_ref]. A report of a national LGBTQ family poll showed that more families identifying as LGBTQ compared to others reported serious financial difficulties (66%:44%) and job loss (64%:45%) (Movement Advancement Project, 2020). The disproportionately greater numbers that work in highly impacted employment sectors like the service industry exacerbate this dynamic. Intensified by pandemic dynamics is the well-documented, pre-existing difficulty SGV groups have with access to health care free of discrimination. Evidence from a three-cohort study, indicated that compared to adults who identified as completely heterosexual, those identifying as mostly heterosexual, bisexual or gay/lesbian disproportionately reported: (a) experiencing past adverse health care experiences; (b) delaying care; (c) relying on emergency department urgent care; and (d) having unstable health insurance [bib_ref] Sexual orientationrelated disparities in healthcare access in three cohorts of U.S. adults, Tabaac [/bib_ref]. Indeed, the latter SGV groups were 2 to 3 times more likely to report delaying care due to past negative health care experiences. Within the pandemic, specialized gender-affirming care has been severely curtailed, resulting in delays or cancellations of medications, surgeries, and other supportive care and closure of outreach programs (e.g., for illicit drug use treatment) [bib_ref] Sexual and gender minority health vulnerabilities during the COVID-19 health crisis, Gibb [/bib_ref]. Paramount is reversal of these outcomes and acceleration of health care delivery and policy reform toward culturally congruent and inclusive care for vulnerable groups, including for SGV individuals. In summary, more data disaggregated to reveal the vulnerabilities of women representing SGV sub-groups to COVID-19 severity outcomes is sorely needed. ## Access to srh services for women Invoking negative influences on health care available to women are pandemic-related supply disruptions, health care personnel diversions or site shutdowns. Supply chain interruptions for contraceptives curtailed access to ongoing or emergency contraception. Shutdowns have meant no access to care for unwanted pregnancies [bib_ref] Sex and gender disparities in the COVID-19 pandemic, Gausman [/bib_ref] or for prevention and treatment of sexually transmitted infections, including HIV. These dynamics have aggravated the social challenges of unwanted pregnancies, prevalence of sexual disease acquisition/transmission and likely boosted risk of future infertility. The latter in addition to concerns regarding potential infertility issues in women who acquire COVID-19 infections. Access to abortion services has been curtailed in many countries and U.S. states due to movement restrictions and lack of protective equipment for providers [bib_ref] Reproductive health service for women during COVID-19 pandemic, Rizvi [/bib_ref]. Governments of Nepal and India ordered national movement lockdowns for several months that prevented providers and clients from attending clinics, thus restricting access to contraceptive or abortion services. As well, many U.S. states declared time-sensitive abortions as non-essential or elective; by 2020, as many as 11 states had introduced legislation to restrict abortion access. However, in the U.S. after pandemic onset, telehealth consultations for early and medical abortions reportedly increased by 25%. South Africa, Ethiopia and Nepal already had in place the provision of medical abortion at home by nurses via telehealth consultation. During and after the COVID-19 pandemic, it remains to be seen whether/ how telehealth will circumvent barriers to safe abortion access. A further interference with health care access is the high demand for life-saving health care of COVID-19 infected individuals, which has diverted care workers and economic resources away from SRH services and raised concerns for the long-range effects on women's health [bib_ref] COVID-19's impact on women: a stakeholderengagement approach to increase public awareness through..., Allen [/bib_ref]. Particularly in underresourced areas, such diversion leaves low-income women impoverished for ongoing care. In some countries, SRH services were not classed as essential and closed. Marie Stopes International operating in 37 countries predicted that SRH services closures could result in as many as 9.5 million girls and women losing access to contraception and safe abortion in 2020 and could result in as many as 2.7 million unsafe abortions and 11,000 pregnancy-related deaths. Even if SRH services remain available, loss of income, lack of health insurance plus increased role demands, mainly from "stay at home" orders during the pandemic, has led to patient delays in visiting SRH care providers. Some of this delay is attributed to women's fear of being unable to afford SRH care. According to a pandemic-related Guttmacher survey of reproductive health experiences, one in three women reported delaying or canceling a health care provider visit for SRH care or had trouble obtaining birth control. More Black (38%) and Hispanic (45%) women than White women (29%) and more queer (46%) than straight women (31%) reported SRH interferences. Also, lower-income women were more likely than higher-income women to report delays or being unable to get contraceptive or SRH care due to the pandemic (36% vs. 31%) . Particularly vulnerable are underserved youth, immigrants, LGBTQ+, homeless, and those in the foster care and criminal justice systems . Some clinic staff reported declining numbers of patients possibly due to fears of infection, but possibly due to limited public transportation. In summary, the most under-advantaged women are more likely to suffer the consequences of diminished health care services. While telehealth has filled some of the SRH service gaps, not all women have easy access to this type of service. Given that pharmacies have remained open, promoting clinical services through them by aligned policies for expedient access to self-use SRH products (e.g., condoms, contraceptives pills, patches rings, emergency contraception, standard days method, and potentially self-injection of subcutaneous depot medroxyprogesterone acetate) seems prudent. ## Key points for research, practice and policy Our commentary regarding the consequences of the COVID-19 pandemic for women's health points to the need for greater clarity of sex/gender differences in viral infection susceptibility, manifestations, disease trajectory, treatment responses and short/long-term recovery as a springboard for better health care delivery plus relevant health policy that supports optimal health care services. Research support is available from public and private funders. Examples can be found at https://grants.nih.gov; https;//research.sdsu. edu; and https://crsreports.congress.gov. As evidence emerges, rapid translation into practice and clinical services supported by relevant policy substantiation and reinforcement is crucial. SRH services restoration and preservation with integration of in-person and online access should support family planning, healthy pregnancies, agerelated disease screening and treatment and health/wellness promotion delivered as inclusive, sensitive and congruent care for all individuals regardless of racial/ethnic origins, sexual orientation/identity and socioeconomic status. See [fig_ref] Table 1: -AAN Policy Priorities & Women's Sexual/Reproductive Health and Access Challenges amid COVID-19... [/fig_ref] for a summary. [table] Table 1: -AAN Policy Priorities & Women's Sexual/Reproductive Health and Access Challenges amid COVID-19 Research is needed in support of: a. Uncovering sex differences in multiple mechanisms of viral biological defense and infectious consequences b. Individuals with a strong desire to live as another sex or are undecided about being male or female Socioeconomic Stressors We recommend policies which directly support the downstream effects of COVID-19 on women's unemployment, employment, and childcare benefits and resources given that women overwhelmingly serve as primary care givers and constitute nearly half of the US workforce Policy Recommendations:1. Encourage government subsidies to replace pay for women who provide child care or serve as informal or formal caregiver during the pandemic 2. Suspend work requirements for government assistance programs until school and daycare centers fully re-open and for those serving as unpaid caregivers for family members who are COVID-19 infected 3. Remove requirement to be actively seeking work to obtain unemployment insurance until school and daycare centers re-open 4. Extend unemployment benefits to workers who voluntarily leave employment to provide childcare and caregiving to loved ones 5. Extend tenure clocks for junior faculty in response to the COVID-19 pandemic; address gender disparities during the pandemic as more women than men are responsible for childcare that may not allow them to conduct research and scholarship Pregnancy and Childbirth We recommend policies requiring data reporting and gathering on the effects of COVID-19 on pregnancy and birth outcomes. [/table]	None	http://www.nursingoutlook.org/article/S0029655422000033/pdf	None
bfead8e40b1177160d2e60a97bb5fa0b97329aa0	pubmed	Secondary Prevention of Cervical Cancer: ASCO Resource–Stratified Guideline Update	Secondary Prevention of Cervical Cancer: ASCO Resource–Stratified Guideline Update PURPOSE To update resource-stratified, evidence-based recommendations on secondary prevention of cervical cancer globally.METHODS American Society of Clinical Oncology convened a multidisciplinary, multinational Expert Panel to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, formal consensus-based process, and modified ADAPTE process to adapt existing guidelines was conducted. Other experts participated in formal consensus.RESULTSThis guideline update reflects changes in evidence since the previous update. Five existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement.RECOMMENDATIONS Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies vary by the following setting: maximal: age 25-65 years, every 5 years; enhanced: age 30-65 years, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: age 30-49 years, every 10 years; basic: age 30-49 years, one to three times per lifetime. For basic settings, visual assessment is used to determine treatment eligibility; in other settings, genotyping with cytology or cytology alone is used to determine treatment. For basic settings, treatment is recommended if abnormal triage results are obtained; in other settings, abnormal triage results followed by colposcopy is recommended. For basic settings, treatment options are thermal ablation or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure or ablation is recommended; with a 12-month follow-up in all settings. Women who are HIV-positive should be screened with HPV testing after diagnosis, twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed.Additional information is available at www.asco.org/resource-stratified-guidelines.JCO Global Oncol 8:e2200217. # Introduction The purpose of this guideline is to provide updated expert guidance on the secondary prevention of cervical cancer to clinicians, public health authorities, policymakers, and laypersons in all resource settings. The target population is women in the general population at risk for developing cervical cancer (specific target age depends on the resource level). There are large disparities regionally and globally in incidence of and mortality resulting from cervical cancer, in part because of disparities in the provision of mass screening and primary prevention. Different regions of the world, both among and within countries, even within districts, differ with respect to access to prevention and, also, treatment. In addition, marginalized populations within the United States face barriers to cervical cancer screening. Black, Asian, Pacific Islander, Native Hawaiians/other Pacific Islanders, American Indians or Alaskan Natives, and Hispanics are less likely to receive screening compared with White people to undergo cervical cancer screening. [bib_ref] Persistent racial disparities in cervical cancer screening with Pap test, Mcdaniel [/bib_ref] Sexual and gender minority people, particularly sexual and gender minority people of color, are also less likely to undergo cervical cancer - HPV DNA testing is recommended in all resource settings, either self-or clinician-collected. - The recommended age ranges (years) and frequencies in each setting are as follows: - maximal, age 25-65 years every 5 years - enhanced, age 30-65 years, if two consecutive negative tests at 5-year intervals, then 10 years - limited, age 30-49 years every 10 years - basic, not more than every 10 years (with a plan to transition to not less than every 5 years). - VIA may be used in basic settings and should move to population-based screening with HPV testing at the earliest opportunity. Exiting screening. - Maximal and enhanced: age 65 years with consistently negative results during the past ≥ 15 years. - Limited and basic: age 49 years, resource-dependent, see specific recommendations. Triage. - In basic settings, when a molecular (HPV) test is used for screening and has a positive result, visual assessment for treatment may be used to determine whether the woman should be treated with thermal ablation or loop electrosurgical excision procedure (LEEP). - For other settings, HPV genotyping with cytology or cytology alone may be used. After triage (if a triage test was performed). - Women with negative triage results should receive a follow-up HPV test in 12 months (if primary screening was positive and then triage results were negative, then follow-up at 12 months). - In limited settings, women with abnormal results from triage should receive colposcopy, if available, or treatment, if it is not. - In maximal and enhanced settings, women with abnormal and/or positive results from triage should receive colposcopy. ## Treatment of women with precursor lesions. - In basic and limited settings, treatment options are thermal ablation or LEEP, if a high level of quality assurance is recommended (for LEEP). - In enhanced and maximal settings, LEEP (if there is a high level of quality assurance) or, where LEEP is contradicted, ablative treatments may be offered. - A 12-month post-treatment follow-up including HPV testing is recommended for all settings. Special populations. - Women who are HIV-positive or immunosuppressed for other reasons should be screened with HPV as soon as diagnosed, twice as many times in a lifetime as the general population. (continued on following page) screening given a myriad of barriers to primary care including stigma and structural discrimination. [bib_ref] Human papillomavirus vaccination initiation among sexual orientation identity and racial/ethnic subgroups of..., Agenor [/bib_ref] [bib_ref] Breast and cervical cancer screening disparities in transgender people, Oladeru [/bib_ref] [bib_ref] Enacting power and constructing gender in cervical cancer screening encounters between transmasculine..., Peitzmeier [/bib_ref] American Society of Clinical Oncology (ASCO) published its first guideline on secondary prevention of cervical cancer in 2016. [bib_ref] Secondary prevention of cervical cancer: ASCO resource-stratified clinical practice guideline, Jeronimo [/bib_ref] In 2021 and 2019, the WHO published updated guidelines on screening and treatment and the use of thermal ablation, respectively, for eligible women in all settings; this guideline reinforces those recommendations; in addition, updated US guidelines from American Cancer Society (ACS), American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Task Force were published. The screening modalities addressed by these five guidelines, as well as in this guideline, include cytology (also known as Pap smear), visual inspection (eg, visual inspection with acetic acid [VIA]), and human papillomavirus (HPV) DNA testing (screening); for evaluation of positive results, the WHO guidelines include colposcopy, and for treatment, excisional and ablative treatments. The screening tests are sometimes used and have been studied alone or in combination. The guidelines that ASCO reviewed are described in the Data Supplement (Appendix [fig_ref] TABLE 1: Four-Tiered Resource Settings for Secondary Prevention [/fig_ref]. (This ASCO guideline also addresses self-collection and emerging screening technologies.) ASCO has established a process for resource-stratified guidelines, which includes mixed methods of guideline development, adaptation of the clinical practice guidelines of other organizations, and formal expert consensus. This article summarizes the results of that process and presents updated resource-stratified recommendations, which are based, in part, on formal consensus and adaptation from existing guidelines on the screening, triage of screening results, and treatment of women with cervical cancer precursor lesions (the Results section and Appendix [fig_ref] TABLE 1: Four-Tiered Resource Settings for Secondary Prevention [/fig_ref] list these guidelines). Although we refer to the sex of cervical cancer screening eligible people as women throughout this guideline document, all people with cervixes are eligible for cervical screening and the guidelines apply uniformly to all such people. This mirrors the statement of WHO in its screen and treat guideline (p. 23), which states, in part, that WHO recommendations "recognize that most of the available evidence on cervical cancer is based on study populations of cisgender women" and "sexual and reproductive health service providers and cervical cancer prevention services must consider the needs ofand provide equal care toall individuals independently of gender identity or its expression." 7 ASCO uses an evidence-based approach to inform guideline recommendations. In developing resourcestratified guidelines, ASCO has adopted its framework from the four-tier approach (basic, limited, enhanced, and maximal; [fig_ref] TABLE 1: Four-Tiered Resource Settings for Secondary Prevention [/fig_ref] developed by the Breast Health Global Initiative and made modifications to that framework on the basis of the Disease Control Priorities 3. [bib_ref] Breast cancer in limited-resource countries: An overview of the breast health global..., Anderson [/bib_ref] [bib_ref] Cancer in low-and middle-income countries: An economic overview, Horton [/bib_ref] Separate ASCO resource-stratified guidelines provide guidance on the treatment of women with invasive cervical cancer 10,11 and primary prevention. 12 ## Guideline questions This clinical practice guideline addresses four overarching clinical questions: (1) What are the best method(s) for screening for each resource stratum? [bib_ref] Human papillomavirus vaccination initiation among sexual orientation identity and racial/ethnic subgroups of..., Agenor [/bib_ref] What is the best triage and/or management strategy for women with positive results or other abnormal (eg, discordant HPV and/or THE BOTTOM LINE (CONTINUED) - The management of abnormal results for screening for women with HIV and positive results of triage is the same as in the general population. - Women who are postpartum should be offered primary screening 6 weeks postpartum in basic settings and at 6 months in other settings. - Screening may be discontinued in women who have received a total hysterectomy for benign causes with no history of cervical dysplasia or HPV. Women who have received a subtotal hysterectomy (with an intact cervix) should continue receiving routine screening. Qualifying statement. In basic settings without current mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed. Complete recommendations are given in Appendix [fig_ref] TABLE A2: Summary of Recommendations [/fig_ref]. ## Additional resources Definitions for the quality of the evidence and strength of recommendation ratings are available in Appendix In addition, the guideline addresses screening and management strategies for defined special populations. # Methods These recommendations were developed by an ASCO Expert Panel with multinational and multidisciplinary representation, which included a patient representative and an ASCO guidelines staff member with health research methodology expertise (Appendix [fig_ref] TABLE A4: Panel Members [/fig_ref]. The Expert Panel met via webinar and corresponded through e-mail. On the basis of the consideration of the evidence, the authors were asked to contribute to the development of the guideline, provide critical review, and finalize the guideline recommendations. The guideline recommendations were sent for Formal Consensus review and for an open comment period of 2 weeks, allowing the public to review and comment on the recommendations after submitting a confidentiality agreement. These comments were taken into consideration while finalizing the recommendations. Members of the Expert Panel were responsible for reviewing and approving the penultimate version of the guideline, which was then circulated for external review and submitted to a peer-reviewed journal for editorial review and consideration for publication. Apply acetic acid to cervix to determine whether a woman is eligible for ablative treatment. VAT is scored as eligible or ineligible. All VAT-eligible women will be offered ablative treatment; ineligible women will be referred for other treatment. Core resources or fundamental services absolutely necessary for any public health/primary health care system to function; basic-level services typically are applied in a single clinical interaction; screening is feasible for highest-need populations. Limited: Second-tier resources or services that produce major improvements in outcomes, such as incidence and cost effectiveness, but that are attainable with limited financial means and modest infrastructure; limited-level services may involve single or multiple interactions; universal public health interventions are feasible for a greater percentage of population than the primary target group. Enhanced: Third-tier resources or services that are optional but important; enhanced-level resources may produce further improvements in outcome but increase the number and quality of screening/treatment options and individual choice (perhaps ability to track patients and links to registries). Maximal: May use high-resource settings' guidelines; high-level/state-of-the art resources or services that may be used or in some high-resource countries and/or may be recommended by high-resource setting guidelines that do not adapt to resource constraints; this should be considered lower priority than in the other settings on the basis of cost impracticality for limited-resource environment. NOTE. Data adapted. [bib_ref] Breast cancer in limited-resource countries: An overview of the breast health global..., Anderson [/bib_ref] [bib_ref] Cancer in low-and middle-income countries: An economic overview, Horton [/bib_ref] Panel (Appendix provides a list of members). Eleven experts (plus eight who were on the Expert Panel) participated. All ASCO guidelines are ultimately reviewed and approved by the Expert Panel and the ASCO Evidence-Based Medicine Committee before publication. All funding for the administration of the project was provided by ASCO. The guideline development process was also informed by the ADAPTE methodology [bib_ref] The ADAPTE process: resource toolkit for guideline adpatation. Version2.0: Guideline International Network, The [/bib_ref] ; this and consensus processes were used together as an alternative to de novo recommendation development. Adaptation of guidelines is considered by ASCO in selected circumstances, when one or more quality guidelines from other organizations already exist on the same topic. The objective of the ADAPTE process is to take guideline. On the basis of the formal review of the emerging literature, ASCO will determine the need to update. The ASCO Guidelines Methodology Manual (available at www.asco.org/guideline-methodology) provides additional information about the guideline update process. This is the most recent information as of the publication date. ## Guideline disclaimer The Clinical Practice Guidelines and other guidance published herein are provided by the ASCO to assist providers in clinical decision making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations specify the level of confidence that the recommendation reflects the net effect of a given course of action. The use of words like "must," "must not," "should," and "should not" indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO does not endorse third party drugs, devices, services, or therapies used to diagnose, treat, monitor, manage, or alleviate health conditions. Any use of a brand or trade name is for identification purposes only. ASCO provides this information on an "as is" basis and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions. ## Guideline and conflict of interest The Expert Panel was assembled in accordance with ASCO's Conflict of Interest Policy Implementation for Clinical Practice Guidelines ("Policy," found at https://www. asco.org/guideline-methodology). All members of the Expert Panel completed ASCO's disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker's bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Policy, the majority of the members of the Expert Panel did not disclose any relationships constituting a conflict under the Policy. ## Note Where authors are identified as personnel of the International Agency for Research on Cancer and/or WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer or WHO. # Results ## Characteristics of studies identified in the literature search As part of the systematic literature review, updates of previous non-ASCO guidelines that ASCO adapted in 2016 were reviewed. On the basis of these reviews of the results, the Expert Panel selected five high-quality guidelines from ACS, [bib_ref] Cervical cancer screening for individuals at average risk: 2020 guideline update from..., Fontham [/bib_ref] ASCCP, [bib_ref] ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and..., Perkins [/bib_ref] and US Preventive Task Force 17 and two from WHO for adaptation. In addition, the IARC perspective on cervical cancer screening informed the context of the guideline update development. [bib_ref] The IARC perspective on cervical cancer screening, Bouvard [/bib_ref] The identified guidelines were published between 2018 and 2021. Five were all or in part systematic review (SR)based guidelines. [bib_ref] American Society for Colposcopy and Cervical Pathology, and American Society for Clinical..., Saslow [/bib_ref] All but the WHO guidelines were developed for maximal resource-level settings; the WHO guideline has the largest global constituency. Costeffectiveness analyses (CEAs) were also reviewed. Because of lack of evidence for some clinical questions, formal expert consensus was used. An overview of and information on these guidelines' clinical questions, target populations, development methodology, and key evidence is presented in the Data Supplement. The evidence and guidelines supporting unchanged recommendations are reviewed in the previous guideline publication. [bib_ref] Secondary prevention of cervical cancer: ASCO resource-stratified clinical practice guideline, Jeronimo [/bib_ref] ## Recommendations (only changes are discussed below) Primary Screening Discussion All the primary screening recommendations now include self-collection as an option for samples to test. This is consistent with WHO guidance, discussed in the IARC Handbook, 27 and the addition is a change from the previous ASCO guideline. Self-collection may be more acceptable to some people, including transgender people, less resourceintensive than clinician-collected samples, and its accuracy is like clinician-collected samples. 28 WHO based its recommendation on a meta-analysis of HPV testing on self-collection versus clinician-collected samples, Arbyn et al 29 originally performed in 2018 and updated in 2020, which showed similar specificity and sensitivity on polymerase chain reaction-based HPV DNA testing. In addition, it may be more cost-effective. Self-collection is highly sensitive and feasible; regions should start pilot projects at a minimum. ASCO continues to recommend HPV DNA screening over cytology or cotesting (ie, HPV DNA testing plus cytology) in all settings and 5-year frequency in maximal and enhanced settings, with encouragement that limited and basic settings move toward this frequency. Cost-effectiveness analyses The 2016 guideline reviewed several CEAs-this section presents data from CEAs conducted since then. Maximal-resource settings: A cost-effectiveness study modeling screening of unvaccinated women in Sweden found that primary HPV testing was more cost-effective than alternative strategies. 30 A cost-effectiveness study on the basis of a randomized clinical trial (RCT) in Canada found that primary HPV testing was less costly and more effective at detecting precursor lesions than cytology-based screening. A modeling study from Norway found that self-collected HPV testing may be more cost-effective than clinician-collected HPV testing 31 screening programs, and other studies project that HPV self-collection offered to underscreened women may increase health benefits and be cost-effective. 32,33 Limited-resource settings: Several CEAs in middle-income countries (ie, Iran, El Salvador, and China) have also examined primary HPV screening intervals of 5 years and found these to be an efficient use of resources. 34-36 In settings where screening coverage is low, it is generally more cost-effective to expand coverage of unscreened women rather than increasing the number of lifetime screenings among women who already have access. 37 Depending on the delivery model and uptake among underscreened women, HPV self-collection may be a costeffective strategy to expand coverage in low-resource settings and among underscreened people, including transgender people, in higher-resource settings. [bib_ref] Breast and cervical cancer screening disparities in transgender people, Oladeru [/bib_ref] Recommendation 4.1-screening in basic settings. Health systems in basic settings should move to population-based screening with HPV testing at the earliest opportunity (either self-or clinician-collected). If HPV DNA testing for cervical cancer screening is not available, then VIA should be offered with the goal of developing health systems. Screening should be offered to women 30-49 years of age, not more than every 10 years (with a plan to transition to not less than every 5 years). This section specifically regards the portion that says "Health systems in basic settings should move to population-based screening with HPV testing at the earliest opportunity (either self-or cliniciancollected). If HPV DNA testing for cervical cancer screening is not available, then VIA should be offered with the goal of developing health systems." Discussion These updated recommendations are based on the WHO guideline and formal consensus. WHO recommends "using HPV DNA detection as the primary screening test rather than VIA or cytology" (source: WHO screen and treat, 7 p. xi, recommendation 1 and recommendation 21 [latter for those with HIV]). WHO considered the balance of benefits and risks when comparing VIA and HPV DNA testing and based the recommendation on RCTs and modeling. In basic settings, where there is no mass screening and no culture of screening, VIA may be used, with the goal of moving to population-based screening with HPV testing at the earliest opportunity. In addition, the recommendation continues to state that in limited settings, the recommended age range is 30-49 years. When more resources become available, policymakers may consider extending the upper age range. Qualifying statement: In limited settings, the preference is to do direct treatment, with triage using partial genotyping. Discussion In basic settings, visual assessment for treatment (VAT) after positive HPV DNA results is recommended to determine the appropriate type of treatment . Regarding the portion of Recommendation 3.2 (Limited) with the inclusion of the statement that if institutions are currently using reflex cytology, they should transition from cytology to HPV genotyping. The Panel recommends that in basic settings where a molecular (HPV) test is used as the primary screening test, and further triage testing is not feasible, all positive results are referred for VAT to determine whether ablation or excisional procedures should be used for treatment. When programs use self-collection, partial genotyping may be more possible because of its lower cost than that of cytology. Partial genotyping is preferred because it is less resource-intensive, and if the patient does not have a highrisk variant of HPV, they may not need treatment. The Panel added a qualifying statement preferring provision of direct treatment in limited settings to reduce the number of visits that a person in the screening algorithm must make. Direct treatment of everyone who has positive primary screening results, aka screen-and-treat, can reduce the possibility of losing patients to follow-up. If direct treatment is not feasible or acceptable, the options could be either partial genotyping or treating only those who are HPV 16/18-positive or VIA-based triage, as enumerated in the 2019 ASCCP guidelines. [bib_ref] ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and..., Perkins [/bib_ref] Although even large programs might not have that option, over time, most programs will transition to self-sampling with partial genotyping. The recommendations are based on the trade-off between feasibility and desirability of high-quality impact, noting that different health systems and countries will have to weigh clinical performance with the ability to perform certain treatments and tests. Cost-effectiveness analyses The cost-effectiveness of HPV screen-and-treat versus HPV screen-triage-treat algorithms (with triage strategies including HPV 16/18 genotyping, VIA, colposcopy, and cytology) has been evaluated in several studies. 7,44-46 HPV screen-and-treat has generally been found to be a more cost-effective strategy, because of limited screening opportunities in lower-resource settings and the need to maximize detection of people at high risk of cervical cancer; however, the high burden of HPV in some settings may overwhelm the capacity to provide treatment, making triage testing necessary. Few studies have examined the cost-effectiveness of HPV 16/18 genotyping in limited settings, but it appears to have similar costs and only slightly lower benefits than HPV screen-and-treat. 7 Ablation is now recommended in basic settings (as it was already in limited settings). Discussion In 2016, the ASCO guideline did not recommend thermal ablation over other treatments for patients with precursor lesions in the basic setting; it was already recommended in limited settings. More evidence has become available since that time. WHO produced a guideline on thermal ablation, published in 2019, comparing ablation with cryotherapy and surgical approaches. For the 2019 version, WHO used evidence from RCTs, SRs, and meta-analyses and data from ongoing trials and assessed the evidence with Grading of Recommendations, Assessment, Development and Evaluations. They found no difference between benefits and harms of cryotherapy and thermal ablation. Cryotherapy is less feasible, has issues with availability of parts of its process (eg, with supply), and is more costly. 18 Therefore, ablation is more feasible and at lower cost, and providers may find it more acceptable and usable with less delay than cryotherapy. Therefore, the Expert Panel states a preference for ablation and recommends institutions transition from cryotherapy. Maximal and enhanced. Overall: There are no changes in the maximal and enhanced setting recommendations, except for self-collection. ## Asco recommendations for special populations Recommendations for populations such as those with HIV have not changed and are consistent with WHO recommendations. ASCO recommendations on the screening strategy for women who have received HPV vaccination The previous recommendation to continue screening in women who have received HPV vaccination is still in force. Recommendations for women who have received HPV vaccination have not changed, and these populations should continue to receive screening. HPV-based screening at 5-year intervals is recommended for women who have received HPV vaccination until there are further data on the efficacy of the currently available HPV vaccines in preventing all cases of CIN2+. ## Cost and policy implications The secondary prevention of cervical cancer is a costeffective strategy to reduce the incidence and mortality of cervical cancer. CEAs discussed in this guideline support the use of HPV DNA tests in maximal, enhanced, limited, and basic resource settings. However, there are specific implementation issues regarding providing screening and treatment in limited and basic settings in primary care, outside of research studies. In addition to cost and policy implications discussed in the 2016 guideline and in this version, other delivery strategies may involve some combination of screening campaigns, mobile clinics, and HPV self-sampling. 48,49 These strategies can improve screening uptake and linkage to treatment for screen-positive women. Although several novel biomarkers for triage of HPV-positive women remain to be validated, incorporating triage tests that identify women at high risk of cervical precancer may improve the cost-effectiveness of screening if fewer women can be treated while avoiding false-negative screening results. In addition to providing value, accurate triage tests may avert overburdening health care systems in settings with a high prevalence of HPV. ## External review and open comment The draft recommendations were released to the public for open comment from April 12 through April 22, 2022. Response categories of "Agree as written," "Agree with suggested modifications," and "Disagree. See comments" were captured for every proposed recommendation with 34 written comments received. A total of 85%-100% of the 34 responses either agreed or agreed with slight modifications to the recommendations, and 0%-15% of the responses disagreed. Expert Panel members reviewed comments from all sources and determined whether to maintain original draft recommendations, revise with minor language changes, or consider major recommendation revisions. All changes were incorporated before Evidence-Based Medicine Committee review and approval. ## Guideline implementation ASCO guidelines are developed for implementation across health settings. Barriers to implementation include the need to increase awareness of the guideline recommendations among front-line practitioners and women in general populations and also to provide adequate services in the face of limited resources. Implementation should reflect the latest implementation research. The guideline Bottom Line Box was designed to facilitate the implementation of recommendations. This guideline will be distributed widely, including through many forms of ASCO communications and the ASCO website. # Limitations of research There were limitations in the evidence regarding screening after HPV vaccination and emerging technologies. Future research is suggested in these areas. ## Future directions In addition to addressing research limitations, future research is needed in other areas, eg, self-collection, biomarkers, needs and preferences of women/people with cervixes, improving screening for transgender people, cost-effective strategies, lowcost technology, and the impact of vaccination on screening. Addressing policy and health system barriers may include the following: - Education of medical and public health communities to change practices and incorporate new technologies - Participation and sponsorship from policymakers - Partnerships with institutions, regions, and countries with treatment facilities - Coordinated volume purchasing and procurement of HPV testing - Improvement of health information systems to have better follow-up and treatment of women with positive screening results - Quality control - Monitoring and evaluation - Assessing the impact of COVID-19 disease ASCO believes that cancer and cancer prevention clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate. ## Additional resources Additional information including a supplement with additional tables and clinical tools and resources is available at www.asco.org/resource-stratified-guidelines. Patient information is available at www.cancer.net. ## Gender-inclusive language ASCO is committed to promoting the health and well-being of individuals regardless of sexual orientation or gender identity. Transgender and nonbinary people, in particular, may face multiple barriers to oncology care including stigmatization, invisibility, and exclusiveness. One way that exclusiveness or lack of accessibility may be communicated is through gendered language that makes presumptive links between gender and anatomy. 51-54 With the acknowledgment that ASCO guidelines may affect the language used in clinical and research settings, ASCO is committed to creating gender-inclusive guidelines. For this reason, guideline authors use gender-inclusive language whenever possible throughout the guidelines. In instances in which the guideline draws upon data on the basis of gendered research (eg, studies regarding women with ovarian cancer), the guideline authors describe the characteristics and results of the research as reported. ## Affiliations disclaimer It is the view of American Society of Clinical Oncology that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guidelines are intended to complement but not replace local guidelines. ## Editor's note ## This american society of clinical oncology (asco) clinical practice Guideline provides recommendations, with comprehensive review and analyses of the relevant literature for each recommendation. Additional information, including a supplement with additional evidence tables, slide sets, clinical tools and resources, and links to patient information at www. cancer.net, is available at www.asco.org/resource-stratified-guidelines. # Equal contribution ## Term definitions Quality of evidence High High confidence that the available evidence reflects the true magnitude and direction of the net effect (eg, balance of benefits v harms) and further research is very unlikely to change either the magnitude or direction of this net effect Intermediate Intermediate confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research is unlikely to alter the direction of the net effect; however, it might alter the magnitude of the net effect Low Low confidence that the available evidence reflects the true magnitude and direction of the net effect. Further research may change the magnitude and/or direction of this net effect Insufficient Evidence is insufficient to discern the true magnitude and direction of the net effect. Further research may better inform the topic. Reliance on consensus opinion of experts may be reasonable to provide guidance on the topic until better evidence is available # Strength of recommendation ## Strong There is high confidence that the recommendation reflects best practice. This is based on the following: Strong evidence for a true net effect (eg, benefits exceed harms); Consistent results, with no or minor exceptions; Minor or no concerns about study quality; and/or The extent of panelists' agreement. Other compelling considerations (discussed in the guideline's literature review and analyses) may also warrant a strong recommendation ## Moderate There is moderate confidence that the recommendation reflects best practice. This is based on the following: Good evidence for a true net effect (eg, benefits exceed harms); Consistent results with minor and/or few exceptions; Minor and/or few concerns about study quality; and/or The extent of panelists' agreement. Other compelling considerations (discussed in the guideline's literature review and analyses) may also warrant a moderate recommendation ## Weak There is some confidence that the recommendation offers the best current guidance for practice. This is based on the following: Limited evidence for a true net effect (eg, benefits exceed harms); Consistent results, but with important exceptions; Concerns about study quality; and/or The extent of panelists' agreement. Other considerations (discussed in the guideline's literature review and analyses) may also warrant a weak recommendation [fig] Recommendation 3. 3: Limited): If cytology triage results are abnormal (ie, ≥ atypical squamous cells of undetermined significance), women should be referred to quality-assured colposcopy (the first choice, if available and accessible for women who are ineligible for thermal ablation), during which biopsies of any acetowhite (or suggestive of cancer) areas should be taken, even if the acetowhite lesion might appear insignificant. If colposcopy is not available, then perform VAT. (Type: evidence-based; Evidence quality: intermediate; Strength of recommendation: moderate.)Addition of clarification of use of colposcopy in limited: The Panel added women who are ineligible for thermal ablation to the cytology triage recommendation. If a person has positive results and is eligible for thermal ablation and with a low suspicion of cancer, they can proceed to treatment without colposcopy, in part, to lessen number of recalls. However, if clinicians have a higher suspicion of cancer and patients have factors making them ineligible for ablation, colposcopy is used to rule out cancer. This is in line with the ASCCP guidance and the WHO thermal ablation guideline.TreatmentMaximal and enhanced. There are no changes in the maximal and enhanced setting recommendations. [/fig] [fig] Recommendation 4. 2: Basic): If the results of available HPV testing are positive, clinicians should then perform VAT followed by treatment with thermal ablation and/or loop electrosurgical excision procedure, depending on the size and location of the lesion. (Type: formal consensus-based; Evidence quality: low; Strength of recommendation moderate.) [/fig] [fig] Recommendation 4. 3: Basic): If primary screening is VIA and results are positive, then treatment should be offered with thermal ablation and/or loop electrosurgical excision procedure, depending on the size and location of the lesion. (Type: evidence-based; Evidence quality: intermediate; Strength of recommendation: moderate.) [/fig] [table] Table A3: More information, including a supplement with additional evidence tables, slide sets, and clinical tools and resources, is available at https://www.asco.org/practice-patients/guidelines/resource-stratified. Patient information is available at www.cancer.net.ASCO believes that cancer and cancer prevention clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate. [/table] [table] TABLE 1: Four-Tiered Resource Settings for Secondary Prevention [/table] [table] TABLE A1: Adapted Guidelines and Links [/table] [table] TABLE A2: Summary of Recommendations [/table] [table] TABLE A4: Panel Members [/table]	None	https://ascopubs.org/doi/pdfdirect/10.1200/GO.22.00217?role=tab	PURPOSE To update resource-stratified, evidence-based recommendations on secondary prevention of cervical cancer globally. METHODS American Society of Clinical Oncology convened a multidisciplinary, multinational Expert Panel to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, formal consensus-based process, and modified ADAPTE process to adapt existing guidelines was conducted. Other experts participated in formal consensus. RESULTS This guideline update reflects changes in evidence since the previous update. Five existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement. RECOMMENDATIONS Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies vary by the following setting: maximal: age 25-65 years, every 5 years; enhanced: age 30-65 years, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: age 30-49 years, every 10 years; basic: age 30-49 years, one to three times per lifetime. For basic settings, visual assessment is used to determine treatment eligibility; in other settings, genotyping with cytology or cytology alone is used to determine treatment. For basic settings, treatment is recommended if abnormal triage results are obtained; in other settings, abnormal triage results followed by colposcopy is recommended. For basic settings, treatment options are thermal ablation or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure or ablation is recommended; with a 12-month follow-up in all settings. Women who are HIV-positive should be screened with HPV testing after diagnosis, twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed. Additional information is available at www.asco.org/resource-stratified-guidelines.
262d063e82e842d7b7178a33cf3d352c7995af86	pubmed	Triage of patients with venous and lymphatic diseases during the COVID-19 pandemic – The Venous and Lymphatic Triage and Acuity Scale (VELTAS)	Triage of patients with venous and lymphatic diseases during the COVID-19 pandemic – The Venous and Lymphatic Triage and Acuity Scale (VELTAS) The coronavirus disease 2019 global pandemic has resulted in diversion of healthcare resources to the management of patients infected with SARS-CoV-2 virus. Elective interventions and surgical procedures in most countries have been postponed and operating room resources have been diverted to manage the pandemic. The Venous and Lymphatic Triage and Acuity Scale was developed to provide an international standard to rationalise and harmonise the management of patients with venous and lymphatic disorders or vascular anomalies. Triage urgency was determined based on clinical assessment of urgency with which a patient would require medical treatment or surgical intervention. Clinical conditions were classified into six categories of: (1) venous thromboembolism (VTE), (2) chronic venous disease, (3) vascular anomalies, (4) venous trauma, (5) venous compression and (6) lymphatic disease. Triage urgency was categorised into four groups and individual conditions were allocated to each class of triage. These included (1) medical emergencies (requiring immediate attendance), example massive pulmonary embolism; (2) urgent (to be seen as soon as possible), example deep vein thrombosis; (3) semi-urgent (to be attended to within 30-90 days), example highly symptomatic chronic venous disease, and (4) discretionary/non-urgent-(to be seen within 6-12 months), example chronic lymphoedema. Venous and Lymphatic Triage and Acuity Scale aims to standardise the triage of patients with venous and lymphatic disease or vascular anomalies by providing an international consensus-based classification of clinical categories and triage urgency. The scale may be used during pandemics such as the current COVID-19 crisis but may also be used as a general framework to classify urgency of the listed conditions.European Venous Forum (EVF)Interventional Radiology Society of Australasia (IRSA) [bib_ref] Phlebology training curriculum. A consensus document of the International Union of Phlebology..., Parsi [/bib_ref] Latin American Venous Forum (LAVF) [bib_ref] Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study, Decousus [/bib_ref] Venous Association of India (VAI) [bib_ref] Medical management of acute superficial vein thrombosis of the saphenous vein, Scovell [/bib_ref] European College of Phlebology (ECoP) # Abstract The coronavirus disease 2019 (COVID-19) global pandemic has resulted in diversion of healthcare resources to the management of patients infected with SARS-CoV-2 virus. Elective interventions and surgical procedures in most countries have been postponed and operating room resources have been diverted to manage the pandemic. The Venous and Lymphatic Triage and Acuity Scale was developed to provide an international standard to rationalise and harmonise the management of patients with venous and lymphatic disorders or vascular anomalies. Triage urgency was determined based on clinical assessment of urgency with which a patient would require medical treatment or surgical intervention. Clinical conditions were classified into six categories of: (1) venous thromboembolism (VTE), (2) chronic venous disease, (3) vascular anomalies, (4) venous trauma, (5) venous compression and (6) lymphatic disease. Triage urgency was categorised into four groups and individual conditions were allocated to each class of triage. These included (1) medical emergencies (requiring immediate attendance), example massive pulmonary embolism; (2) urgent (to be seen as soon as possible), example deep vein thrombosis; (3) semi-urgent (to be attended to within 30-90 days), example highly symptomatic chronic venous disease, and (4) discretionary/non-urgent-(to be seen within 6-12 months), example chronic lymphoedema. Venous and Lymphatic Triage and Acuity Scale aims to standardise the triage of patients with venous and lymphatic disease or vascular anomalies by providing an international consensus-based classification of clinical categories and triage urgency. The scale may be used during pandemics such as the current COVID-19 crisis but may also be used as a general framework to classify urgency of the listed conditions. Keywords COVID-19, pandemic, SARS-CoV-2, triage, vascular, venous, lymphatic, vascular anomalies, vascular malformations # Background The global coronavirus disease 2019 (COVID-19) pandemic has resulted in diversion of healthcare resources including workforce, critical supplies, emergency and intensive care unit (ICU) facilities and personal protective equipment (PPE) to the management of patients infected with SARS-CoV-2 virus. Elective interventions and surgical procedures in most countries have been postponed and operating room resources have been diverted to manage the pandemic. [bib_ref] Elective surgery in the time of COVID-19, Diaz [/bib_ref] Limitations on direct personal contact and physical (social) distancing have influenced access to care and how it is provided. Patients with venous and lymphatic disorders or vascular anomalies continue to need expert care within current public health constraints. In addition, there is growing evidence that COVID-19 may predispose patients to both arterial and venous thromboembolic (VTE) disease and extensive coagulopathies further complicating the prognosis of the affected patients. [bib_ref] Practical diagnosis and treatment of suspected venous thromboembolism during COVID-19 Pandemic, Obi [/bib_ref] [bib_ref] Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Klok [/bib_ref] To facilitate triage in this demanding setting we recommend the use of a standardised scale to rationalise and harmonise the management of these patients during this difficult period. ## Aims The Venous and Lymphatic Triage and Acuity Scale (VELTAS) was developed to provide an international standard for the triage of patients with venous and lymphatic disorders or vascular anomalies. VELTAS aims to improve patient safety and increase triage reliability by providing a standardised framework for the management of these conditions. # Methods ## Stratification of triage urgency Triage urgency is defined as the clinical assessment of urgency with which a patient would require medical treatment or surgical intervention.The principle for triage and prioritisation for admission for medical treatment or procedural interventions and surgery is based on the natural history and expected clinical outcomes of the condition, the rate of progression and deterioration, and the complications that may arise should treatment be delayed or withheld. [bib_ref] Prioritizing patients for elective surgery: a systematic review, Maccormick [/bib_ref] The rationale for triage is 'to do the greatest good for the greatest number'. [bib_ref] Tripartite triage concerns: issues for law and ethics, Hartman [/bib_ref] Various models and strategies for stratifying urgency during the COVID-19 pandemic have been proposed. [bib_ref] How to risk-stratify elective surgery during the COVID-19 pandemic?, Stahel [/bib_ref] In this document, the appropriate timeline to attend to individual conditions was determined by an international panel of vascular experts. ## The consensus process The project was initiated by the International Union of Phlebology (UIP) in conjunction with the Australasian College of Phlebology. The document was written by the primary authors and further reviewed and developed by the co-editors, based on appraisal of current evidence in the literature published in print or online through April 2020. When evidence was lacking or limited, consensus was developed. The document was shared with an international expert panel of phlebologists and vascular specialists representing the endorsing societies and further topics and recommendations were included and the final document formulated. Consensus on triage and acuity was reached when a recommendation was unanimously supported by all authors. In case of any dissenting opinion multiple attempts were made to modify the recommendation. At the end of the consensus process, all participating authors approved the final version of the document and agreed to be accountable for all aspects of the work. ## Utility and target audience The scale is designed primarily for phlebologists and vascular specialists but will be also useful for primary physicians and general practitioners, referring doctors, emergency specialists and other healthcare professionals and health policymakers. VELTAS will be especially relevant during pandemics such as the current COVID-19 crisis but may also be used as a general framework to classify urgency of the listed conditions. ## Scope The scale includes a comprehensive range of conditions seen by phlebologists and other vascular specialists involved in the management of patients with venous and lymphatic disorders or vascular anomalies as defined by the UIP curriculum. 11 ## Recommendations Clinical conditions within the scope of phlebology were classified into six categories of (1) VTE, (2) chronic venous disease (CVD), (3) vascular anomalies, (4) venous trauma, (5) venous compression and (6) lymphatic disease. Triage urgency in each clinical category was classified into four groups of (1) medical emergencies, (2) urgent, (3) semi-urgent and (4) discretionary/ non-urgent. Individual conditions in each clinical category were allocated to a class of triage by the expert panel [fig_ref] Table 1: Venous and Lymphatic Triage and Acuity Scale [/fig_ref]. ## Adaptation to pandemic circumstances We recognise that clinical practice and expectations need to be adapted in times of regional or global crisis. Under pandemic circumstances patients are encouraged to continue to consult their general practitioners and primary care physicians via appropriate means such as tele-health facilities to initiate management and to obtain a referral to phlebologists or other vascular specialists when necessary. During the pandemic, tele-health facilities should be used by treating specialists as much as possible to address patients concerns and provide advice on treatment options. Medical emergencies should continue to be triaged by emergency services where available. ## Additional comments and exclusions 1. This document should be used as a general guideline applicable to both hospital and non-hospital ambulatory settings. 2. Decisions regarding clinical urgency need to consider the patients' individual circumstances and locoregional variations in the clinical practice of medicine, hospital policies and government-enforced guidelines and directives. 3. In developing VELTAS we recognise and acknowledge that some conditions: (i) can be managed differently; (ii) can be managed completely or in part by a variety of other healthcare providers; (iii) are less urgent and hence can be managed more conservatively; (iv) when chronic, can be safely delayed for definitive procedural interventions; and (v) must be dealt with just as promptly despite the pandemic. 4. The scale does not replace the treating physician's clinical judgement of acuity and severity and the requirement for intervention as applicable in different models of healthcare. 5. The specified times for attendance indicate the ideal time frames within which patients should be seen and attended to. Such ideal timelines may be influenced by other factors such as availability of resources, other competing national or regional requirements for critical supplies and PPE, and national, regional, local and individual hospital admission policies. 6. This document should not be used to delay or deny treatment of less urgent cases, deny or minimise reimbursement for services provided, or limit access to healthcare when resources are not limited, and such care does not present a risk to patients or health care workers. # Conclusion VELTAS is a triage and acuity scale dedicated to the care of patients with acute and chronic venous and lymphatic disorders or vascular anomalies. The scale aims to standardise the triage of this group of patients by providing a consensus-based classification of clinical categories and triage urgency. ## Declaration of conflicting interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr William Marston declared consultancy for Boston Scientific Inc. Other authors declared no relevant conflicts of interest. # Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.	None	https://journals.sagepub.com/doi/pdf/10.1177/0268355520930884	The coronavirus disease 2019 (COVID-19) global pandemic has resulted in diversion of healthcare resources to the management of patients infected with SARS-CoV-2 virus. Elective interventions and surgical procedures in most countries have been postponed and operating room resources have been diverted to manage the pandemic. The Venous and Lymphatic Triage and Acuity Scale was developed to provide an international standard to rationalise and harmonise the management of patients with venous and lymphatic disorders or vascular anomalies. Triage urgency was determined based on clinical assessment of urgency with which a patient would require medical treatment or surgical intervention. Clinical conditions were classified into six categories of: (1) venous thromboembolism (VTE), (2) chronic venous disease, (3) vascular anomalies, (4) venous trauma, (5) venous compression and (6) lymphatic disease. Triage urgency was categorised into four groups and individual conditions were allocated to each class of triage. These included (1) medical emergencies (requiring immediate attendance), example massive pulmonary embolism; (2) urgent (to be seen as soon as possible), example deep vein thrombosis; (3) semi-urgent (to be attended to within 30–90 days), example highly symptomatic chronic venous disease, and (4) discretionary/non-urgent- (to be seen within 6–12 months), example chronic lymphoedema. Venous and Lymphatic Triage and Acuity Scale aims to standardise the triage of patients with venous and lymphatic disease or vascular anomalies by providing an international consensus-based classification of clinical categories and triage urgency. The scale may be used during pandemics such as the current COVID-19 crisis but may also be used as a general framework to classify urgency of the listed conditions.
33ebe2d9c331a7d11469bad798a971b620d42093	pubmed	Improving the care and health of populations through optimal use of clinical nurse specialists	Improving the care and health of populations through optimal use of clinical nurse specialists a Acute and Critical Care Expert Panel b Jonas Policy Scholar, Psychiatric, Mental Health and Substance Use Expert Panel c Building Health Care System Excellence Expert Panel d Psychiatric, Mental Health and Substance Use Expert Panel e Quality Health Care Expert Panel A B S T R A C TPatients with complex and chronic illnesses and those who have significant needs related to care coordination and transitions of care are dependent on access to healthcare providers who are skilled at meeting the distinct needs of these populations and are current in the latest evidence-based practices and guidelines. Clinical nurse specialists (CNSs) are uniquely qualified to care for patients with complex illnesses as well as having the skills to optimize care for entire populations with complex needs. The absence of consistent legislative advanced practice registered nurse recognition of CNSs prevents health care systems from optimal use of this advanced practice registered nurse role to improve and provide safe and quality care for these patients. Additional barriers in optimal utilization of CNSs include lack of consistency: in title protection and licensing from state to state; ensuring patient access through identification and tracking of CNS numbers across the United States in order to determine workforce and educational program requirements; and ensuring appropriate reimbursement for care provided by CNSs. Therefore, it is the position of the American Academy of Nursing that addressing public and private sector regulatory, legislative, and policy concerns related to CNSs is essential to achieving optimal population health outcomes across the nation. Patients with complex and chronic illnesses and those who have significant needs related to care coordination and transitions of care are dependent on access to healthcare providers who are skilled at meeting the distinct needs of these populations and are current in the latest evidence-based practices and guidelines. Clinical nurse specialists (CNSs) are uniquely qualified to care for patients with complex illnesses as well as having the skills to optimize care for entire populations with complex needs. The absence of consistent legislative advanced practice registered nurse recognition of CNSs prevents health care systems from optimal use of this advanced practice registered nurse role to improve and provide safe and quality care for these patients. Additional barriers in optimal utilization of CNSs include lack of consistency: in title protection and licensing from state to state; ensuring patient access through identification and tracking of CNS numbers across the United States in order to determine workforce and educational program requirements; and ensuring appropriate reimbursement for care provided by CNSs. Therefore, it is the position of the American Academy of Nursing that addressing public and private sector regulatory, legislative, and policy concerns related to CNSs is essential to achieving optimal population health outcomes across the nation. Cite this article: Tracy, M.F., Oerther, S., Arslanian-Engoren, C., Girouard, S., Minarik, P., Patrician, P., Vollman, K., Sanders, N., McCausland, M., Antai-Otong, D., & Talsma, A. (2020, July/August). Improving the care and health of populations through optimal use of clinical nurse specialists. Nurs Outlook, 68(4), 523À527. https://doi.org/10.1016/j.outlook.2020.06.004. # Background The United States (U.S.) health care system struggles to improve the health of its citizens due to many issues, some of which include challenges in ongoing holistic management of patients and populations with complex and chronic illness, lack of care coordination, as well as a lack of attention to transitions of care [bib_ref] Advanced practice in nursing, Tracy [/bib_ref]. Improving population health is dependent on both modifying the individual effects of social determinants of health as well as changing the structural barriers at system levels that impede population health . These upstream barriers at national and state levels prevent CNSs from improving the health of populations. Advanced practice registered nurses (APRNs) are and will continue to be in positions that are key to identifying care need patterns and gaps in resources in the environments where patients with complex health conditions live and work. Clinical nurse specialists are APRNs who are uniquely prepared to address health care delivery issues at micro, meso and macro levels: individual patient care within the context of their environment; advancing nursing care through use of evidence with nurses; and leading change at the systems and population levels (National Association of Clinical Nurse Specialists (NACNS), 2019a). Clinical nurse specialists use the latest scientific evidence in conjunction with health behavior pattern recognition to improve the quality and safety of care for all populations across the care continuum [bib_ref] Clinical nurse specialists: Leaders in managing chronic conditions, Hansen [/bib_ref]. To safeguard the future health of the nation, CNSs are key champions of wellness and safety of not only vulnerable and complex populations, but also of individual specific patient populations across all health stages and the entire continuum of clinical and community settings [bib_ref] Developing a rural transitional care community case management program using clinical nurse..., Baldwin [/bib_ref] [bib_ref] Improving heart failure outcomes: The role of the clinical nurse specialist, Coen [/bib_ref] [bib_ref] Evolving role of the transitional care nurse in a small rural community, Fels [/bib_ref]. When supported to practice to the full extent of their education and commensurate licensure determined by each state, CNSs lead important system wide innovations [bib_ref] Advanced practice in nursing, Tracy [/bib_ref]. There are barriers, however, in optimal utilization of CNSs that can be addressed at a policy level to ensure consistency in title protection and licensing from state to state, to identify and track numbers of CNSs across the U.S. in order to determine workforce and educational program requirements, and to secure reimbursement for CNS care that improves population health outcomes [bib_ref] Advanced practice in nursing, Tracy [/bib_ref]. In addition, even in states that have legislation that recognizes full CNS scope of practice and the CMS Final Rule 2012 that allows "other practitioners (e.g., advanced practice registered nurses, physician assistants, pharmacists) to perform functions within their scope of practice" (U.S. Department of Health and Human Services, 2012, p. 29034), APRNs are still frequently confined by individual hospital/institution and medical staff privileging rules and preferences that legally restrict their practice. Clinical Nurse Specialists must be able to practice to the level of their educational preparation to optimize their role in achieving positive population health outcomes. The Consensus Model for APRN Regulation outlines the proposed regulatory requirements for APRN licensure, accreditation, certification, and education and serves as the architecture for states to standardize title, licensure and full practice for APRNs, including CNSs . Storfjell and colleagues stress the imperative that APRNs need to be prepared to manage care for patients and their families with complex chronic conditions, including mental health, within their environmental setting. As an example, mental health CNSs (an area of high patient need) encounter practice restrictions, worsening access for patients with mental illness to receive the care they need (National Council of State Boards of Nursing (NCSBN), 2018). Especially problematic are those restrictions that may dissuade new CNSs to enter practice including limited or no prescriptive authority, mandatory collaboration and/or supervision, and limited or no third-party reimbursement . The adoption of the Consensus Model by all states to include updated CNS title protection and licensing legislation also supports the enactment of the National Council of State Boards of Nursing's proposed APRN Compact . This would standardize the educational preparation and role for the CNS as a specialty graduate level-prepared role. The APRN Compact would allow APRNs to hold "one multisite license with a privilege to practice in other Compact states" . Patients with complex conditions frequently require specialized care provided in specialized medical centers, which may be far from home and may be located in another state. Having all states conform to the APRN Compact will improve access to care for patients in rural areas and those requiring more complicated care needs by providing options to be cared for by CNSs who live in nearby states or via telehealth (e.g., tele-mental health). It is imperative that CNSs have legislative APRN recognition in order to continue providing their unique skills regardless of where the patient lives or receives care. Legislation at the state level that provides CNS title protection and full practice authority is the first step in supporting optimal care for patients by CNSs, regardless of their location, ensuring access to care for all patients, and allowing all states to participate in the APRN Compact . In the Bureau of Labor Statistics Occupational Outlook Handbook, CNSs are currently embedded within the general RN category (U.S. Department of Labor, 2018a; U.S. Department of Labor, 2018b). To ensure an adequate workforce of licensed CNSs, the U.S. government, schools of nursing, health care organizations and regulatory agencies require an accurate CNS census in order to match workforce supply with the demand from complex population needs. The ideal and immediate response to address quantifying the CNS workforce is for the Bureau of Labor Statistics to categorize CNSs as defined by legislative and regulatory standards -as APRNs. This provides one source for tracking and monitoring the number of CNSs nationally and would provide consistency with other APRN roles. The Federal Trade Commission (FTC) has been vocal in urging state legislators to avoid enacting restrictions related to APRN scope of practice that go beyond those needed for evidence-supported patient safety concerns . The FTC has stated that such undue restrictions could result in impairment of healthcare professionals and institutions to create new health care models and deny consumers the benefits of competition. Conversely, when APRNs can practice without unnecessary restrictions, they more efficiently meet consumer health care needs and preferences and optimize the use of new technologies . ## Responses and policy options Among public health organizations there is wide spread support, as well as scientific evidence, that CNSs are prepared to practice with specific patient populations in and across the entire continuum of clinical and community settings to the full extent of their education and demonstrated competence (Institute of . The United States Congress has introduced the Title VIII Nursing Workforce Development Act of 2019 (H.R. 728) to reauthorize the federal nursing programs under Title VIII. The House passed the legislation in October 2019 and while awaiting action in the Senate, was ultimately incorporated into the Coronavirus Aid, Relief and Economic Security Act (CARES Act) (H.R. 748) which was signed into law in March, 2020. The reauthorization of this updated legislation recognizes all four types of APRNs including the role of CNSs. This legislation also supports CNS educational programs through significant nursing grants (Congress.gov, 2020). Additionally, government agencies have begun to fully consider full practice authority of APRNs when evaluating ways to improve patient care. This includes the Veteran's Administration (VA) which has crafted clinical guidelines to allow CNSs full practice authority to perform their unique APRN role through consistent title protection and licensing from state to state in the VA regardless of the state in which the individual VA hospital or facility is located (U.S. Department of Veterans Affairs, 2017; NACNS, 2019b). The Centers for Medicare and Medicaid Services (CMS) is also considering this issue as it has previously solicited additional input and recommendations regarding the elimination of specific Medicare regulations that require more stringent supervision than existing state scope of practice laws, or that limit nurses and other health professionals from practicing to the full extent of their education and competence. Late last year, the White House released an Executive Order on "Protecting and Improving Medicare for our Nation's Seniors." Section 5 of this Executive Order directs the Secretary of the Department of Health and Human Services to propose reforms to the Medicare program to enable providers to spend more time with patients by including a "comprehensive review of regulatory policies that create disparities in reimbursement between physicians and non-physician practitioners and proposing a regulation that would, to the extent allowed by law, ensure that items and services provided by clinicians, including physicians, physician assistants, and nurse practitioners, are appropriately reimbursed in accordance with the work performed rather than the clinician's occupation" (Executive Order, 2019). Among state responses to reduce statutory and regulatory barriers for CNS practice, CNSs currently practice independently in 28 states and can prescribe independently in only 19, including the District of Columbia (NCSBN, 2019). Fifteen states require CNSs to have collaborative practice agreements or be supervised by physicians in order to prescribe, while CNSs have no authority to prescribe in 16 states . Clinical nurse specialists were included in legislation giving them (with nurse anesthetists and nurse midwives) prescriptive authority for use of buprenorphine through medication-assisted treatment programs . While nurse practitioners and physician assistants were given lasting prescriptive authority in this same legislation, the three additional APRN groups were given prescribing authority for 5 years. It is important that this prescribing authority be expanded to lasting authority for consistency with nurse practitioner APRN practice. State legislatures are slowly and individually amending legislation regarding the definition of 'provider.' These legislative changes broaden language to terms such as 'healthcare professionals', allowing for inclusion of APRNs. Even slower to occur are amendments that require elimination of payment differentials between physicians and APRNs [bib_ref] 28th annual APRN legislative update: Advancements continue for APRN practice, Phillips [/bib_ref]. While these are some examples that demonstrate initial progress in addressing inconsistencies and nonevidence based restrictions to CNS practice, changes have been gradual and challenging to put into place and significant inconsistencies and barriers remain. ## The academy's position The American Academy of Nursing has a long history of championing policies and practices that improve the health of populations and the delivery of healthcare. In 2014, the Academy advocated for policy changes to support the role of acute and critical care APRNs as providers of high quality, cost-effective and safe patient care (American Academy of Nursing, 2014). Consistent with this position is the support of the Academy for the removal of barriers that inhibit the optimal utilization of CNSs, who as APRNs, are uniquely prepared to lead transformational and innovative process and quality improvement changes across the care continuum to improve outcomes and reform healthcare, particularly for those patients with the most complex and chronic needs. ## Recommendations 1. For states that have not already done so, state policymakers should pass legislation that defines clinical nurse specialists as advanced practice nurses and provides title protection and full, nonsupervised scope of practice. 2. Federal agencies should eliminate regulations that require more stringent supervision than existing state scope of practice laws, or that limit CNSs from practicing to the full extent of their education and competence. [table] 3: The U.S. Department of Labor, Bureau of Labor Statistics should remove the CNS role from the general RN census category in the Occupational Outlook Handbook and realign the CNS into the APRN category. 4. Reimbursement should be consistent among and expanded for all APRNs, including CNSs, across all federal agencies. R E F E R E N C E S [/table]	None	http://www.nursingoutlook.org/article/S0029655420304681/pdf	None
caeaafb5f5d04f7c2a0fd102821b27634268fc80	pubmed	Suggestions for the care of patients with liver disease during the Coronavirus 2019 pandemic	Suggestions for the care of patients with liver disease during the Coronavirus 2019 pandemic Cautionary statementThis document, written by the French Association for the Study of the Liver (AFEF) board, aims to provide information to physicians involved in the care of patients with liver disease during the Coronavirus disease (COVID-19) epidemic. These are not based on a systematic review of the literature and a rigorous evaluation using the GRADE method. These are recommendations based on feedback from China available in the form of original articles or lettersfor which the scientific evidence is often modestand the rules put forward by American (1) and European (2) hepatology societies, the French National Digestive Cancer Thesaurus (3) and the Francophone Transplantation Society (4). These suggestions require adjustment according to the geographical particularities of the epidemic, available standard procedures and access to local resources. This document will be updated as regularly as possible according to the evolution of our knowledge and characteristics on the epidemic. ## General information on liver and covid-19 COVID-19 disease, linked to the SARS-CoV-2 virus, is rapidly spreading around the world. Following the city of Wuhan and the province of Hubei, European healthcare systems are facing an outbreak of seriously ill patients, but few are fully equipped to deal with this health crisis. In this totally unprecedented and unexpected context, we must readapt the procedures with respect to the care of patients with liver disease. The aims of this document are to examine what is currently known about the relationship between COVID-19 and the liver, and to anticipate the safest possible care procedures in order to reduce the impact of the pandemic on patients with liver disease. Feedback from China indicates: -the presence of underlying chronic liver disease in 2-11% of patients cared for with COVID-19 infection [bib_ref] Liver injury in COVID-19 : management and challenges, Zhang [/bib_ref]. -an increase in transaminase levels in 25-35% of patients, generally moderate (median 23-39 UI/L), with higher levels in symptomatic and/or severe forms and/or requiring intensive care hospitalisationand/or fatalities [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. To date the mechanism involved is unclear. Indeed, data suggesting the possibility of localisation of the virus in the liver are preliminary, and it is plausible that elevated liver enzymes in the context of COVID-19 infection could be related to the inflammatory response syndrome, drug induced toxicities (paracetamol, antibiotics), and ischemia liver or viral myocarditis frequent in this situation. Moreover, serological testing for hepatotropic viruses is recommended in this situation. -The expression of SARS-CoV-2 receptor (the angiotensin-converting enzyme 2 receptor) by cholangiocytes. -the fact that populations believed to be at risk for severe forms of COVID-19 include patients with cirrhosis, those with autoimmune hepatitis on immunosuppressive drugs, and pre-and post-transplant patients on immunosuppressive therapy (9). In addition to the classical barrier precautions (regular hand washing with soap and water and/or use of alcohol-based gel, discarding handshakes and hugs), the extension of expired prescription administration into the 1st quarter of 2020 (until May 31st, according to the Decree of 1 April 2020) and the implementation of social isolation and home confinement since the 17th March, other simple measures are suggested such as, for example, adapting patient follow-up for stable patients, ideally by tele or video consultation, automatic temporary cessation of employment for fragile patients whose employment would be incompatible with teleworking (https://solidaritessante.gouv.fr/IMG/pdf/arret-travail-covid-19_2.pdf), the direct admission of patients to non-COVID units and the withdrawal of visits from relatives to hospitalised patients. Recommended Care ## Patients without signs suggestive of covid-19 aims -Protect patients against SARS-CoV-2 and continue their care in safe conditions by avoiding their movement. -Free healthcare facilities of their functions to allow them to receive and concentrate their medical and paramedical resources on serious patients (with or without COVID-19). Potential adjustments to etiological treatment of liver diseases -HBV: continuation of ongoing analogous treatments or initiation them in emergency cases (cirrhosis, reactivation) or in situations of high transmission risk (drug users, migrants living in crowded conditions, etc.). -HCV: continue ongoing direct anti-viral treatments; as a general rule, defer treatment initiation until the end of social isolation in waiting patients by repeating the barrier precautions, except in emergency situations (high risk of transmission such as on-going drug users, migrants living in overcrowded conditions, etc.). -HDV: continue ongoing Bulevirtide therapy in combination or not with interferon-α in the temporary use authorisation cohort framework; as a general rule, postpone therapy initiation until the end of social isolation in waiting patients. It is recommended to repeat the advice regarding strict patient confinement and barrier precautions, to delegate if possible to a third party the monthly retrieval of treatments from the hospital pharmacy (if the latter cannot dispatch them) and to carry out monthly check-ups during home visits by a registered nurse. -Alcohol: advise on consumption moderation including 2 days of abstinence per week, and not to take advantage of the confinement to begin an abrupt withdrawal that could require hospital care. 1. On-going immunosuppressive treatments: Continue without change of dosage. 2. Treatment initiation for acute autoimmune hepatitis: discuss on a case-bycase basis according to the regional epidemic, if necessary, together with local Competence Centres. The option preferred for AIH treatment by the French Reference Centre is corticosteroid therapy (prednisolone 0.5 mg/kg/day or budesonide 9 mg/day for non-severe forms) with delayed onset of other immunosuppressive regimens as a general rule. -Liver transplant recipients: continue immunosuppressive therapy without change (4). ## 1.a-stable patients / outpatients 1.a-1-without advanced hepatic fibrosis or liver-related complications ## Temporary cessation of professional activity consultations Exclusively for patients with comorbidity(ies) (9) whom employer cannot guarantee the possibility of teleworking (https://solidarites-sante.gouv.fr/IMG/pdf/arrettravail-covid-19_2.pdf). Continuation of primary or secondary prophylaxis in patients with ascites, clinically significant portal hypertension and/or encephalopathy is essential to avoid hospitalisation. Presence required (diagnosis and pre-treatment consultations for liver cancer, new patients with clinically significant signs: jaundice, increased serum ALAT level > 10 times the upper limit of normal values, recent hepatic decompensation) -Screening for signs of COVID-19 before coming to the hospital and at the reception desk (+body temperature taken at arrival), and if in doubt, screen for COVID-19 ideally before arriving in the department according to the facility's standard procedures. -Having patients wear a surgical mask (resources permitting) as soon as they arrive at the medical facility. -Implementation of barrier precautions: disinfect equipment (seats, handles, etc.) between each patient, avoid waiting in groups, reduce waiting times in waiting rooms, eliminate newspapers, maintain a minimal 1 metre distance between patients, frequently ventilate waiting rooms, enforce as strongly as possible the rules concerning hygiene and protection of nursing staff. Reschedule stays and/or non-urgent procedures => In regions heavily impacted by the outbreak (peak or plateau phases), carried out in urban areas by mobilising available resources otherwise postpone with an approximate average delay of 1 to 2 months: -periodic surveillance imaging of previous HCC or current HCC under treatment; -biannual screening for HCC in high risk patients; -non-urgent liver biopsies; -measurements of liver stiffness and/or CAP. It is cautious to defer pre-transplant check-ups when possible according to the risk/benefit balance, or to perform most tests outside the hospital depending on local resources. ## Adaptation of non-urgent follow-up consultations initially planned face-to-face => -Maintenance of scheduled stays within non-COVID units by ensuring that before each admission patients do not present any signs of COVID-19 and by being extra careful to protect them (surgical mask as soon as they arrive in the facility, implement barrier precautions with avoidance of waiting in groups, especially at admissions and in waiting rooms, reduce waiting times, single rooms when possible, maintain a minimal 1 metre distance between patients, apply hygiene rules for the nursing staff and limit the number of health carers involved) for the following main indications: -curative treatments of primary liver cancer (surgery and interventional radiology) (3); -ascites paracentesis; -esophageal variceal ligation and gastric variceal sclerotherapy in secondary prevention; -urgent liver biopsies. -Defer inclusions to the end of confinement if possible, except for COVID-19 trials and non COVID-19 observational trials (assessment of individual benefit/risk balances). -On a case-by-case basis, evaluate with the promoter the possibility of carrying out remote consultations, blood sampling at home by registered nurses and home dispatching of the treatments under investigation. In the absence of immunization against pneumococcus: carry out pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) if this does not jeopardise confinement, otherwise defer it until the end of social isolation. ## 1.b-patients requiring traditional hospitalisation action to be taken Hospitalise in a NON COVID-19 unit/department : -ensuring before each admission that patients present no signs of COVID-19 and taking patient temperature on arrival; -performing a thoracic CT scan to screen for COVID-19 prior to admission in the event of unexplained recent hepatic decompensation (2); -favouring direct admissions without prior passage to the emergency department; -taking all measures to avoid contamination (surgical mask for all patients as soon as they arrive in the unit, hand washing using alcohol-based gel, implement barrier precautions with avoidance of waiting in groups, particularly at admissions, reduce waiting times, maintain a minimal 1 metre distance between patients, apply hygiene rules for nursing staff, limit the number of nursing staff involved in care and visits if they remain authorised. NB: These very strict measures have proven their effectiveness in terms of mortality among 111 Chinese patients with decompensated cirrhosis, 2/3 of whom were hospitalised and 1/3 ambulatory (10). ## Patients with signs suggestive of covid-19 aim Protect, as much as possible, healthcare staff and NON-COVID patients from SARS-CoV-2 contamination by caring for patients under safe conditions. Potential adjustments of etiological treatment of the liver disease -HBV: continue on-going analogous treatments or their initiation in emergency situations (cirrhosis, reactivation) if the patient's condition permits. -HCV: continue on-going direct antiviral treatments if the patient's condition permits, but defer treatment initiation in waiting patients. -HDV: continue (or decrease in dosage) on-going anti-viral treatments with Bulevirtide in combination or not with interferon-α in the Temporary Use Authorisation cohort framework on a case-by-case according to the severity of COVID-19 and its impact on liver disease (individual risk-benefit balance). If outpatient treatment continues, it is imperative to repeat the strict advice with regards to confinement and barrier precautions, to delegate if possible to a third party the monthly retrieval of treatments from the hospital pharmacy, and to have monthly check-ups carried out at home by a registered nurse in the absence of hospitalisation. For patients with impaired renal function (clearance < 60ml/min), and/or decompensated liver disease, Bulevirtide should be discontinued. The possible continuation or reduction in dosage of immunosuppressive treatments must be discussed on a case-by-case basis according to the severity of COVID-19 infection and the individual benefit/risk balance with the internist/infectious disease specialist/intensive care staff on one hand and the hepatologist on the other hand, together if necessary with the help of local Competence Centres or the French Reference Centre. For corticosteroids, a decrease in dosage may be discussed if necessary but maintaining a dose of at least 10 mg/day to avoid adrenal insufficiency. Other immunosuppressants, such as azathioprine (Imurel®) or mycophenolic acid (Cellcept®) may be reduced if necessary, especially in patients with lymphopenia, bacterial or fungal superinfection, or lung aggravation related to COVID-19. -Liver transplant recipients (4) : ## Outpatient or inpatient with symptomatic covid-19 not presenting Severe Form Signs (not requiring oxygen) 1.1 -Patients < 1 year since transplantation -Discontinue corticosteroid treatment unless there is a high immunological risk of rejection or recurrence of autoimmune disease, in which case the corticosteroid needs to be reduced and maintained at 5 mg/day. -Discontinue mycophenolic acid (Cellcept® or Myfortic®) or azathioprine (Imurel®) immunosuppressive therapy and resume after viral recovery at the same dose prior to cessation. -Continue treatment with tacrolimus with target residual blood concentrations between 4-8 ng/mL, or continue treatment with cyclosporin with target residual blood concentrations between 100-150 ng/mL or target blood concentrations between 400-600 ng/mL at 2 hours after intake (C2). For patients treated with mTOR inhibitors: -For patients under tacrolimus + mTOR inhibitor dual therapy: discontinue mTOR inhibitor (Rapamune® or Certican®) treatment and resume treatment following recovery at the same dose prior to cessation, maintenance of tacrolimus treatment with target residual blood concentrations between 4 and 8 ng/mL. -For patients under mycophenolic acid (Cellcept® or Myfortic®) + mTOR inhibitor dual therapy: halve the dosage of mycophenolic acid and continue of mTOR inhibitor (Rapamune® or Certican®) treatment with target residual blood concentrations between 4 and 6 ng/ml, resumption after recovery at the same dose prior to cessation. ## -patients > 1 year since transplantation -Patients treated with corticosteroid treatment due to a high immunological risk of rejection or recurrence of autoimmune disease: maintain corticosteroids (same dose). -Discontinue mycophenolic acid (Cellcept® or Myfortic®) treatment and resumption after recovery at the same dose prior to cessation. -For patients treated with calcineurin inhibitors, maintain tacrolimus and cyclosporin at the same doses. -For patients treated with mTOR inhibitors: -For patients under tacrolimus + mTOR inhibitor dual therapy: discontinue mTOR inhibitor (Rapamune® or Certican®) treatment and resume treatment following recovery at the same dose prior to cessation, maintain tacrolimus and cyclosporin treatments at the same doses. -For patients under mycophenolic acid (Cellcept® or Myfortic®) + mTOR inhibitor dual therapy: discontinue mycophenolic acid treatment and resume treatment following recovery at the same dose prior to cessation, continuation of mTOR inhibitor treatment at the same dose. -For patients under mycophenolic acid (Cellcept® or Myfortic®) or mTOR inhibitor monotherapy: continue treatment at the same doses. ## -in all cases -Resumption of pre-infectious episode treatment from D14 of symptom onset. -Daily self-monitoring (temperature, dyspnea, chest pain). -Regular phone calls from the doctor with patient responsibility (for example: D3, then D7 -important given it corresponds to the acute phase). -Home confinement for up to 10 days after onset of symptoms. -Outings with a mask until D14 after onset of symptoms. 2. COVID-19 Inpatient Requiring Oxygen and/or Lymphophenic -Maintain corticosteroids at a dose of 10 mg/day (prednisone equivalent). -Discontinue remaining immunosuppressive therapy. -If the patient is at high immunological risk or close to the transplant date and does not present lymphopenia:  Continue treatment with calcineurin inhibitors with target residual blood concentrations between 4 et 8 ng/mL for tacrolimus and 100-150 ng/ml (C0) and 400-600 ng/mL at 2 hours after intake (C2) for cyclosporin.  Resume pre-infectious episode treatment as soon as oxygen therapy is withdrawn. ## Severe covid-19 infection with acute respiratory distress syndrome -Maintain corticosteroids at a dose of 10 mg/day (prednisone equivalent). -Discontinue remaining immunosuppressive therapy. -Resume tacrolimus at 3-5 ng/mL dosages within 72 hours of ventilation withdrawal. Resume pre-treatment as soon as viral recovery occurs, taking into account the prolonged duration of viral excretion. General mesures -Limit the use of paracetamol for antipyretic purposes to 2-3 g/day, especially for patients with cirrhosis and/or with excessive alcohol consumption. -Formally contraindicate the use of NSAIDs. -Verify that there are no drug interactions between the standard treatment for liver disease and those used for COVID-19 (Annex). Due to the potentially severe liver damage among some patients, the magnitude of these interactions may be significant and caution must be taken. -Limit diagnostic or therapeutic endoscopies to emergencies (gastrointestinal haemorrhage, bacterial cholangitis or other vital emergencies) -Optimise nutritional care with the prescription of at least 3 oral nutritional supplements per day for all patients who cannot eat except those in intensive care unit and with limited care (11). ## 2.a-patients without advanced hepatic fibrosis or liver-related complications: These patients should receive the same care as the general population. Without signs of severe COVID-19, these patients should be cared for at home under strict confinement. ## 2.b-patients with advanced liver disease or acute hepatitis not requiring hospitalisation In suspected COVID-19, the need or not for hospitalisation should be confirmed by the attending physician and/or staff within the emergency unit and/or emergency medical services. These patients need to be tested by PCR and/or thoracic CT (12). Without signs of severe COVID-19 infection, these patients should be cared for at home in isolation with close monitoring. Follow-up procedures should be decided based on medical assessment: simple self-monitoring of symptoms without the need for planning further consultation medical follow-up (tele or video consultation preferred if possible) between Day 6 and Day 10 for monitoring reinforced follow-up at home by a registered nurse for patients at risk being unable to selfmonitor If a patient does visit for consultation, they must notify the healthcare staff of their arrival, report their condition and wear a mask as far upstream as possible in general procedures. ## 2.c-patients with advanced chronic liver disease or acute hepatitis requiring hospitalisation for liver-related complications These patients should be cared in a COVID-19 unit/department, if possible within the facility where the patient is already known and routinely followed-up and with the hepatology team that usually takes care of them. ## Bibliography [fig] -: Alcohol: repeat advice on consumption moderation including at least 2 days of abstinence per week and if possible not to begin an abrupt withdrawal. NASH: remain alert as many of these patients are at risk for the severe form (if they have component(s) of metabolic syndrome(s) listed in reference 9). 3. Genetic hemochromatosis: temporarily stop phlebotomies. Rare liver diseases (Autoimmune Hepatitis, PBC, PSC, Wilson, etc.) : [/fig]	None	None	None
f9aacb4a857cfb2dbc0441f23052fc525e75bdaf	pubmed	The Role of Oral Health Practitioners in Tobacco Cessation	The Role of Oral Health Practitioners in Tobacco Cessation ## Scope This Policy Statement aims to increase awareness of the fundamental role of oral health practitioners to reinforce tobacco cessation in clinical and community settings. It also provides recommendations on the use of electronic cigarettes and heated tobacco products (HTPs) and develops implementable recommendations on tobacco cessation activities at organizational, community and national levels. ## Definitions Oral health practitioners: people involved in promoting oral health, such as dentists and other members of the dental team. E-cigarettes: electronic devices that are designed to create aerosols by heating a solution that contains glycerin, propylene glycol, flavours, and other substances, commonly known as "electronic cigarettes," "Electronic Nicotine Delivery Systems (ENDS)," or "Electronic Non-Nicotine Delivery Systems (ENNDS), also called "e-cigs," "dab pens," "dab rigs," "vapes," "vape pens," "mods," "pod-mods," "e-hookahs," "tanks," or "JUUL." Heated tobacco products (HTPs): devices that heat tobacco to generate aerosols containing nicotine and other chemicals (e.g., flavours), namely iQOS, Ploom TECH, Glo, and PAX. ## Principles Tobacco in all forms is harmful and is a risk factor that poses public health burdens worldwide. Oral health practitioners, as health care personnel who are most likely to encounter "healthy tobacco users," have an important role in discouraging tobacco use by delivering brief tobacco cessation interventions (5A's) or giving Very Brief Advice (VBA; 3A's) to all patients at the first dental visit and every recall visit. ## Policy ## Fdi recommends the following actions Oral health practitioners should: ideally deliver the 5A's: ask all patients about their tobacco use to identify tobacco users, advise them to quit, assess their quitting motives, assist their patients in quitting and arrange follow-up contacts; at least deliver the 3A's: ask all patients about their tobacco use to identify tobacco users, advise them to quit and refer them to tobacco cessation clinics or services (act), bearing in mind that the 3A's are not recommended when other tobacco cessation services are inaccessible or unavailable; not recommend using e-cigarettes and heated tobacco products as an alternative to conventional tobaccos, nor as a tobacco cessation tool since they have not been proved to be safe and these products prompt initiation of combustible cigarettes in younger users; attend tobacco cessation training to maintain a consistent protocol in their dental practice and work with interdisciplinary teams to coordinate services and update tobacco cessation techniques and skills; with the consent of the patient, cooperate with other departments, including medical practitioners, to share patients' tobacco use information and refer patients to other departments when necessary; international dental journal 7 2 ( 2 0 2 2 ) 2 2 − 2 3 ensure that their working environments (e.g., hospitals, dental clinics, etc.) are tobacco-free or smoke-free; arrange and/or participate in tobacco cessation programmes in the community (e.g., tobacco cessation training for volunteers, tobacco cessation programmes in schools, etc.) as primary prevention; assist in mass communication as part of anti-tobacco advocacy along with the discouragement of the use of harmful tobacco alternatives. Providers of dental education should: educate students on different tobacco products and their health effects and integrate tobacco cessation trainings (3A's and 5A's) in their dental curriculum; create a tobacco-free environment in their offices, buildings or campuses and encourage staff members and students to quit tobacco use; support research that applies the common risk factor approach, such as oral health promotion through tobacco cessation for prevention of non-communicable diseases and oral diseases, with special emphasis on oral cancer. National Dental Associations and their member organisations should: encourage policy-makers to raise public awareness of the harm, especially on oral health, caused by tobacco products via advertisement and campaigns; lobby the government for implementation of MPOWER measures for tobacco control, the restriction of flavoured tobacco products and actions to address the social determinants of health and health behaviours; disseminate information about successful innovations and activities for tobacco cessation among dental and other health personnel; encourage dental public health services to incentivise dental practices to be involved in tobacco cessation activities and advise the government to include tobacco cessation counselling and treatments in public health insurance coverage (e.g., national health insurance, occupational-based health insurance). ## Disclaimer The information in this Policy Statement was based on the best scientific evidence available at the time. It may be interpreted to reflect prevailing cultural sensitivities and socioeconomic constraints. ## F u r t h e r r e a d i n g	None	None	None
04ffb99d8f03fb2040f4697e431b9658a4b8ad69	pubmed	Clinical Practice Guideline for Systemic Antifungal Prophylaxis in Pediatric Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients	Clinical Practice Guideline for Systemic Antifungal Prophylaxis in Pediatric Patients With Cancer and Hematopoietic Stem-Cell Transplantation Recipients PURPOSE To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients.METHODSRecommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients.RESULTSThere were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made.CONCLUSION We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps. # Introduction Children and adolescents receiving intensive myelosuppressive chemotherapy and some pediatric hematopoietic stem-cell transplantation (HSCT) recipients are at high risk for invasive fungal disease (IFD) caused by yeasts and molds. [bib_ref] Microbiologically documented infections and infection-related mortality in children with acute myeloid leukemia, Sung [/bib_ref] [bib_ref] Association between corticosteroids and infection, sepsis, and infectious death in pediatric acute..., Dix [/bib_ref] [bib_ref] Infections and association with different intensity of chemotherapy in children with acute..., Sung [/bib_ref] [bib_ref] Risk factors for invasive fungal disease in pediatric cancer and hematopoietic stem..., Fisher [/bib_ref] In these patients, infections with Candida and Aspergillus species are most common. [bib_ref] Microbiologically documented infections and infection-related mortality in children with acute myeloid leukemia, Sung [/bib_ref] [bib_ref] Association between corticosteroids and infection, sepsis, and infectious death in pediatric acute..., Dix [/bib_ref] [bib_ref] Infections and association with different intensity of chemotherapy in children with acute..., Sung [/bib_ref] IFDs are important because they are associated with substantial morbidity, delayed cancer treatment, increased health services utilization, and treatmentrelated mortality. [bib_ref] Classification of treatment-related mortality in children with cancer: A systematic assessment, Alexander [/bib_ref] Systemic antifungal prophylaxis can be an effective approach to reducing IFD. A clinical practice guideline (CPG) facilitates evidence-based clinical care by describing risks and benefits of different management options based on a systematic review of the literature. Risks and benefits are weighed against each other by a panel of experts to arrive at care recommendations. Previously published CPGs [bib_ref] Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic..., Science [/bib_ref] [bib_ref] Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric..., Groll [/bib_ref] addressing systemic antifungal prophylaxis in pediatric patients are . 5 years old and thus do not consider results of recent trials. In addition, those panels had limited regional and disease representation. Key representatives of two previously published CPGs for pediatric patients (T.L., E.C., L.L.D., A.H.G., E.R., M.S., A.W., P.D.R., and L.S.) [bib_ref] Guideline for primary antifungal prophylaxis for pediatric patients with cancer or hematopoietic..., Science [/bib_ref] [bib_ref] Guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric..., Groll [/bib_ref] were brought together to arrive at a single harmonized CPG, thus improving consistency of recommendations internationally. The objective was to develop a CPG for systemic antifungal prophylaxis in pediatric patients with cancer and HSCT recipients. # Methods ## Panel constitution The panel included representatives from the fields of pediatric hematology/oncology, pediatric HSCT, pediatric infectious diseases, nursing, and pharmacy; a patient advocate; and a CPG methodologist (Data Supplement). Panel members were selected based on clinical and methodologic expertise and geographic representation. All panel members declared potential conflicts of interest, and none precluded participation in this CPG (Data Supplement). ## General cpg development approach We used standard approaches to create this CPG, [bib_ref] Improving the use of research evidence in guideline development: Introduction, Oxman [/bib_ref] including the Appraisal of Guidelines for Research and Evaluation II instrument, to direct development. [bib_ref] Development of the AGREE II, part 1: Performance, usefulness and areas for..., Brouwers [/bib_ref] Financial support for CPG creation was provided by the Pediatric Oncology Group of Ontario. However, CPG development, drafting of recommendations and the manuscript, and the decision to submit for publication were independent from the funder. The key clinical questions were developed by the panel and are listed in [fig_ref] TABLE 1: Summary of Recommendations for Systemic Antifungal Prophylaxis in Children and Adolescents With... [/fig_ref]. The target population is children and adolescents (age 0-18 years) receiving chemotherapy for cancer or undergoing HSCT. Target users are physicians, microbiologists, nurse practitioners, nurses, pharmacists, antibiotic stewards, and other health care professionals who are concerned with infectious complications in pediatric patients receiving chemotherapy or undergoing HSCT. Panel members identified and rated the importance of outcomes by consensus. Outcomes that were considered critical for decision making were proven or probable IFD, mold infection or yeast infection, fungal infection-related mortality, and overall mortality. Outcomes considered important were drug-related adverse effects and antifungal resistance. Empirical antifungal therapy was not considered important and, thus, not evaluated. Because changing diagnostic technologies can influence possible IFD events, possible IFD was included post hoc as an outcome. To rate the level of evidence and to formulate recommendations, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used. [bib_ref] Grading quality of evidence and strength of recommendations in clinical practice guidelines...., Brozek [/bib_ref] The level of evidence indicates the degree of certainty that estimates from the systematic review reflect effects of prophylaxis in our target population, namely pediatric patients with cancer and HSCT recipients. Evidence was rated as high, moderate, low, or very low. Rating was downgraded if there were limitations in study design, lack of consistency, or imprecision or if direct data were lacking. Considering the level of evidence, strong or weak recommendations were made. Strong recommendations were made where benefits clearly outweighed the risks or vice versa and, thus, patients should receive or not receive the intervention as a general policy. Weak recommendations were made where the benefits and risks were closely matched or where there was uncertainty in their estimates. Efficacy, toxicity, and resources, including costs, influenced recommendation formulation. ## Searching, selecting, and describing the evidence The evidence base used to create this CPG was founded on randomized clinical trials because they are generally less susceptible to bias in comparison with observational trials. [bib_ref] Bias and causal associations in observational research, Grimes [/bib_ref] The literature search was performed with the assistance of a library scientist in the following databases: MEDLINE, MEDLINE In-Process, MEDLINE Epub Ahead of Print, and Embase. The Data Supplement shows the full search strategy. Inclusion criteria were fully published randomized trials with a parallel group design that compared the administration of a systemic antifungal agent to any control group as prophylaxis. At least 90% of study participants had to be patients with cancer receiving prophylaxis be administered to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. When systemic antifungal prophylaxis is warranted, an echinocandin or a mold-active azole should be used. ## Context key objectives ## Relevance This clinical practice guideline for systemic antifungal prophylaxis is important because of the impact of invasive fungal disease in pediatric patients with cancer and HSCT recipients and because of the presence of multiple approaches to invasive fungal disease prophylaxis, including no prophylaxis. Remarks: This strong recommendation is based on the increasing benefit of systemic antifungal prophylaxis versus no prophylaxis to reduce proven or probable IFD as the risk for IFD increases. Although this recommendation advocates for a universal prophylaxis approach, future research should identify patient and treatment factors that may allow tailoring of prophylaxis to those at the highest risk for IFD. Acute lymphoblastic leukemia 2. Consider administering systemic antifungal prophylaxis to children and adolescents with newly diagnosed and relapsed acute lymphoblastic leukemia at high risk for IFD. Weak recommendation; low-quality evidence Remarks: Children and adolescents with acute lymphoblastic leukemia encompass a group with wide variability in IFD risk that is not solely accounted for by relapse status. Those with relapsed acute lymphoblastic leukemia receiving intensive myelosuppressive chemotherapy are most likely to warrant systemic antifungal prophylaxis, whereas greater uncertainty is present for those with newly diagnosed acute lymphoblastic leukemia. Given the heterogeneity in IFD risk across protocols overall and by phase of treatment, adaptation will be required for each protocol to recommend whether and when systemic antifungal prophylaxis should be administered. 3. Do not routinely administer systemic antifungal prophylaxis to children and adolescents with acute lymphoblastic leukemia at low risk for IFD. ## Strong recommendation; low-quality evidence Remarks: A low risk for IFD can be inferred based on absence of risk factors such as prolonged neutropenia and corticosteroid administration and observed IFD rates across different protocols. This group includes, for example, pediatric patients receiving maintenance chemotherapy for acute lymphoblastic leukemia. Other malignancies including most patients with lymphomas and solid tumors Strong recommendation; moderatequality evidence Remarks: The panel recognized that these two phases of therapy are associated with different epidemiology of IFD. However, the nature of the trials included in the systematic review precluded the ability to make separate recommendations for them. This strong recommendation was influenced by the finding in the systemic prophylaxis versus no systemic prophylaxis stratified analysis that HSCT recipients experienced greater benefit in IFD reduction compared with chemotherapy recipients. In addition, the subgroup analysis showed that among the HSCT stratum, prophylaxis significantly reduced fungal infection-related mortality. 6. We suggest that systemic antifungal prophylaxis not be used routinely in children and adolescents undergoing autologous HSCT. ## Weak recommendation; low-quality evidence Remarks: This weak recommendation was based on the lower risk for IFD associated with autologous HSCT. There is less certainty in the setting of tandem transplantations where the cumulative duration of neutropenia may be longer. If systemic antifungal prophylaxis is planned, which agents should be used? The primary outcome of the systematic review was proven or probable IFD. Other outcomes were proven or probable mold infection, proven or probable invasive aspergillosis (IA), proven or probable yeast infection, overall mortality, fungal infection-related mortality, and discontinuation of antifungal prophylaxis as a result of an adverse effect. For all IFD outcomes (namely IFD, mold infection, IA, and yeast infection), if the study used the European Organisation for Research and Treatment in Cancer (EORTC)/Mycosis Study Group criteria for categorization, proven or probable IFD outcomes were abstracted. If a study did not use the EORTC criteria, IFD outcomes were mapped to EORTC categories (2008 revised version) [bib_ref] Revised definitions of invasive fungal disease from the European Organization for Research..., De Pauw [/bib_ref] by four investigators (T.L., P.P., P.D.R., and L.S.) by consensus where possible. These outcomes were considered missing if mapping was not possible. We compared systemic antifungal prophylaxis, mold-active prophylaxis, and non-mold-active prophylaxis (fluconazole) versus no systemic prophylaxis, both by group and then stratified by specific agent evaluated. We next compared different systemic antifungal prophylaxis agents focusing on mold-active agents (amphotericin, mold-active azole, or echinocandin) versus fluconazole as a group and then broken down by subcategories and specific agents. We also compared mold-active azole versus echinocandin. Study and demographic characteristics were year of publication, country of study conduct, age of participants, cancer diagnosis or HSCT type, and number of randomly assigned participants. Study-level covariates were participant age group (adult, pediatric, or both), treatment group (chemotherapy only, HSCT only, or both chemotherapy and HSCT), and EORTC criteria use to classify IFD (yes or no). Age group was categorized as adult when all participants were older than 15 years of age, and it was categorized as pediatric when all participants were younger than 25 years of age or when the median or mean age was younger than 15 years. Agent dose and schedule, start and stop criteria, and use of therapeutic drug monitoring were also collected. The Cochrane Collaboration's tool for assessing risk of bias in randomized trials was used.Titles and abstracts of articles identified by the systematic review were screened, and articles potentially meeting eligibility criteria were evaluated at full text. All steps, including screening, full text review, and data abstraction, were performed in duplicate (V.F., P.P., or P.D.R.). If ## Health questions and recommendations ## Strength of recommendation and level of evidence Remarks: This strong recommendation was based on the comparison of different systemic antifungal prophylaxis agents where mold-active agent versus fluconazole significantly reduced proven or probable IFD, mold infection, and IA, and reduced fungal infection-related mortality. Direct pediatric data were available, increasing quality of the evidence. [bib_ref] Improving the use of research evidence in guideline development: Introduction, Oxman [/bib_ref]. In choosing a mold-active agent, administer an echinocandin or a mold-active azole. Strong recommendation; moderatequality evidence Remarks: The choice of specific mold-active agent is influenced by multiple factors including local epidemiology, adverse effect profile, potential for drug interactions, costs, and jurisdictional availability. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested based on efficacy and adverse effects. In those 13 years of age and older, posaconazole also is an option. 9. Do not use amphotericin routinely as systemic antifungal prophylaxis. Strong recommendation; low-quality evidence Remarks: This strong recommendation was based on the finding that both conventional and lipid formulations of amphotericin were not more effective than fluconazole in reducing IFD. It is important to note that liposomal amphotericin was not included in studies comparing amphotericin versus fluconazole and, thus, there is less certainty about the benefits and risks of this formulation. When should systemic antifungal prophylaxis be started and stopped? 10. If systemic antifungal prophylaxis is warranted, consider administration during periods of observed or expected severe neutropenia. For allogeneic HSCT recipients, consider administration during systemic immunosuppression for graft-versus-host disease treatment. Weak recommendation; low-quality evidence Remarks: There are limited data that inform the decision of when to initiate and discontinue systemic antifungal prophylaxis. This recommendation was based on the criteria used in the included randomized trials and the anticipated highest risk period. Abbreviations: HSCT, hematopoietic stem-cell transplantation; IA, invasive aspergillosis; IFD, invasive fungal disease. disagreement occurred, it was resolved by consensus or with arbitration by a third reviewer (T.L. or L.S.). Agreement in study inclusion was described using the kappa statistic. [bib_ref] A general methodology for the analysis of experiments with repeated measurement of..., Koch [/bib_ref] # Statistical analysis Data synthesis used the risk ratio (RR) with the 95% CI to describe prophylaxis effects. In this analysis, RR , 1 indicates that the intervention is better than control. The Mantel-Haenszel random effects model in Review Manager 5.3 (Cochrane Collaboration, Nordic Cochrane Centre, London, United Kingdom)was used to estimate treatment effects. Outcomes were synthesized where there were at least three studies for main analysis and where there were at least two studies for each stratum in stratified analysis. If the number of events was zero in both groups, that study was not included in synthesis, which is considered a standard approach in meta-analyses.If a study included more than two randomized groups, the control group weight was proportionately divided between the different intervention groups, and all intervention versus control comparisons were included in the meta-analysis.We also calculated the I 2 value, which is the percentage of total variation across studies as a result of heterogeneity rather than chance.Stratified analysis focused on two comparisons and four outcomes to limit multiple testing. The two comparisons were systemic antifungal prophylaxis versus no systemic antifungal prophylaxis, and mold-active agent versus fluconazole. The four outcomes were proven or probable IFD, proven or probable mold infection, fungal infection-related mortality, and antifungal discontinuation as a result of adverse effect (only for mold-active agent v fluconazole comparison). Strata evaluated were study-level covariates and, in addition, the risk for IFD and mold in the control group (above and below the median value). P value for interaction (P int) was used to determine whether heterogeneity in the prophylaxis effect could be explained by study-level covariates; we did not focus on stratum-specific P values.Funnel plots were used to explore the possibility of publication bias when at least 10 studies were available for an analysis.Funnel plots are graphical displays of the effect measure on the x-axis and precision on the y-axis. An absence of studies in the right lower quadrant (for this specific analysis) may indicate publication bias. If there was a suggestion of publication bias, we used the trim and fill technique to describe its potential impact. In this event, we removed outlying studies (trim) and added hypothetical negative studies with equal weight (fill).We used the peer-review mechanism as an efficient approach to external review. We plan to update this CPG in 5 years or sooner in the event of important new information. # Results The search strategy identified 68 randomized trials that were included in the systematic review. Agreement in study inclusion between reviewers was perfect (k 5 1.00). The Data Supplement illustrates the flow diagram of study identification, selection, and reasons for exclusion. Health questions, recommendations, strength of recommendation, level of evidence, and remarks are summarized in [fig_ref] TABLE 1: Summary of Recommendations for Systemic Antifungal Prophylaxis in Children and Adolescents With... [/fig_ref]. Characteristics of the included trials are listed in [fig_ref] TABLE 2: Characteristics of Studies Included in the Systematic Review [/fig_ref] , and study-level details are provided in the Data Supplement. Among the five trials of voriconazole and six trials of posaconazole, none used therapeutic drug monitoring to systematically guide dosing. Six studies were conducted solely in a pediatric population (Data Supplement). increased discontinuation of antifungal prophylaxis as a result of an adverse effect (RR, 1.72; 95% CI, 1.09 to 2.71; P 5 .02). When stratified by type of antifungal, amphotericin (conventional or lipid formulations) did not reduce proven or probable IFD (RR, 0.99; 95% CI, 0.52 to 1.88; P 5 .98) but did significantly increase discontinuation of antifungal prophylaxis as a result of an adverse effect (RR, 5.63; 95% CI, 1.17 to 27.02; P 5 .03). In contrast, the benefits of echinocandin versus fluconazole and mold-active azole versus fluconazole in reducing proven or probable IFD, proven or probable mold infection, and proven or probable IA were similar to the overall comparison of mold-active agent versus fluconazole.also shows that mold-active azole, when compared with echinocandin, did not have a statistically significant different effect on IFD, mold infection, IA, or yeast infection, but did significantly increase discontinuation of antifungal prophylaxis as a result of an adverse effect. The Data Supplement shows stratified analyses of The Data Supplement shows systemic antifungal prophylaxis initiation and discontinuation criteria by diagnosis or treatment group and also illustrates sensitivity analyses where publication bias was suggested in funnel plots. None substantially altered interpretation of the base analyses. In addition, the Data Supplement shows synthesis in which possible IFD, mold, or IA was reported. These did not substantially alter interpretation of the base analysis. Research gaps are outlined in . ## Recommendation 1 Administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia that is expected to result in profound and prolonged neutropenia (Evidence quality: high; Strength of recommendation: strong). Explanation. This recommendation was informed by the systematic review of risk factors identifying that patients with acute myeloid leukemia are at high risk for IFD. The benefit of systemic antifungal prophylaxis was greater for those at higher risk for proven or probable IFD, leading to this strong recommendation. ## Recommendation 2 Consider administering systemic antifungal prophylaxis to children and adolescents with newly diagnosed and relapsed acute lymphoblastic leukemia at high risk for IFD (Evidence quality: low; Strength of recommendation: weak). Explanation. The risk for IFD in pediatric acute lymphoblastic leukemia is protocol and phase specific. This risk is also dependent on remission status; chemotherapyrelated neutropenia; and corticosteroid formulation, dose, and duration of administration. On the basis of the systematic review of risk factors for IFD, 4 the panel believed that there are likely to be subgroups of pediatric patients with acute lymphoblastic leukemia who would benefit from systemic antifungal prophylaxis. However, the panel was unable to identify comprehensive baseline data on IFD incidence in the various acute lymphoblastic leukemia populations that would permit more specific recommendations. The panel also acknowledged that treatments for poor-risk acute lymphoblastic leukemia are changing. For example, immunotherapies are being used increasingly and may be associated with a lower risk for IFD compared with conventional, myelosuppressive chemotherapy. Given these factors, the panel did not make a strong recommendation for antifungal prophylaxis in pediatric patients with acute lymphoblastic leukemia. Rather, the panel made a weak recommendation with the understanding that protocol-specific recommendations adjusted to specific phases of therapy such as induction or reinduction are required. Abbreviations: AE, adverse effects; IA, invasive aspergillosis; IFD, invasive fungal disease; RR, risk ratio. a No synthesis possible because there were less than three studies with an event in at least one arm. ## Recommendation 3 Do not routinely administer systemic antifungal prophylaxis to children and adolescents with acute lymphoblastic leukemia at low risk for IFD (Evidence quality: low; Strength of recommendation: strong). Explanation. For children and adolescents with acute lymphoblastic leukemia, a low risk for IFD can be inferred based on absence of risk factors such as prolonged neutropenia and corticosteroid administration, combined with observed IFD rates across different protocols and phases of therapy. This group includes, for example, pediatric patients receiving maintenance chemotherapy for acute lymphoblastic leukemia. ## Recommendation 4 Do not routinely administer systemic antifungal prophylaxis to children and adolescents with cancer at low risk for IFD, such as most pediatric patients with lymphomas and solid tumors (Evidence quality: moderate; Strength of recommendation: strong). Explanation. In pediatric patients at low risk for IFD, benefit of systemic antifungal prophylaxis is likely to be small and outweighed by the risk for adverse effects, costs, and inconvenience. Thus, systemic antifungal prophylaxis should not routinely be administered in this setting. It is important to emphasize that some patients with lymphomas and solid tumors are at high risk for IFD, such as those with advanced Burkitt lymphoma and some infants with brain tumors. Thus, implementation must consider patient-and treatmentspecific risk factors rather than relying on diagnosis alone in deciding which populations merit antifungal prophylaxis. ## Recommendation 5 Administer systemic antifungal prophylaxis to children and adolescents undergoing allogeneic HSCT pre-engraftment and to those receiving systemic immunosuppression for the treatment of graft-versus-host disease (GVHD; Evidence quality: moderate; Strength of recommendation: strong). Explanation. The panel recognized that pre-engraftment and during systemic immunosuppression for the treatment of GVHD were two distinct periods, each increasing the risk for IFD but with different epidemiology. The Data Supplement shows that many studies of allogeneic HSCT recipients included both periods, with few studies focusing on the period of immunosuppression for GVHD treatment. Thus, the panel felt this lack of granularity precluded separate recommendations for these two different periods. This strong recommendation was influenced by the finding in the systemic prophylaxis versus no systemic prophylaxis stratified analysis that HSCT recipients experienced greater benefit in proven or probable IFD reduction compared with chemotherapy recipients (Data Supplement). In addition, the subgroup analysis showed that among the HSCT stratum, antifungal prophylaxis significantly reduced fungal infection-related mortality (Data Supplement). Although the adult data were clearer, these data may be less generalizable to pediatric patients because of different transplantation approaches such as stem-cell source. As a result, the evidence quality was reduced. The panel suggested that administration in patients receiving systemic treatment of GVHD was reasonable based on risk factors for IFD but could not provide more granularity around whether there is a subgroup in which GVHD treatment is sufficiently short as to not warrant antifungal prophylaxis. ## Recommendation 6 We suggest that systemic antifungal prophylaxis not be used routinely in children and adolescents undergoing autologous HSCT (Evidence quality: low; Strength of recommendation: weak). Explanation. A lower risk for IFD associated with autologous HSCT can be inferred from the systematic review of IFD risk factors. [bib_ref] Risk factors for invasive fungal disease in pediatric cancer and hematopoietic stem..., Fisher [/bib_ref] Consequently, systemic antifungal prophylaxis was not recommended for this group. However, there was less certainty in the setting of tandem transplantations where the cumulative duration of neutropenia may be longer. The degree of mucositis associated with specific conditioning regimens may also influence IFD risk and may affect the decision to administer antifungal prophylaxis. ## Recommendation 7 If systemic antifungal prophylaxis is warranted, administer a mold-active agent (Evidence quality: high; Strength of recommendation: strong). Explanation. This strong recommendation was based on the comparison of different systemic antifungal prophylaxis agentswhere a mold-active agent versus fluconazole significantly reduced proven or probable IFD, mold infection, and IA, and reduced fungal infection-related mortality. Although a mold-active agent also increased adverse effects, the panel felt the benefits outweighed the negative aspects. Direct pediatric data were available, increasing quality of the evidence. Trials comparing a mold-active agent versus fluconazole were presumably conducted in settings where there is an appreciable risk for mold infection. In settings where the risk for mold is sufficiently low, fluconazole may be an appropriate choice for prophylaxis. ## Recommendation 8 In choosing a mold-active agent, administer an echinocandin or a mold-active azole (Evidence quality: moderate; Strength of recommendation: strong). Explanation. If systemic antifungal prophylaxis is warranted, the choice of which specific mold-active agent is influenced by multiple factors including local epidemiology, adverse effect profile, drug interaction potential, costs, and jurisdictional availability. All mold-active agents have disadvantages. For example, echinocandins must be administered intravenously daily, which may make this option less desirable for ambulatory populations. Use of moldactive azoles may be limited by drug interactions, hepatotoxicity, and adverse effects resulting in discontinuation of prophylaxis. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested based on efficacy, adverse effects, and availability of pediatric dosing information. In settings where all agents are available, either an echinocandin or voriconazole is favored based on toxicity profile. However, itraconazole may be used if other options are not available. Posaconazole may also be used in those 13 years of age and older. When using mold-active azoles, best practices with respect to therapeutic drug monitoring should be applied. ## Recommendation 9 Do not use amphotericin routinely as systemic antifungal prophylaxis (Evidence quality: low; Strength of recommendation: strong). Explanation. This strong recommendation was based on the finding that amphotericin was not more effective than fluconazole in reducing proven or probable IFD but was associated with more adverse effects. Stratified analysis did not reveal differential efficacy based on whether amphotericin was administered on a daily or nondaily schedule (Data Supplement). ## Recommendation 10 If systemic antifungal prophylaxis is warranted, consider administration during periods of observed or expected severe neutropenia. For allogeneic HSCT recipients, consider administration during systemic immunosuppression for GVHD treatment (Evidence quality: low; Strength of recommendation: weak). Explanation. There are limited data that inform the decision of when to initiate and discontinue systemic antifungal prophylaxis. This recommendation was based both on criteria used in the included randomized trials and the anticipated highest risk periods. # Discussion This CPG of systemic antifungal prophylaxis is important because of the impact of IFD in pediatric patients with cancer and HSCT recipients and uncertainty in the ideal approach. If systemic antifungal prophylaxis is warranted, the panel made a strong recommendation to administer a mold-active agent with an echinocandin or a mold-active azole. In choosing a specific agent, local epidemiology, adverse effect profile, potential for drug interactions, costs, and jurisdictional availability must be weighed against each other for specific settings. If all agents are available and appropriate from a microbiologic perspective, echinocandins may be favored when limiting adverse effects and hepatotoxicity are valued. Conversely, mold-active azoles may be favored when oral administration and convenience are favored. It is possible that more broad-spectrum antifungal prophylaxis will change the choice of empirical antifungal therapy, and if the new choice has more adverse effects, the strategy could result in more toxicity overall. Future comparative effectiveness studies should evaluate the overall impact of antifungal prophylaxis selection on empirical antifungal choice and overall toxicities. We found that fluconazole, when compared with no systemic antifungal prophylaxis, was associated with a reduction in fungal infection-related mortality but not overall mortality. It is possible that the reduction in fungal infection-related mortality occurred because these trials were conducted at a time when there were fewer IFD treatment options. It is also possible that this reduction is related to classification bias given the challenges in assigning cause of death. [bib_ref] Classification of treatment-related mortality in children with cancer: A systematic assessment, Alexander [/bib_ref] As with all CPGs, a structured approach to local adaptation, implementation, and evaluation is a key consideration. Important factors in this process include a baseline understanding of local and disease-specific epidemiology, establishing a leadership team that will oversee the process, and appropriate engagement and education of key stakeholders. Pediatric acute lymphoblastic leukemia is a particularly challenging population in which to make universal recommendations regarding systemic antifungal prophylaxis because of the wide variability in treatment regimens, each with differing IFD risk patterns and limitations to specific antifungal agents. Implementation of this CPG will likely require protocol-specific recommendations for patients with acute lymphoblastic leukemia. In summary, we created a CPG for systemic antifungal prophylaxis in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guidelineconcordant rates and impacts are important future steps. ## Affiliations [fig] 4: Do not routinely administer systemic antifungal prophylaxis to children and adolescents with cancer at low risk for IFD, such as most pediatric patients with lymphomas and solid tumors. Strong recommendation; moderatequality evidence Remarks: In pediatric patients at low risk for IFD, the benefit of systemic antifungal prophylaxis is likely to be small and outweighed by the risk for adverse effects, costs, and inconvenience. Thus, systemic antifungal prophylaxis should not routinely be administered in this setting. HSCT 5. Administer systemic antifungal prophylaxis to children and adolescents undergoing allogeneic HSCT pre-engraftment and to those receiving systemic immunosuppression for the treatment of graft-versushost disease. [/fig] [fig] 3: provides comparisons between systemic antifungal prophylaxis versus no systemic antifungal prophylaxis for all studies and stratified by mold-active agent and non-moldactive agent (fluconazole). The Data Supplement further stratifies these analyses by agent evaluated, namely amphotericin (all formulations), lipid amphotericin formulations, and itraconazole. Compared with no systemic prophylaxis, systemic antifungal prophylaxis significantly reduced proven or probable IFD (RR, 0.47; 95% CI, 0.36 to 0.60; P , .00001), proven or probable yeast infection (RR, 0.31; 95% CI, 0.22 to 0.44; P , .00001), and fungal infection-related mortality (RR, 0.57; 95% CI, 0.40 to 0.81; P 5 .002). The effects of mold-active agent and non-moldactive agent versus no systemic antifungal prophylaxis were similar to the overall analysis for the reduction of IFD, yeast infection, and fungal infection-related mortality. The Data Supplement shows stratified analyses of comparisons between systemic antifungal prophylaxis versus no systemic prophylaxis for the outcomes of proven or probable IFD, proven or probable mold infection, and fungal infectionrelated mortality.For the outcome of proven or probable IFD, significantly greater benefit was observed with increasing risk for IFD in the control group, both when the risk was dichotomized (P int 5 .03; Data Supplement) and when the risk was divided into quartiles (P int 5 .0009; Data Supplement). More specifically, the effect of prophylaxis was an RR of 0.72 (95% CI, 0.43 to 1.20) for those in the lowest quartile (smallest risk for IFD) compared with an RR of 0.25 (95% CI, 0.17 to 0.36) for those in the highest quartile (greatest risk for IFD). Benefit was also significantly greater in patients receiving HSCT only compared with chemotherapy only or chemotherapy plus HSCT (P int 5 .03). The effect of prophylaxis did not differ based on risk for mold infection in the control group (P int 5 .90). We also performed an analysis of amphotericin (conventional or lipid formulations) versus no systemic antifungal prophylaxis stratified by daily dosing versus nondaily dosing. Effects on IFD and fungal infection-related mortality were similar when comparing daily and nondaily dosing (Data Supplement). [/fig] [fig] 5: Key Knowledge Gaps Related to Systemic Antifungal Prophylaxis Among Children and Adolescents With Cancer and Pediatric Hematopoietic Stem-Cell Transplantation Recipients Knowledge Gap Identifying personalized risk factors for IFD, allowing for more targeted prophylaxis among patients at highest risk for IFD Describing the risk for IFD with recently developed modalities of cancer therapy including immunotherapy Determining whether fluconazole prophylaxis combined with sensitive diagnostic tests and procedures to detect IFD is as effective as prophylaxis with mold-active agents Describing the risks and benefits of lipid formulations of amphotericin prophylaxis compared with other mold-active agent prophylaxis Identifying optimal systemic antifungal prophylaxis for infants and neonates Determining ideal dosing and scheduling of systemic antifungal prophylaxis agents Determining whether therapeutic drug monitoring has a role in guiding mold-active azole dosing when administered for prophylaxis In an era of mold-active prophylaxis, evaluating the comparative effectiveness of different diagnostic and therapeutic antifungal approaches including preemptive and empirical treatment Determining how to best develop and implement a fungal surveillance program Evaluating antifungal resistance after implementation of different prophylactic antifungal strategies Understanding how to adapt this clinical practice guideline for low-and middle-income country settings Understanding the contribution of environmental interventions such as high-efficiency particulate air filtration to the prevention of IFD Assessing clinical practice guideline concordance in routine clinical care and impact of concordant v nonconcordant practices Abbreviation: IFD, invasive fungal disease. [/fig] [table] TABLE 1: Summary of Recommendations for Systemic Antifungal Prophylaxis in Children and Adolescents With Cancer and Pediatric HSCT Recipients Administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia that is expected to result in profound and prolonged neutropenia. [/table] [table] TABLE 2: Characteristics of Studies Included in the Systematic Review [/table]	None	https://ascopubs.org/doi/pdfdirect/10.1200/JCO.20.00158	PURPOSE To develop a clinical practice guideline for systemic antifungal prophylaxis in pediatric patients with cancer and hematopoietic stem-cell transplantation (HSCT) recipients. METHODS Recommendations were developed by an international multidisciplinary panel that included a patient advocate. We conducted a systematic review of systemic antifungal prophylaxis in children and adults with cancer and HSCT recipients. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to make strong or weak recommendations and to classify level of evidence as high, moderate, low, or very low. The panel considered directness of the data to pediatric patients. RESULTS There were 68 randomized trials included in the systematic review, of which 6 (9%) were conducted in a solely pediatric population. Strong recommendations were made to administer systemic antifungal prophylaxis to children and adolescents receiving treatment of acute myeloid leukemia, to those undergoing allogeneic HSCT pre-engraftment, and to those receiving systemic immunosuppression for graft-versus-host disease treatment. A strong recommendation was made to administer a mold-active agent with an echinocandin or a mold-active azole when systemic antifungal prophylaxis is warranted. For children younger than 13 years of age, an echinocandin, voriconazole, or itraconazole is suggested. Posaconazole may also be used in those age 13 years or older. A strong recommendation against routine administration of amphotericin as systemic antifungal prophylaxis was made. CONCLUSION We developed a clinical practice guideline for systemic antifungal prophylaxis administration in pediatric patients with cancer and HSCT recipients. Implementation and assessment of guideline-concordant rates and impacts are important future steps.
6faa20d54f9433371c4b8df53c93467ed0e34c54	pubmed	Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline	Evaluation and Management of Obesity Hypoventilation Syndrome. An Official American Thoracic Society Clinical Practice Guideline Evidencetable E1: Should serum bicarbonate (HCO3 -) rather than partial pressure of carbon dioxide in arterial blood (PaCO2) be used to screen for OHS in obese adults with sleep-disordered breathing? Patient or population: obese adults with OSA New test: serum bicarbonate \| Cut-off value: 27 mmol/l Pooled sensitivity: 0.86 (95% CI: 0.70 to 0.94) \| Pooled specificity: 0.77 (95% CI: 0.60 to 0.89) Test result Number of results per 1,000 patients tested (95% CI) Number of participants (studies) Certainty of the Evidence (GRADE) Prevalence 5% Typically seen in patients with OSA and BMI 30-34 Prevalence 10% Typically seen in patients with OSA and BMI 35-40 ## Prevalence 20% Typically seen in patients with Explanations a. One more study included very few patients with OHS and was excluded from analysis . Sensitivity analysis including this study did not show a difference in accuracy. ## References: 1) Bingol Z, Pihtili A, Cagatay P, Okumus G, Kiyan E. Clinical predictors of obesity hypoventilation syndrome in obese subjects with obstructive sleep apnea. Respir Care 2015;60:666-672. We acknowledge Drs. Esen Kiyan and Züleyha Bingöl for sharing revised data for g. Studies reported the range of resolution of OHS between 1.5% and 62%. We could not explain these differences with either length of follow-up, apparent severity of disease, or mode of ventilation. h. One study enrolled patients without severe OSA and the effect in this population was smaller but excluding this study would not change the overall estimate. RR among those with severe OSA: 1.27 (95% CI: 1.01 to 1.6) and among those without: 1.07 (95% CI: 0.74 to 1.54). There were some baseline imbalances in the proportions of patients with ESS≤10. The average change from baseline in the proportion of those who had ESS ≤10 among those with severe OSA was 23% more in PAP (NIV or CPAP) group and 7% more in controls , and among those without severe OSA there was a decrease of 3% in those receiving NIV and did not change in controls [bib_ref] Noninvasive ventilation in obesity hypoventilation syndrome without severe obstructive sleep apnea: A..., Masa [/bib_ref] i. One recent observational study with a control group (Bouloukaki 2018) observed patients with NIV and CPAP for 2 years and found similar probability of resolution of OHS in both groups, but the results were not adjusted for baseline differences (NIV was used only in those in whom "oxygen desaturation persisted after obstructive apneas and hypopneas had been eliminated with CPAP"): 114/141 (80.9%) with NIV and 70/84 (83.3%) with CPAP; RR 0.97, 95% CI: 0.86 to 1.10; RD: 25 fewer per 1,000, 95% CI: from 117 fewer to 83 more). j. One study was not blinded and the other did not report the methodology in sufficient detail to assess risk of bias. k. Assuming that MID would be ~2-3 points, the CI does not exclude an appreciable benefit with NIV or no difference. l. One recent observational study with a control group (Bouloukaki 2018) observed patients with NIV and CPAP for 2 years and found slightly lower probability of resolution of daytime sleepiness with NIV compared to CPAP, but the results were not adjusted for baseline differences (NIV was used only in those in whom "oxygen desaturation persisted after obstructive apneas and hypopneas had been eliminated with CPAP"): 133/141 (94.3%) with NIV and 84/84 (100.0%) with CPAP; RR 0.95, 95% CI: 0.90 to 0.99; RD: 5 fewer per 100, 95% CI: from 1 fewer to 10 fewer). m. Results were not adjusted for baseline differences (NIV was used only in those in whom "oxygen desaturation persisted after obstructive apneas and hypopneas had been eliminated with CPAP") and 8% were lost to follow-up. n. Assuming that MID would be ~20 to 40 m, the CI does not exclude an appreciable benefit with NIV or no difference. o. One recent observational study with a control group (Bouloukaki 2018) observed patients with NIV and CPAP for 2 years found that the probability of not requiring supplemental O2 was similar in both groups, but the results were not adjusted for baseline differences (NIV was used only in those in whom "oxygen desaturation persisted after obstructive apneas and hypopneas had been eliminated with CPAP"): 137/141 (97.2%) with NIV and 84/84 (100.0%) with CPAP; RR 0.97, 95% CI: 0.94 to 1.01; RD: 3 fewer per 100, 95% CI: from 6 fewer to 1 more). p. see description of results q. Only 169 patients which likely does not meet optimal information size. [formula] Resolution of OHS -not reported - - - - - - - - - - - - CRITICAL Motor vehicle accidents -not measured - - - - - - - - - - - - CRITICAL Quality of life -not measured - - - - - - - - - - - - CRITICAL Daytime sleepiness -not reported - - - - - - - - - - - - CRITICAL Cardiovascular events -not reported - - - - - - - - - - - - CRITICAL Hospitalization -not reported - - - - - - - - - - - - [/formula] CRITICAL CI: Confidence interval; OR: Odds ratio; RD: Risk difference Explanations a. Analysis of individual patient data from several single-arm studies or individual arms of comparative studies; we were not able to obtain data from 1 study [bib_ref] Obesity-associated hypoventilation in hospitalized patients: Prevalence, effects, and outcome, Nowbar [/bib_ref] ; we did not perform an individual patient data meta-analysis for this guideline but we assumed that given the scarcity and limitations of the source data the results would be similar and not more certain. b. This was an indirect comparison across several single-arm studies. We did not lower the certainty of evidence for this reason because it has already been very low and the analysis attempted to account for that (IPD). c. There were few events in total which do not meet the optimal information size; the confidence interval in the adjusted analysis did not exclude both benefit and small harm. d. Analysis was adjusted for age, sex and baseline PaCO2. d. Analysis was adjusted for age and sex. Evidence table E5: Should a weight loss intervention or no such intervention be used for adults with OHS? [table] table E2: Should adults with OHS be treated with positive airway pressure (PAP)-either continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV)-or not be treated with PAP? CI: Confidence interval; MD: Mean difference; RR: Risk ratio; OR: Odds ratioExplanations a. Studies were not blinded and other risk of bias criteria was suboptimally reported. b. No events c. Series of cases; no direct comparison with a control group d. Studies reported mortality between 4% and 36%; we were not able to explain it with duration of observation, patient age, or severity of disease. e. Confidence interval does exclude an appreciable benefit with PAP or small and likely negligible difference. f. CI does not exclude an appreciable benefit or almost no difference. [/table] [table] table E3: Should adults with OHS be treated with CPAP or with NIV? Daytime sleepiness (assessed with: change from baseline in Epworth Sleepiness Scale (range of scores: 0-24; lower score is better; MID ~2-3 points)) 5 CI: Confidence interval; RR: Risk ratio; SMD: Standardised mean difference; MD: Mean difference; PSQI: Pittsburgh Sleep Quality Index; : Adjusted for age, sex, smoking habits and forced vital capacity. One recent observational study with a control group (Bouloukaki 2018) observed patients with NIV and CPAP for 2 years and found similar risk of death in both groups, but the results were not adjusted and very imprecise (7/141 with NIV and 4/84 with CPAP, RR: 1.04, 95% CI: 0.31 to 3.46, RD: 2 more per 1,000, 95% CI: from 33 fewer to 117 more). e. Confidence interval does not exclude an appreciable benefit with either intervention compared to the other. f. Confidence interval does not exclude a small additional benefit with either intervention compared to the other. g. One relatively small study reported results as median and IQR --if this study were not included in analysis the SMD would [/table] [table] table E4: Should hospitalized adults suspected of having OHS, in whom the diagnosis has not yet been confirmed, be discharged from hospital with or without PAP treatment while awaiting confirmation of the diagnosis? [/table] [table] Table E5A: Laparoscopic adjustable gastric banding (LAGB) compared to intensive nutritional care in patients with OHS a Resolution of OHS (follow up: 3 years; assessed with: weaning from NIV) Apnea-hypopnea index (AHI) (follow up: 1 years; assessed with: change from baseline of 52 episodes/h) CI: Confidence interval; RR: Risk ratio; MD: Mean difference 1. Feigel-Guiller B, Drui D, Dimet J, Zair Y, Le Bras M, Fuertes-Zamorano N, et al. Laparoscopic gastric banding in obese patients with sleep apnea: A 3-year controlled study and follow-up after 10 years. Obes Surg 2015;25:1886-1892. [/table] [table] Table E5B: Gastric bypass compared to no bariatric surgery in patients with OHS Average weight loss: -50 kg (95% CI: 39 to 60) from baseline 155 kg in 30 patients (Sugerman 1986) -44 kg (95% CI: 33 to 55) from baseline 163 kg in 38 patients (Sugerman 1992) Pulmonary artery pressure (follow up: 3-6 months) Pulmonary artery pressure fell on average 13 mm Hg (95% CI: 5.8 to 20.2) from baseline 36 mm Hg ⨁◯◯◯ VERY LOW IMPORTANT CI: Confidence interval; MD: Mean difference Explanations a. Series of cases; no direct comparison with a control group b. Only 2 events among 29 patients c. Based on "improved or cured" but definition not provided. d. Only 29 patients. [/table] [table] Table E5C: Biliopancreatic diversion with duodenal switch (BPD/DS) compared to no bariatric surgery in patients with OHS Resolution of OHS (follow up: 5-7 years) CI: Confidence interval Explanations a. Series of cases; no direct comparison with a control group b. Only 16 cases [/table]	None	None	Background: The purpose of this guideline is to optimize evaluation and management of patients with obesity hypoventilation syndrome (OHS). Methods: A multidisciplinary panel identified and prioritized five clinical questions. The panel performed systematic reviews of available studies (up to July 2018) and followed the Grading of Recommendations, Assessment, Development, and Evaluation evidence-to-decision framework to develop recommendations. All panel members discussed and approved the recommendations. Recommendations: After considering the overall very low quality of the evidence, the panel made five conditional recommendations. We suggest that: 1) clinicians use a serum bicarbonate level <27 mmol/L to exclude the diagnosis of OHS in obese patients with sleep-disordered breathing when suspicion for OHS is not very high (<20%) but to measure arterial blood gases in patients strongly suspected of having OHS, 2) stable ambulatory patients with OHS receive positive airway pressure (PAP), 3) continuous positive airway pressure (CPAP) rather than noninvasive ventilation be offered as the first-line treatment to stable ambulatory patients with OHS and coexistent severe obstructive sleep apnea, 4) patients hospitalized with respiratory failure and suspected of having OHS be discharged with noninvasive ventilation until they undergo outpatient diagnostic procedures and PAP titration in the sleep laboratory (ideally within 2–3 mo), and 5) patients with OHS use weight-loss interventions that produce sustained weight loss of 25% to 30% of body weight to achieve resolution of OHS (which is more likely to be obtained with bariatric surgery). Conclusions: Clinicians may use these recommendations, on the basis of the best available evidence, to guide management and improve outcomes among patients with OHS.
bbbb453d9862b7a9f52191c6e49a7787454f967b	pubmed	Viral disease prevention after hematopoietic cell transplantation	Viral disease prevention after hematopoietic cell transplantation ## Preventing exposure Hematopoietic cell transplant (HCT) candidates should be tested for the presence of serum anti-CMV IgG Abs before transplantation to determine their risk for primary CMV infection and reactivation after HCT (AII). CMV is shed intermittently from the oropharynx and from the genitourinary tract of both immunocompetent and immunosuppressed subjects. There are no data showing that avoiding these body fluids is feasible or effective in preventing the acquisition of CMV in CMV-seronegative HCT recipients. As CMV-seronegative pregnant healthcare workers (HCWs) may be at risk for contracting CMV from these and other patients, standard universal precautions should be used in these situations. With proper management, CMV-seronegative patients have a low risk for contracting CMV infection. To reduce the risk of CMV transmission, blood products from CMVseronegative donors or leukocyte-depleted blood products should be used in CMV-seronegative allogeneic HCT recipients (AI). The benefit of using either of these products in autologous HCT recipients to prevent CMV transmission is less clear. However, as many autologous HCT recipients have received previous T-cell-suppressive therapy, such as fludarabine or alemtuzumab, the use of CMV-safe blood products is recommended (BII). In many centers, and even in several countries, leukocyte filtration of blood products is mandatory. No controlled study has examined the potential benefit of the combination of seronegative blood products and filtered blood products. Leukocyte filtration should be performed at the blood bank and the established quality standard of o5 Â 10 6 residual leukocytes per unit should be followed (AII). Preventing disease and disease recurrence Hematopoietic cell transplant recipients at risk for post transplant CMV disease (that is, all CMV-seropositive HCT recipients, and all CMV-seronegative recipients with a CMV-seropositive donor) should be placed on a CMV disease prevention program from the time of engraftment until at least 100 days after HCT (that is, phase II) (AI). Physicians should use either prophylaxis or preemptive treatment for allogeneic recipients (AI). In selecting a CMV disease prevention strategy, physicians should assess the risks and benefits of each strategy, the needs and condition of the patient and the hospital's virology laboratory support capability. A prophylaxis strategy against early CMV replication (that is, o100 days after HCT) for allogeneic recipients involves administering prophylaxis to all allogeneic recipients at risk throughout the period from engraftment to 100 days after HCT (Appendix 1) (AI). Ganciclovir, high-dose acyclovir and valacyclovir have all shown efficacy in randomized studies in reducing the risk for CMV infection after HCT. If ganciclovir is used, the induction course is usually started at engraftment (AI), 214,217,218 although a brief prophylactic course can be added during pretransplant conditioning (CIII). If acyclovir or valacyclovir is used, the patient must also undergo viral monitoring and receive preemptive antiviral therapy if evidence of CMV replication is found (AI). For CMV disease prophylaxis, i.v. Ig is not recommended among HCT recipients (EIII). In patients with CMV disease documented before transplantation, transplantation should be delayed until the disease is adequately treated (BII), and use of secondary anti-CMV prophylaxis during HCT should be considered . Such patients should be closely monitored during the HCT procedure, including during the preengraftment phase if the transplant center usually starts monitoring for CMV reactivation after engraftment, and a low threshold for preemptive treatment should be used . The preemptive strategy targets antiviral treatment to those patients who have evidence of CMV replication after HCT (Appendix 1). It requires the use of sensitive and specific laboratory tests to rapidly diagnose CMV replication after HCT and to enable the immediate administration of effective antiviral therapy after CMV replication has been detected. Allogeneic recipients at risk should be screened for the presence of CMV in blood samples approximately once a week from 10 days to at least 100 days after HCT (that is, phase II) (AIII). CMV-seropositive cord blood transplant recipients are at increased risk of CMV reactivation and disease. 220,221 Thus, some researchers use acyclovir or valacyclovir prophylaxis in combination with preemptive therapy in these patients . A preemptive strategy against early CMV replication (that is, o100 days after HCT) for allogeneic recipients is preferred over prophylaxis for CMV-seronegative HCT recipients of seropositive donor cells (that is, D positive and R negative) because of the low attack rate of CMV replication if screened or filtered blood product support is used . Diagnostic tests to determine the need for preemptive treatment include the detection of CMV pp65 Ag in leukocytes (antigenemia), 217,222 detection of CMV DNA by quantitative PCR or the detection of CMV RNA. HCT centers performing allogeneic transplants should have the capacity to perform one of these tests (AIII). Viral cultures of urine, saliva, blood or bronchoalveolar washings by rapid shell-vial culture 227 or routine culture are today rarely used, as these techniques are less sensitive than CMV-DNA PCR or CMV pp65 antigenemia tests. However, it should be recognized that CMV pp65 antigenemia tests may be falsely negative in patients with neutropenia. Ganciclovir is often used as a first-line drug for preemptive therapy. Although foscarnet is as effective as ganciclovir, 230 it is currently more commonly used as a second-line drug because of practical reasons (for example, requirement for prehydration and electrolyte monitoring). Allogeneic recipients who are p100 days after HCT should begin preemptive treatment if CMV viremia, antigenemia or DNA is detected (AI). Preemptive therapy should be given for a minimum of 2 weeks (A1). 217 If CMV is still detected after 2 weeks of therapy, maintenance therapy can be given until CMV is undetectable, 230 or it can be continued up to day 100 (AI). 217 After discontinuation of preemptive therapy, routine weekly screening is necessary up to at least day 100 because recurrent episodes of CMV viremia commonly occur (BII). At present, only the i.v. formulation of ganciclovir has been approved for use in CMV prophylactic or preemptive strategies (AI). Valganciclovir, a prodrug of ganciclovir, has been increasingly used in preemptive therapy, 231-234 and an interim analysis of a randomized, controlled study has shown comparable results in patients treated with i.v. ganciclovir or valganciclovir. 235 Dose adjustment for renal insufficiency is necessary with either drug to avoid hematological toxicity. Patients who are ganciclovir intolerant should be treated with foscarnet (AI). 236 HCT recipients receiving ganciclovir should have ANCs checked more than twice a week (BIII). Experts report managing ganciclovir-associated neutropenia by adding G-CSF 237 or temporarily stopping ganciclovir for E2 days if the patient's ANC is o1000 (CIII). Ganciclovir can be restarted when the patient's ANC is E1000 for two consecutive days. Alternatively, foscarnet can be substituted for ganciclovir if CMV can still be detected in blood. As neutropenia accompanying ganciclovir administration is usually brief, such patients do not require antifungal or antibacterial prophylaxis (DIII). True CMV antiviral resistance is quite rare in HCT patients, especially in those who have never been previously treated with antiviral agents. Increasing antigenemia or CMV DNA load early after initiation of antiviral therapy is usually not a sign of treatment failure in patients who have not been previously treated with antiviral agents, and therefore does not necessitate a change of therapy. However, if the patient develops signs of CMV disease or if the level of antigenemia or the CMV DNA load continues to rise after more than 2 weeks of therapy, resistant CMV should be suspected and a change of therapy considered (BIII). Development of CMV drug resistance early after HCT has been observed in children transplanted for immunodeficiency or in those who received T-cell-depleted grafts or anti-T-cell Abs. 240 Ganciclovir or foscarnet can be considered as an alternative drug for second-line preemptive therapy (AI). 230 Cidofovir, a nucleoside analog, can be considered for second-line preemptive therapy, but careful monitoring of renal function is required, and it should be noted that cross-resistance with ganciclovir can occur (BII). 241-243 If possible, samples should be sent to a laboratory capable of documenting antiviral resistance (CIII). Certain CMV-seropositive autologous recipients are at increased risk for symptomatic CMV replication or disease. 245 These include patients undergoing conditioning regimens including TBI; patients receiving grafts manipulated to remove T cells; and patients who have recently (for example, within 6 months before HCT) received alemtuzumab, fludarabine or 2-chlorodeoxyadenosine. Such patients may benefit from the use of a preemptive strategy that includes monitoring for CMV reactivation until 60 days after HCT (CII). Patients transplanted with CD34 þselected grafts should be treated at any level of antigenemia 245 (BII). Other autologous recipients at high risk who experience moderately high levels of CMV antigenemia (that is, blood levels of X5 positive cells per slide) or CMV DNA should receive 2 weeks of preemptive treatment with ganciclovir or foscarnet (CIII). 222 A prophylactic approach to CMV disease prevention is not recommended for CMVseropositive autologous recipients (DII). As HCT recipients might develop two or more reactivations, patients considered to be at increased risk for late CMV disease should be routinely screened for evidence of CMV reactivation as long as substantial immunocompromise persists (BII) 247 (Appendix 1). Risk factors for late CMV disease include allogeneic HCT accompanied by chronic GVHD; steroid use; low CD4 counts (o50 cells per mm 3 ); use of grafts from CMV-seronegative donors in CMV-seropositive recipients; and use of unrelated, haploidentical, cord blood or T-celldepleted HCTs. The indication for antiviral therapy if CMV is detected after day 100 has to be determined on an individual basis depending on the patient's risk factors for developing late CMV disease (BIII). The choice and duration of antiviral therapy are similar to those for CMV infection that occurs during the first 100 days post transplant. Strategies for preventing late CMV disease in high-risk patients include the use of continued surveillance and preemptive antiviral therapy, 247 as well as prophylaxis with antiviral drugs and cellular immunotherapy for patients with deficient or absent CMV-specific immune system function. Several small phase I/II studies have been published using adoptive transfer of CMV-specific CD4 þ and/or CD8 þ T cells, especially in patients developing repeated episodes of CMV disease. 252-255 However, none of these adoptive T-cell transfer techniques are in routine clinical practice and therefore cannot be recommended. ## Recommendations regarding ebv Preventing exposure Hematopoietic cell transplant donors and candidates should be tested for the presence of serum anti-EBV IgG Abs before transplantation to determine the risk for primary EBV after HCT. The recommendation is stronger in pediatric patients (AII) than in adults (BII). Although fever and mononucleosis can occur in primary EBV infection, the most significant clinical syndrome associated with EBV replication in HCT recipients, particularly after primary infection, is post transplant lymphoproliferative disease (PTLD). 256 This disorder occurs principally in recipients with profound T-cell cytopenia (for example, after T-cell depletion, use of anti-T-cell Abs, umbilical cord blood transplants and haploidentical transplants). 257-259 Assessment of blood EBV DNA loads with quantitative PCR testing can identify those at risk for PTLD. In HCT recipients, EBV disease typically results from reactivation of endogenous infection or transmission of EBV from the graft. 258 Nevertheless, all transplant candidates, particularly those who are EBV seronegative, should be advised of behaviors that decrease the likelihood of EBV exposure (AII) (see Strategies for Safe Living after HCT). ## Preventing disease For prevention of EBV-related PTLD (Appendix 1), it is important to monitor high-risk (for example, after T-cell depletion, use of anti-T-cell Abs, umbilical cord blood transplants and haploidentical transplants) patients for EBV DNA load using a blood EBV PCR assay (BII). EBV DNA loads have been shown to rise as early as 3 weeks before disease onset. Monitoring for blood EBV DNA loads allows preemptive reduction in immunosuppression, if possible, as the first part of patient management. Owing to the variability of PCR techniques and the difference in risk for EBV-related PTLD depending on the degree of T-cell lymphopenia, no firm recommendation on the threshold for initiation of preemptive therapy can be made. If there is no response to reduction in immunosuppression, preemptive treatment with rituximab can prevent PTLD (BII). 263 Infusion of donor-derived, EBV-specific CTL has shown promise in the prophylaxis of EBV lymphoma among recipients of T-cell-depleted unrelated or mismatched allogeneic recipients (CII). In addition, expanded donor-derived EBV-specific T cells have been used to control blood EBV DNA loads in this setting, but this procedure remains experimental (CII). 266,267 Use of B-cell depletion to minimize the risk of EBV PTLD has also been proposed (CII). 268 Finally, prophylaxis or preemptive therapy with currently available antiviral agents is not recommended because of lack of efficacy (DII). Recommendations regarding HSV ## Preventing exposure Hematopoietic cell transplant candidates should be tested for serum anti-HSV IgG before transplant (AII); however, type-specific anti-HSV IgG serology testing is not necessary. All HCT 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) (see Strategies for Safe Living after HCT). Any person with disseminated, primary or severe mucocutaneous HSV disease should be placed under contact precautions for the duration of illness (AII) 144 to prevent transmission of HSV to HCT recipients. Preventing disease and disease recurrence Acyclovir. Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early post transplant period (AI). The standard approach is to begin acyclovir prophylaxis at the start of conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or E30 days after HCT (AI) 272 (Appendix 1). The continued use of acyclovir seems to prevent HSV reactivation disease in patients who received it for VZV or CMV prophylaxis (CII). 274 Routine acyclovir prophylaxis is not indicated for HSV-seronegative HCT recipients, even if the donor is HSV seropositive (DIII). Use of ganciclovir prophylaxis for CMV in HCT recipients is sufficient for the prevention of HSV because of this drug's in vitro activity against HSV-1 and HSV-2 (AII), 214,275 although ganciclovir has not been approved for use against HSV. Acyclovir-resistant HSV infection occurs mainly in the setting of low-dose prophylaxis, intermittent treatment or with HSV-seronegative donors. Foscarnet is the treatment of choice for resistant disease (BI); cidofovir may serve as an alternative (CIII). If post-engraftment acyclovir prophylaxis is given, experts recommend a sufficiently high dose to prevent the emergence of resistance (Appendix 1). 274 Valacyclovir. Although valacyclovir is not approved for use in preventing HSV disease among HCT recipients, comparative studies have shown that valacyclovir and acyclovir are equally effective in suppression of HSV after autologous HCT 278,279 in patients who can tolerate oral medications (CIII). Regarding safety, valacyclovir has been used for 1 year in HCT recipients for suppression of VZV without toxicity. 280 Physicians wishing to use valacyclovir in recipients with renal impairment should exercise caution and decrease the dose as needed. Foscarnet. Owing to its substantial renal and infusionrelated toxicity, foscarnet is not recommended for routine HSV prophylaxis in HCT recipients (DIII). However, patients who receive foscarnet for other reasons (for example, CMV prophylaxis) do not require additional acyclovir prophylaxis (DIII). Famciclovir. At present, data regarding safety and efficacy of famciclovir among HCT recipients are limited; therefore, no recommendations for HSV prophylaxis with famciclovir can be made. Other recommendations HSV prophylaxis lasting 430 days after HCT might be considered for persons with frequent recurrences of HSV infection (BIII) (Appendix 1). Acyclovir or valacyclovir can be used during phase I (preengraftment) for administration to HSV-seropositive autologous recipients who are likely to experience substantial mucositis from the conditioning regimen (CIII). Acyclovir prophylaxis doses should be modified for use among children (Appendix 1). Owing to limited published data regarding valacyclovir safety and efficacy among children, no recommendations for the pediatric population can be made. 281 ## Recommendations regarding vzv ## Preventing exposure Hematopoietic cell transplant candidates should be tested for the presence of serum anti-VZV IgG Abs (AII). However, these tests are not 100% reliable, particularly among severely immunosuppressed patients. All HCT 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 (AII). Although the majority of VZV disease after HCT is caused by reactivation of endogenous VZV, HCT candidates and recipients who are VZV seronegative, or VZV seropositive and immunocompromised, should avoid exposure to persons with active VZV infections (AII). HCWs, family members, household contacts and visitors who are healthy and who 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 HCT recipient (AIII). Ideally, VZV-susceptible family members, household contacts and potential visitors of immunocompromised HCT recipients should be vaccinated as soon as the decision is made to perform HCT and the vaccination schedule should be completed E4-6 weeks before HCT is performed (BIII). To date, no serious disease has been reported among immunocompromised patients from transmission of VZV vaccine virus, and the VZV vaccine strain is susceptible to acyclovir. However, HCT recipients undergoing conditioning therapy should avoid contact with any VZV vaccine recipient who experiences a rash after vaccination (BIII). Rash after vaccination can be due to wild-type VZV (median: 8 days; range: 1-20 days) or the VZV vaccine strain (median: 21 days; range: 5-42 days). All HCT recipients with multidermatomal VZV disease should be placed under airborne and contact precautions (AII) 144 to prevent transmission to other HCT recipients. Dermatomal zoster requires contact precautions until all skin lesions are crusted (AII), and some researchers also recommend airborne precautions because in immunocompromised patients, there is a high risk for dissemination of the zoster rash (CII). Airborne precautions should be instituted 8 days after exposure to VZV and continued until 21 days after last exposure (AII) or 28 days after exposure if the patient received varicella-zoster Ig (VZIG) (BII), 144 because a person infected with VZV can be infectious before the rash appears. The VZIG product currently available in the United States is VariZIG (Cangene Corporation, Winnipeg, Canada). 286 Preventing disease Antiviral drugs. Long-term acyclovir prophylaxis to prevent recurrent VZV infection is routinely recommended for the first year after HCT for VZV-seropositive allogeneic (BI) 280,287 and autologous (CII) HCT recipients (Appendix 1). The 1-year regimen of acyclovir is highly effective in reducing the risk of VZV disease during the year of acyclovir administration (BI). 280,287 Acyclovir prophylaxis may be continued beyond 1 year in allogeneic HCT recipients who have chronic GVHD or who require systemic immunosuppression (BII). The optimal duration of prophylaxis is poorly defined in patients with chronic GVHD, as there seems to be a persistent risk of VZV reactivation disease even if acyclovir is continued until all systemic immunosuppressive drugs are discontinued and the CD4 þ count exceeds 200 cells per ml. 288 Some clinicians advocate continuing acyclovir prophylaxis until 6 months after discontinuing all systemic immunosuppressive agents (CIII). Valacyclovir is a prodrug of acyclovir and may be used as an alternative to acyclovir at any time that oral medications are used. Valacyclovir may provide higher drug levels in severely immunosuppressed patients than does acyclovir (BII). Although valacyclovir is not licensed in the United States for use in HCT recipients, a large randomized trial in HCT recipients found no safety issues with valacyclovir, even when used at very high doses. No data on famciclovir in HCT recipients were found; consequently, no recommendations can be made regarding its use in place of acyclovir or valacyclovir. Resistance to acyclovir has been rarely documented to date in HCT recipients; 289 however, when clinically suspected or virologically documented, acyclovir resistance occurs among patients, HCT physicians should use foscarnet for preemptive treatment of VZV disease (BIII). Any HCT recipient or candidate undergoing conditioning therapy who experiences a VZV-like rash (whether after exposure to a person with wild-type varicella or shingles or exposure to a VZV vaccinee with a rash) should receive preemptive i.v. acyclovir until E2 days after all lesions have crusted (BII). Treatment may be completed with oral valacyclovir if the patient can tolerate oral medication. Passive immunization and VZV-seronegative HCT recipients Owing to the high morbidity of VZV-associated disease among severely immunocompromised HCT recipients and until further data are published, there are situation-specific indications for the administration of VZIG or VariZIG, where available, for VZV-seronegative HCT recipients. Immunocompromised HCT recipients (that is, an allogeneic patient o24 months after HCT; X24 months after HCT and on immunosuppressive therapy; or having chronic GVHD) should receive VZIG or VariZIG as soon as possible, and no later than 96 h after close or household contact with a person having either chickenpox or shingles (AII). Post-exposure acyclovir or valacyclovir (Appendix 1) may be used as an alternative if VZIG or VariZIG is not available (CII). 291,292 VZIG or VariZIG, acyclovir or valacyclovir should also be administered to all VZVseronegative HCT recipients undergoing conditioning therapy who are exposed to a VZV vaccinee having a varicella-like rash (BIII). If VZV-seronegative HCT recipients undergoing conditioning therapy are closely exposed to varicella 43 weeks after receiving VZIG or VariZIG, they should receive another dose of VZIG or VariZIG, or another course of valacyclovir if VZIG or VariZIG is not available (BIII). 282 Passive immunization and VZV-seropositive HCT recipients Varicella-zoster Ig or VariZIG, acyclovir, or valacyclovir can be used after VZV exposure, including exposure to a VZV vaccinee having a varicella-like rash, for HCT recipients who were VZV seropositive before HCT and are highly immunosuppressed (that is, because of high-dose steroid therapy or T-cell depletion) (CIII). 292 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 post-vaccination vesicular rashes. 282 Furthermore, varicella vaccination is only E85% effective. Thus, vaccine recipients may still become infected with wild-type virus years after vaccination 293 and may thus be a source of transmission to immunocompromised patients. VZV vaccines. Use of VZV vaccines (Varivax and Zostavax, Merck, Whitehouse Station, NJ, USA) is discussed in the HCT Recipient Vaccination section. A vaccine-associated rash occurs in E1-5 and 0.5% of recipients of the varicella and zoster vaccine, respectively. This rash is a potential source of transmission of the vaccine virus strain to HCT recipients. As the risk of vaccine virus transmission is low, particularly in the absence of a vaccine-associated rash, household members should receive varicella vaccine to protect HCT recipients from potential exposure to wild-type disease (AIII). Individuals who experience a vaccine-associated rash should avoid close contact with HCT recipients in the home setting (BIII). If contact occurs, the HCT recipient should be considered for post-exposure prophylaxis with valacyclovir, as outlined above (CIII). An inactivated VZV vaccine has been used investigationally among HCT recipients. Studies are ongoing to further define its utility and no recommendation regarding its use can be made at this time. ## Other recommendations Recommendations for VZV prevention are the same for allogeneic or autologous recipients. Recommendations are also the same for allograft recipients with different-intensity conditioning regimens. Recommendations for preventing VZV disease among pediatric or adult HCT recipients are the same, except that appropriate dose adjustments for acyclovir derivatives and VZIG should be made for pediatric HCT recipients (AIII) (Appendix 1). ## Recommendations regarding community-acquired respiratory viral infections: influenza, respiratory syncytial virus, human metapneumovirus and parainfluenza virus Preventing exposure Preventing community-acquired respiratory viral (CRV) exposure is critical in preventing CRV disease. Measures for preventing nosocomial CRV transmission are presented in the Infection Prevention and Control in Healthcare Facilities: Recommendations Regarding CRV Infections section. Use of PCR testing in donors with respiratory infections remains investigational (CIII). Viral cultures of asymptomatic HCT candidates are unlikely to be useful. Whether multiplex PCR testing can identify asymptomatic shedders before HCT is presently being studied. PCR-based routine surveillance of asymptomatic patients after HCT remains investigational. Hematopoietic cell transplant recipients with symptoms of an upper respiratory infection (URI) or lower respiratory infection should be placed under contact precautions to avoid transmitting infection to other HCT candidates and recipients, HCWs and visitors until the etiology of illness are identified (BIII). 144 Optimal isolation precautions should be modified as needed after etiology is identified (BIII). HCT recipients and candidates, their family members and visitors, as well as all HCWs, should be informed regarding CRV infection-control measures and the potential severity of CRV infections among HCT recipients (BIII). Preventing disease Hematopoietic cell transplant physicians should determine the etiology of a URI in an HCT recipient, if possible, because respiratory syncytial virus (RSV), influenza, parainfluenza and adenovirus URIs can progress to more serious lower respiratory infection, and certain CRVs can be treated (BIII). Appropriate diagnostic samples include nasopharyngeal washes, swabs or aspirates; throat swabs (in combination with nasal samples); and bronchoalveolar lavage fluid. HCT candidates with URI symptoms at the time that conditioning therapy is scheduled to start should postpone their conditioning regimen until URIs resolve, if possible, because certain URIs might progress to lower respiratory infection during immunosuppression (BIII). The clinical relevance of recently discovered viruses (for example, human bocavirus, non-severe acute respiratory syndrome coronaviruses, human rhinoviruses, human metapneumovirus) that are detectable by molecular methods is currently undefined and no recommendations can be made for the routine screening of these viruses (CIII). ## Recommendations regarding influenza Lifelong seasonal influenza vaccination with the trivalent inactivated vaccine is recommended for all HCT candidates and recipients (see Vaccination section) (AII). In addition, influenza vaccination of family members and close or household contacts is strongly recommended during each influenza season (for example, October-May in the Northern hemisphere), starting from the season before HCT and continuing E24 months after HCT (AII) 303 to prevent influenza. All family members and close or household contacts of HCT recipients should continue to be vaccinated annually as long as the HCT recipient's immunocompromise persists, even if beyond 24 months after HCT (AII). 303 Seasonal influenza vaccination is strongly recommended for all HCWs of HCT recipients (AI). If HCWs, family members or other close contacts of HCT recipients receive influenza vaccination during an influenza outbreak, they should receive chemoprophylaxis, if feasible, for 2 weeks after influenza vaccination (BI) while the immunological response to the vaccine develops. However, if an outbreak occurs with an influenza strain that is not contained in the available influenza vaccine, all healthy family members, close and household contacts, as well as HCWs of HCT recipients and candidates, should receive influenza chemoprophylaxis with an active agent against the current circulating strain of influenza until the end of the outbreak (BIII). 303 Zanamivir may be given for the prevention of influenza A and B, including influenza from strains resistant to oseltamivir. The duration of prophylaxis depends on the type of exposure. Zanamivir can be administered to persons 5 years of age or older for prevention of influenza and 7 years or older for treatment of influenza. Oseltamivir can be administered to persons E1 year of age or older. Patients with influenza should be placed under droplet and standard precautions (AIII) to prevent transmission of influenza to HCT recipients. HCWs with influenza should be excused from patient care until they are no longer infectious (AIII). Hematopoietic cell transplant recipients o6 months after HCT should receive chemoprophylaxis with neuraminidase inhibitors during community influenza outbreaks that lead to nosocomial outbreaks (AII). During community outbreaks, all HCT recipients who have not yet received a current influenza vaccination should be vaccinated against influenza immediately if they are more than 4 months after HCT (BIII). In addition, to allow sufficient time for the patient to experience an immunological response to influenza vaccine, chemoprophylaxis can be used for these HCT recipients for 2 weeks after vaccination during a nosocomial or community influenza outbreak (CIII). Influenza chemoprophylaxis has been recommended for all influenza-exposed HCT recipients who are o24 months after HCT or who are 424 months after HCT and substantially immunocompromised regardless of vaccination history, because of their likely suboptimal immunological response to influenza vaccine (BII). 305,306 Drug resistance patterns of circulating influenza strains should guide the choice of prophylactic agent. Healthy children who receive influenza vaccination for the first time might not generate protective Abs until 2 weeks after receipt of the second dose of influenza vaccine. Therefore, during an influenza A outbreak, pediatric recipients who are o9 years old, are p6 months after HCT and receiving their first influenza vaccination should be given E6 weeks of influenza A chemoprophylaxis after the first dose of influenza vaccine (BIII) (Appendix 1). 307,308 To prevent severe disease, HCT patients with influenza URI should receive early preemptive therapy with drugs shown to be susceptible to the circulating strain. (AII). Recommendations regarding RSV Respiratory secretions of any hospitalized HCT 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 E2 days apart do not identify a respiratory pathogen despite the persistence of lower respiratory symptoms, bronchoalveolar lavage and further testing are advised (BIII). This testing is critical because of the high morbidity and case fatality of RSV disease and the frequent presence of significant co-pathogens among HCT recipients when it occurs during the peritransplant period. 311,312 HCT recipients, particularly those who are preengraftment and lymphopenic or those who have preexisting obstructive airway disease, are at highest risk for severe RSV pneumonia. These patients should have their illness diagnosed early (that is, during RSV URI) and receive aggressive treatment to prevent fatal RSV disease (BIII). On the basis of retrospective studies, as well as a prospective trial with inadequate accrual, some researchers recommend preemptive aerosolized ribavirin for patients with RSV URI, especially those with lymphopenia (during the first 3 months after HCT) and preexisting obstructive lung disease (late after HCT) (CIII). 310,313 Although a definitive, uniformly effective preemptive therapy for RSV infection among HCT recipients has not been identified, certain other strategies have been proposed, including systemic ribavirin, 314-316 RSV Abs (that is, passive immunization with high-RSV-titer i.v. Ig and RSV Ig) in combination with aerosolized ribavirin 301,317 and RSV MoAb. No randomized trial has been completed to test the efficacy of these strategies. No specific recommendation regarding any of these strategies can be given at this time. To prevent RSV disease, some centers provide monthly palivizumab prophylaxis during RSV season (for example, November-April in the Northern hemisphere) for pediatric recipients at risk for primary RSV disease (that is, children o4 years old) (CIII). Routine i.v. Ig therapy would still be required if indicated 319 (that is, for those with hypogammaglobulinemia) (Appendix 1). ## Recommendations regarding parainfluenza virus Immunoprophylaxis, withdrawal of immunosuppression to prevent progression and preemptive treatment for parainfluenza virus infections among HCT recipients have been proposed. 320 However, no recommendation can be made in these guidelines because of insufficient data. No commercially licensed drugs or vaccines against parainfluenza viruses are currently available. ## Recommendations regarding human metapneumovirus Human metapneumovirus can cause pneumonia in HCT recipients. 321 Ribavirin has in vitro and animal model activity against human metapneumovirus. 322,323 However, no recommendations can be made in these guidelines because of lack of treatment data. ## 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 308,319,324,325 and adults, but with appropriate adjustments in antiviral drug and influenza vaccine doses for children (Appendix 1). Progression to lower tract disease seems to be less common in HCT recipients with nonmyeloablative conditioning, but no specific recommendations for these patients can be made at this time. ## Recommendations regarding adenoviruses Preventing exposure Adenovirus infections after HCT can result from reactivation or de novo acquisition. As many different serotypes exist and knowledge about cross-reactive immunity is limited, pretransplant serological testing of either the patient or the donor is not likely to be helpful. As cellular immune responses are cross-reactive across various serotypes and are likely to provide long-term protection against adenovirus reactivation, serious adenovirus infections in adults are uncommon. 326,327 HCT recipients should follow similar preventive measures as those for other respiratory or enteric viruses (see recommendations regarding CRV, CMV and enteric viruses) with regard to contact and nosocomial spread (see Infection Prevention and Control in Healthcare Facilities and Safe Living after HCT). ## Preventing infection and disease Hematopoietic cell transplant patients can be stratified according to their risk for adenoviral disease: Lowest risk-autologous HCT recipients Intermediate risk-T-cell replete, related-donor allograft recipients without GVHD Higher risk-recipients of T-cell-depleted (2-3 log 10 ), related-or unrelated-donor transplants; 331,332 HLA-mismatched transplant recipients other than allele DRB1 mismatch; 333 patients with GVHD who receive systemic steroids 328,334,335 and pediatric recipients. Highest risk-refractory GVHD, umbilical cord blood transplantation, haploidentical transplantation, stem cell graft T-cell depletion of 42-3 log 10 , use of anti-T-cell Abs (for example, ATG (antithymocyte globulin), alemtuzumab). For patients at highest risk, weekly monitoring for active adenovirus infection by PCR either for the first 6 months after HCT or for the duration of severe immunosuppression/lymphopenia could be considered (CII). Quantitative PCR testing should be strongly considered for monitoring progression of adenovirus infection and response to treatment (BII). There are no definitive data on a critical value for viral load in peripheral blood to indicate initiation of intervention; thus, no recommendation can be made. Clearance of adenovirus has been shown to be associated with recovery of adenovirus-specific T-cell immunity. When possible, rapid tapering or withdrawal of immunosuppression constitutes the best way to prevent progression of adenovirus infection (AII). However, this strategy might not always be feasible in severe GVHD or with severe lymphopenia because of the use of anti-T-cell Abs or T-cell depletion of the graft. Few antiviral agents have in vivo activity against adenoviruses, and no randomized, placebo-controlled study of antiviral drug therapy for adenoviral infection has been conducted. The available data suggest that cidofovir or ribavirin could be used as preemptive antiviral therapy of adenoviral disease in selected high-risk HCT patients (CII) (Appendix 1). A reduction of DNA load has been shown mainly with cidofovir 342,343 , but the evidence of its efficacy in preventing mortality in HCT patients is inconsistent. 344 Differences in responses may be due to strain-specific susceptibilities. The duration of preemptive therapy is subject to tolerance and clearance of viral load. Current evidence strongly supports the role of adenovirus-specific T cells in controlling the progression of adenoviral disease. 346 However, this approach is at an early stage of development and should not be used outside the context of a clinical trial. ## Recommendations regarding polyomaviruses, bk and jc Human polyomavirus type I, commonly called BK virus (BKV), and human polyomavirus type II, commonly called JC virus (JCV), infect 50-90% of humans worldwide before the age of 10 years, without known symptoms or signs. 347,348 Urinary shedding of BKV and/or JCV occurs in 5-20% of healthy immunocompetent blood donors. 349 BKV and JCV are nonenveloped virions found in urban sewage and fairly resistant to environmental inactivation. Polyomavirus disease in HCT patients most often corresponds to secondary BKV replication with impaired polyomavirus-specific cellular immunity. Urinary shedding of BKV occurs in 60-80% of HCT recipients. The major disease linked to high-level polyomavirus replication is BKV-associated hemorrhagic cystitis (PVHC), which affects 5%-15% of HCT recipients at 3-6 weeks after transplant. 352,354 PVHC occurs typically after engraftment and must be distinguished from hemorrhagic cystitis caused by other pathogens (for example, adenovirus or CMV) and from early-onset hemorrhagic cystitis, which arises before engraftment and has been linked to urotoxic conditioning regimens with CY, ifosfamide, BU and/or TBI. 352,354 BKV viruria reaching high viral loads of 410 7 genome equivalents per ml (geq/ml) is observed in 20-80% of HCT patients, but less than one-fifth of HCT recipients develop PVHC. 354 PVHC is diagnosed in HCT patients with post-engraftment cystitis who have pain and urinary urgency, together with hematuria of grade II (macrohematuria 352 ) or higher, high-level BKV replication (that is, X10 7 geq/ml) and exclusion of other pathogens. There are reports of sporadic cases of JCV-associated PVHC, 355 BKV-or JCV-associated polyomavirus nephropathy 347,356-359 and JCV-or BKV-mediated polyomavirus multifocal leukoencephalopathy. Preventing exposure There is no evidence to support routine testing of HCT recipients or donors for the presence of BKV-specific or JCV-specific Abs (DIII). There are no commercially available, standardized or Food and Drug Administration-approved assays to measure BKV-or JCV-specific Abs. The role of primary infection, of donor-recipient mismatch and of BKV-specific Ab titers in HCT recipients is presently unknown. There is no evidence to support specific infection-control measures for HCT patients with BKV viruria (DIII). In patients with disseminated BKV replication involving the respiratory and gastrointestinal tract, separation from other patients with significant immunodeficiency should be considered (CIII). ## Preventing disease and disease recurrence There is no evidence to support the use of quinolones or cidofovir as specific universal prophylaxis for PVHC or other polyomavirus-associated complications (DIII). There is insufficient evidence to support the use of quinolones for preemptive treatment of asymptomatic HCT patients who develop BKV viruria or viremia (DIII). Fluoroquinolones can inhibit BKV replication in tissue culture and have been reported to reduce BKV loads in HCT patients, but a significant reduction of PVHC has not been shown. Ciprofloxacin and levofloxacin are frequently used, alone or in combination with other antibiotics, in patients undergoing HCT in antibacterial prophylaxis during neutropenia and in empiric or specific antibiotic therapy, and seemingly resistant BKV isolates have been reported. There is no evidence to support the use of cidofovir for preemptive treatment of asymptomatic HCT patients who develop BKV viruria or viremia (DIII). Cidofovir has been administered i.v. in a low dose (that is, up to 1 mg/kg thrice weekly, without probenecid) or a high dose (that is, 5 mg/kg per week with probenecid) to HCT patients with PVHC, but no randomized trials are available proving its clinical efficacy (CIII). ## Recommendations regarding hepatitis a virus The seroprevalence of hepatitis A virus (HAV) varies widely, with higher rates in resource-limited societies. Testing of HCT candidates or donors for HAV IgG Abs is generally not recommended, as its sole positivity in the absence of IgM indicates remote exposure and has no impact on HCT outcome (DIII). However, testing for IgM is indicated as a part of the workup of patients with signs of acute hepatitis (AII). If an HCT candidate tests positive for HAV IgM, transplantation should be delayed because of an increased risk of sinusoidal obstruction syndrome after liver-toxic myeloablative conditioning regimens (DII). If the HCT donor tests positive for HAV IgM, transplantation should be delayed because of a high risk of transmission and increased morbidity and mortality (EII). HAV vaccination recommendations for HCT recipients are provided in [fig_ref] Table 6: Vaccinations considered optional or not recommended for both autologous and allogeneic HCT... [/fig_ref]. ## Recommendations regarding hepatitis b virus Hepatitis B virus (HBV) can cause severe hepatitis after HCT. However, rates of HBV-associated cirrhosis and hepatocellular carcinoma do not seem higher in HCT patients compared with non-HCT patients. Severe hepatitis B has been observed in HCT recipients in the following situations: HBV-naive HCT recipients exposed to HBV through an infected donor, infected blood products or through sexual contact; HCT recipients with chronic hepatitis B experiencing prolonged immune suppression; HCT recipients with serological evidence of resolved HBV infection who have reverse seroconversion after prolonged immune suppression; HCT patients-generally in countries with endemic HBV-with latent occult hepatitis B (all serological markers negative) that activates after prolonged immune suppression. 365 Risk factors for reactivation and exacerbation of HBV replication in HCT recipients include treatment with highdose steroids, 366,367 fludarabine/rituximab 368 or alemtuzumab. Clinical hepatitis may become further exacerbated during immune recovery and discontinuation of immunosuppression. ## Preventing exposure Testing both recipients and potential donors for evidence of active or past HBV infection is critical for the prevention of HBV exposure and disease in HCT recipients. Appropriate assays include HBV surface Ag (HBsAg), Abs to HBsAg (anti-HBs) and Abs to HBV core Ag (anti-HBc) (AII). All anti-HBc-positive and HbsAg-positive donors and recipients should also be tested for HBV DNA (AIII). HBVnaive HCT candidates should not receive transplants from HBsAg-positive or HBV DNA-positive donors, if another equally suitable donor is available (AII). However, the use of a donor with active HBV replication is not absolutely contraindicated for an HBV-naive recipient, as viral transmission is not universal (BIII). The overriding concern must be HLA matching and other outcome-related issues. Vaccination of all HBV-naive HCT candidates should be considered (AIII). An attempt should be made to provide hepatitis B immunization to HBV-seronegative HCT candidates with HBsAg-positive donors, preferably before chemotherapy for the initial two doses 3-4 weeks apart and for a third dose 6 months later, ideally before HCT (BIII). If this schedule cannot be met, the third dose should be No data regarding safety among HCT recipients. EIII Abbreviation: HCT ¼ hematopoietic cell transplant. a Current Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics guidelines for post-exposure human rabies Ig and vaccine administration should be followed, which include administering five doses of rabies vaccine administered on days 0, 3, 7, 14 and 28 post-exposure. administered a few months after completion of chemotherapy. It is noteworthy that the response to vaccination is likely to be poor in patients undergoing chemotherapy. If the post-vaccination anti-HBs titer is o10 IU/l or the pretransplantation vaccination is impractical, HBIG (0.06 ml/kg) should be administered immediately before infusion of stem cells (AIII). HCT recipients who fail to respond to pretransplant vaccination, but remain uninfected after transplant (that is, negative for HBsAg, anti-HBc, anti-HBs and HBV DNA) should be revaccinated after immune recovery with 1-3 doses of hepatitis B vaccine (BII). If the donor has a detectable HBV DNA load, the following measures are recommended (BIII): Administer antiviral treatment to the donor for at least 4 weeks, or until HBV DNA is undetectable (if time permits). Many experts prefer entecavir for this purpose (CIII). Reduce harvest volume to the minimum possible without compromising the planned CD34 þ cell dose, and test an aliquot of the cell product for HBV DNA. If, at the time of harvest, both the donor and harvested cells are HBV DNA negative, monitor alanine aminotransferase (ALT) levels monthly in the recipient for the first 6 months. If the ALT level increases, test the recipient for HBV DNA (AIII). If HBV DNA testing is not available, testing for HBsAg is an acceptable alternative. If HBV DNA is detected or a positive HBsAg is identified, antiviral treatment is indicated (AIII). If the donor or cell product is positive for HBV DNA at the time of harvest, provide the HCT recipient prophylaxis with lamivudine from day zero through at least 6 months after discontinuation of immunosuppressive drugs. Consider the administration of a second dose of HBIG at 4 weeks after transplantation (AIII). Monitor ALT and HBV DNA monthly. If HBV DNA is positive during lamivudine prophylaxis, treatment may be modified as detailed below. If the donor is anti-HBc positive, but negative for both HBsAg and anti-HBs, the donor should be tested for HBV DNA (BIII). If the HBV DNA assay is positive, treat as described in the bullets above for a donor with a detectable HBV viral load (BIII). If HBV DNA testing is negative, repeat testing of the donor at the time of harvest should be considered. If HBV DNA remains negative, HCT is performed without further precaution (DIII). If the repeat test is positive, treat as described above (BIII). HBV-naive HCT recipients who are in a monogamous relationship with a known HBsAg carrier, or who are sexually active and not in a long-term monogamous relationship, should always use latex condoms during sexual contact to reduce their risk of primary HBV infection (AIII). 370 ## Preventing disease For HCT candidates with evidence of past exposure to HBV (that is, who are anti-HBc positive), the specific recommendations depend on the pattern of test results. As the risk of post-HCT hepatitis is reduced because of the adoptive transfer of a donor's natural immunity, equally suitable donors showing natural immunity (anti-HBs positive, anti-HBc positive) are preferred over donors without natural immunity for recipients with evidence of previous HBV exposure. If the HCT recipient is anti-HBc positive and anti-HBs positive, the risk of HBV reactivation is considered low during chemotherapy/conditioning but higher after prolonged treatment with prednisone for GVHD. Serum ALT should be followed in such patients, and if the level increases, HBV DNA load should be assessed. Patients with a positive HBV DNA load should receive preemptive antiviral treatment as described below (AIII). Prophylactic antiviral treatment may be considered for anti-HBcpositive and anti-HBs-positive recipients before, and for 1-6 months after, HCT (CIII). In addition, anti-HBs levels should be monitored every 3 months. Reduction in anti-HBs titer should prompt HBV DNA testing (BIII). Patients who lose anti-HBs responses but have no HBV DNA in serum should receive active immunization in an attempt to restore protective levels of anti-HBs (BIII). Patients with positive HBV DNA assays should receive antiviral therapy (AIII). The duration of antiviral treatment in this setting has not been studied, but a common practice is to continue therapy for at least 6 months after discontinuation of immune suppressive drugs (BIII). Rebound HBV replication and clinical hepatitis may follow discontinuation of antiviral treatment and should be monitored by regular measurement of ALT and HBV DNA (for example, biweekly) (BIII). Hematopoietic cell transplant candidates with evidence of active HBV replication (HBsAg positive and/or HBV DNA positive) should have a liver biopsy before HCT, because preexisting biopsy-proven cirrhosis and hepatic fibrosis can increase transplant-related morbidity and mortality (BIII). Antiviral therapy should be initiated before conditioning. If HCT is not urgent, antiviral treatment should be administered for 3-6 months before conditioning. In patients with persisting HBV DNA while on therapy with lamivudine, treatment may be modified as detailed below. Rebound HBV replication and fulminant hepatitis may occur after discontinuation of antiviral treatment. Therefore, discontinuation of antiviral therapy should be performed judiciously, with frequent monitoring of liver function and HBV DNA (BIII). Hematopoietic cell transplant candidates who are positive for anti-HBc but negative for HBsAg and anti-Hbs should be tested for HBV DNA. If HBV DNA is undetectable, the patient should receive HBV vaccination as described above and proceed to HCT. Further management regarding monitoring and antiviral treatment should be performed as described for anti-HBc-positive and anti-HBs-positive HCT candidates (BIII). If HBV DNA is positive, proceed to HCT with preemptive antiviral therapy as described above. Antiviral treatment. Therapy should be coordinated between the HCT physician and Infectious Disease and/or Hepatology specialist(s) with expertise in chronic viral hepatitis. Lamivudine (100 mg/day) is the first choice for antiviral therapy (AI). Antiviral therapy should be continued for at least 6 months after transplant in autologous HCT patients, for 6 months after discontinuation of immune suppressive drugs in allogeneic HCT patients and longer in patients receiving immunosuppression for chronic GVHD (BIII). Extended use of lamivudine not only results in reduction of HBV reactivation and the resultant complications but also lowers HBV-associated mortality. Recommendations regarding Hepatitis C virus Hematopoietic cell transplant from donors who are Hepatitis C virus (HCV)-RNA positive invariably transmits HCV to uninfected recipients, with development of viremia in the immediate post transplantation period. Conversely, the risk of transmission is decreased if HCV-RNA is undetectable at the time of hematopoietic cell donation. There is no evidence of adverse short-term effects of HCV infection in HCT recipients, and HCVinfected HCT patients have similar morbidity up to 10 years after transplant. 378 Subsequently, however, these patients are at risk for progression to cirrhosis, which may occur more rapidly than in non-HCT patients. The cumulative incidence of biopsy-proven cirrhosis is 11 and 24% at 15 and 20 years after transplant, respectively, with a median of 18 years compared with 40 years for non-HCT HCV-infected patients. Extrahepatic manifestations and infection with HCV genotype 3 increase the risk of progression. Preventing exposure All HCT candidates should be assessed for risk of HCV infection with a careful history, physical examination and serum ALT testing (BIII), as well as by the measurement of anti-HCV Ab titers (AII). Even if anti-HCV titers are negative, nucleic acid testing for HCV-RNA should be undertaken in patients whose history indicates increased risk for HCV infection (for example, transfusion with blood not tested for HCV-reliable testing of blood supply began in 1992 in developed countries; i.v. or inhaled drug abuse; or tattoos) or who have an unexplained elevation of serum ALT (AII). Hepatitis C virus-infected patients requiring HCT and for whom there is no alternative donor can proceed with HCT from an HCV-positive donor, provided they have a full understanding of the long-term side effects (BIII). The donor should be assessed for chronic liver disease and other extrahepatic manifestations of HCV, which might contraindicate donation (EIII). Similar to recipients, all donors should be screened for anti-HCV Abs, and those found to be anti-HCV positive or at a high risk for HCV infection should be tested for HCV-RNA (AII). If feasible, viral clearance with standard combination antiviral therapy before stem cell harvest may be attempted in donors with detectable HCV-RNA. However, there are few reports on the success of this method. Both the donor and recipient should be counselled on individual risks (BIII). ## Preventing disease progression All HCT candidates with HCV infection must be assessed for evidence of chronic liver disease. To assess the risk of conditioning and HCT, liver biopsy is warranted in the following clinical situations (AIII): Associated iron overload History of excessive alcohol intake History of hepatitis C for 410 years Clinical evidence of chronic liver disease. Patients with evidence of cirrhosis or hepatic fibrosis should not be considered for conventional myeloablative conditioning therapy that contains either CY or TBI X12 Gy (DIII), as these regimens are associated with a 9.6-fold increased risk of fatal sinusoidal obstruction syndrome in these patients. Instead, regimens that contain neither CY nor TBI, which pose a lower risk for fatal sinusoidal obstruction syndrome, should be used. However, for patients with cirrhosis, even a reducedintensity conditioning regimen poses a mortality risk. Treatment for chronic HCV should be considered in all HCV-infected HCT recipients, because limited data suggest improved outcome in those who respond to combination therapy (BIII). To qualify for antiviral treatment, the patient must be in CR from the original disease; be X2 years after transplant without evidence of either protracted acute GVHD or chronic GVHD; have been off immunosuppression for 6 months; and have normal blood counts and serum creatinine (BIII). Treatment should consist of full-dose peginterferon and ribavirin (BIII). Dose modifications should be made if intolerance develops (for example, development of cytopenias). In survivors whose neutrophil and plt counts are below normal at baseline, daily IFN-a can be substituted for peginterferon to assess hematological toxicity before moving to peginterferon. Treatment should be continued for 24-48 weeks, depending on response. ## Human herpesviruses 6 and 7 Preventing exposure Human herpesvirus 6 (HHV-6) is the cause of the classic childhood illness roseola, which is also known as exanthema subitum or Sixth Disease. 386 Clinical disease associated with HHV-7 infection remains to be defined. Nearly all children are infected with HHV-6 by 2-3 years of age 387-389 and with HHV-7 by the age of 5 years. 390 Preventing disease and disease recurrence The spectrum of HHV-6-associated complications after HCT has not been completely described. HHV-6 reactivation is common during the early allogeneic HCT transplant period, with viremia occurring in E40-60% of patients. The clinical significance of detection of HHV-6 viremia is unknown, although it has been associated in the post transplant setting with hepatitis, fever, rash, idiopathic pulmonary syndrome and delayed plt and monocyte engraftment. HHV-6 can also be chromosomally integrated, potentially resulting in a false-positive PCR assay result. 395 A post transplantation acute limbic encephalitis syndrome associated with HHV-6 reactivation in the cerebrospinal fluid has been reported. This syndrome is uncommon, occurring in E1-2% of HCT patients in some series. It typically occurs 1-2 months after transplantation and seems to be more common after receipt of an umbilical cord blood or HLA-mismatched graft. Manifestations include profound memory loss, seizures, hyponatremia, mild cerebrospinal fluid pleocytosis and significant mesial temporal lobe abnormalities on magnetic resonance imaging. In addition, HHV-6 may interfere with MHC class I Ag presentation and augment local immunosuppression; 398 however, the implications of this viral property are unknown. The role of HHV-7 in post transplant complications remains to be defined. At this time, there are no data to guide a preemptive monitoring or a prophylactic antiviral strategy to prevent potential HHV-6-associated disease (DIII). Ganciclovir, cidofovir and foscarnet have variable in vitro activity against HHV-6 and may have a role in treating HHV-6associated disease. There are no data to support recommendations for monitoring of potential HHV-7associated disease (DIII). ## Human herpesvirus 8 Preventing exposure Human herpesvirus type 8 is the cause of Kaposi's sarcoma and is also known as Kaposi's sarcoma-associated herpesvirus. Unlike other herpesvirus infections, HHV-8 infection is not ubiquitous. There is significant geographic variability in the prevalence of HHV-8 infection, with high infection rates reported in sub-Saharan Africa (50%), modest rates in the United States (about 5%) and low rates in Japan (o1%). In the United States, higher rates of HHV-8 infection have been identified in men who have sex with men, perhaps indicating sexual transmission or enhanced transmission through saliva. Preventing disease and disease recurrence Human herpesvirus type 8-associated disease (for example, Kaposi's sarcoma) occurs only rarely after HCT. At this time, there are no data to guide monitoring or preemptive antiviral treatment for post transplant HHV-8associated disease (DIII). ## Human immunodeficiency virus In patients infected with the HIV and receiving highly active antiretroviral therapy, cancer is now the leading cause of death. Consequently, HCT may need to be considered for these patients. ## Preventing exposure As described in the Hematopoietic Cell Graft Safety section, regulations are in place in both the United State and the European Union for evaluation of donors to minimize risk of transmissible diseases. Using a related donor with known HIV harbors significant risks that likely outweigh any benefits of transplantation to a seronegative recipient, and should not be considered (DIII). ## Preventing disease and disease recurrence Patients with HIV and a malignancy treated by transplantation should not automatically be excluded from this potentially life-saving therapy. Reports of autologous transplantation suggest that this is a feasible approach in patients with controlled HIV disease (BIII). 406-410 Outcomes after allogeneic transplantation are quite limited, although one report suggests that in the current era of highly active antiretroviral therapy, this may be considered (CIII). Owing to significant complexity in the management of HIV-positive patients, it is recommended that any HIV-positive patient considered for HCT be enrolled in a clinical trial and the patient be co-managed by an HIV specialist. [table] Table 6: Vaccinations considered optional or not recommended for both autologous and allogeneic HCT recipients [/table]	None	https://www.nature.com/articles/bmt2009258.pdf	None
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Community-based Argentine tango dance program is associated with increased activity participation among individuals with Parkinson's disease. Archives of Physical Medicine & Rehabilitation 2013; 2: 240-9 78. Frazzitta, G., Bertotti, G., Riboldazzi, G., Turla, M., Uccellini, D., Boveri, N., Guaglio, G., Perini, M., Comi, C., Balbi, P., Maestri, R. Effectiveness of intensive inpatient rehabilitation treatment on disease progression in parkinsonian patients: a randomized controlled trial with 1-year follow-up. Neurorehabilitation & Neural Repair 2012; 2: 144-50 79. Frazzitta, G., Bossio, F., Maestri, R., Palamara, G., Bera, R., Ferrazzoli, D. Crossover versus Stabilometric Platform for the Treatment of Balance Dysfunction in Parkinson's Disease: A Randomized Study. BioMed Research International 2015; 0: 878472 80. Frazzitta, G., Maestri, R., Bertotti, G., Riboldazzi, G., Boveri, N., Perini, M., Uccellini, D., Turla, M., Comi, C., Pezzoli, G., Ghilardi, M. F. Intensive rehabilitation treatment in early Parkinson's disease: a randomized pilot study with a 2-year follow-up. Neurorehabilitation & Neural Repair 2015; 2: 123-31 81. Frazzitta, G., Maestri, R., Ghilardi, M. F., Riboldazzi, G., Perini, M., Bertotti, G., Boveri, N., Buttini, S., Lombino, F. L., Uccellini, D., Turla, M., Pezzoli, G., Comi, C. Intensive rehabilitation increases BDNF serum levels in parkinsonian patients: a randomized study. Neurorehabilitation & Neural Repair 2014; 2: 163-8 82. Frazzitta, G., Maestri, R., Uccellini, D., Bertotti, G., Abelli, P. Rehabilitation treatment of gait in patients with Parkinson's disease with freezing: a comparison between two physical therapy protocols using visual and auditory cues with or without treadmill training. Movement Disorders 2009; 8: 1139-43 83. Furnari, A., Calabro, R. S., De Cola, M. C., Bartolo, M., Castelli, A., Mapelli, A., Buttacchio, G., Farini, E., Bramanti, P., Casale, R. Robotic-assisted gait training in Parkinson's disease: a three-month follow-up randomized clinical trial. International Journal of Neuroscience 2017; 11: 996-1004 84. Gage, H., Grainger, L., Ting, S., Williams, P., Chorley, C., Carey, G., Borg, N., Bryan, K., Castleton, B., Trend, P., Kaye, J., Jordan, J., Wade, D. (untitled). NIHR Journals Library. Health Services and Delivery Research 2014; 0: 12 85. Galli, M., Cimolin, V., De Pandis, M. F., Le Pera, D., Sova, I., Albertini, G., Stocchi, F., Franceschini, M. Robot-assisted gait training versus treadmill training in patients with Parkinson's disease: a kinematic evaluation with gait profile score. Functional Neurology 2016; 3: 163-70 86. Gandolfi, M., Geroin, C., Dimitrova, E., Boldrini, P., Waldner, A., Bonadiman, S., Picelli, A., Regazzo, S., Stirbu, E., Primon, D., Bosello, C., Gravina, A. R., Peron, L., Trevisan, M., Garcia, A. C., Menel, A., Bloccari, L., Vale, N., Saltuari, L., Tinazzi, M., Smania, N. Virtual Reality Telerehabilitation for Postural Instability in Parkinson's Disease: A Multicenter, Single-Blind, Randomized, Controlled Trial. BioMed Research International 2017; 0: 7962826 87. Gandolfi, M., Tinazzi, M., Magrinelli, F., Busselli, G., Dimitrova, E., Polo, N., Manganotti, P., Fasano, A., Smania, N., Geroin, C. Four-week trunk-specific exercise program decreases forward trunk flexion in Parkinson's disease: A single-blinded, randomized controlled trial. Parkinsonism & Related Disorders 2019; 0: 03 88. Ganesan, M., Pal, P. K., Gupta, A., Sathyaprabha, T. N. Treadmill gait training improves baroreflex sensitivity in Parkinson's disease. Clinical Autonomic Research 2014; 3: 111-8 89. Ganesan, M., Sathyaprabha, T. N., Gupta, A., Pal, P. K. Effect of partial weightsupported treadmill gait training on balance in patients with Parkinson disease. Pm & R 2014; 1: 22-33 90. Gao, Q., Leung, A., Yang, Y., Wei, Q., Guan, M., Jia, C., He, C. Effects of Tai Chi on balance and fall prevention in Parkinson's disease: a randomized controlled trial. Clinical Rehabilitation 2014; 8: 748-753 91. Gasner, H., Steib, S., Klamroth, S., Pasluosta, C. F., Adler, W., Eskofier, B. M., Pfeifer, K., Winkler, J., Klucken, J. Perturbation Treadmill Training Improves Clinical Characteristics of Gait and Balance in Parkinson's Disease. Journal of Parkinsons Disease Print 2019; 2: 413-426 92. Geroin, C., Nonnekes, J., de Vries, N. M., Strouwen, C., Smania, N., Tinazzi, M., Nieuwboer, A., Bloem, B. R. Does dual-task training improve spatiotemporal gait parameters in Parkinson's disease?. Parkinsonism & Related Disorders 2018; 0: 86-91 93. Giardini, M., Nardone, A., Godi, M., Guglielmetti, S., Arcolin, I., Pisano, F., Schieppati, M. Instrumental or Physical-Exercise Rehabilitation of Balance Improves Both Balance and Gait in Parkinson's Disease. Neural Plasticity 2018; 0: 5614242 94. Ginis, P., Nieuwboer, A., Dorfman, M., Ferrari, A., Gazit, E., Canning, C. G., Rocchi, L., Chiari, L., Hausdorff, J. M., Mirelman, A. Feasibility and effects of home-based smartphone-delivered automated feedback training for gait in people with Parkinson's disease: A pilot randomized controlled trial. Parkinsonism & Related Disorders 2016; 0: 28-34 95. Gobbi, L. T., Teixeira-Arroyo, C., Lirani-Silva, E., VitÃ³rio, R., Barbieri, F. A., Pereira, M. P. Effect of different exercise programs on the psychological and cognitive functions of people with Parkinson's disease. Motriz: revista de educaÃ §Ã£o fÃsica 2013; 3: 597-604 96. Goodwin, V. A., Richards, S. H., Henley, W., Ewings, P., Taylor, A. H., Campbell, J. L. An exercise intervention to prevent falls in people with Parkinson's disease: a pragmatic randomised controlled trial. Journal of Neurology, Neurosurgery & Psychiatry 2011; 11: 1232-8 97. Granziera, S., Alessandri, A., Lazzaro, A., Zara, D., Scarpa, A. Nordic Walking and Walking in Parkinson's disease: a randomized single-blind controlled trial. 2020; 0: 11 98. Grobbelaar, R., Venter, R., Welman, K. E. Backward compared to forward over ground gait retraining have additional benefits for gait in individuals with mild to moderate Parkinson's disease: A randomized controlled trial. Gait & Posture 2017; 0: 294-299 99. Hackney, M. E., Earhart, G. M. Effects of dance on movement control in Parkinson's disease: a comparison of Argentine tango and American ballroom. Journal of Rehabilitation Medicine 2009; 6: 475-81 100. Hackney, M. E., Earhart, G. M. Tai Chi improves balance and mobility in people with Parkinson disease. Gait & Posture 2008; 3: 456-60 101. Harro, C. C., Shoemaker, M. J., Frey, O. J., Gamble, A. C., Harring, K. B., Karl, K. L., McDonald, J. D., Murray, C. J., Tomassi, E. M., Van Dyke, J. M., VanHaistma, R. J. The effects of speed-dependent treadmill training and rhythmic auditory-cued overground walking on gait function and fall risk in individuals with idiopathic Parkinson's disease: a randomized controlled trial. Neurorehabilitation 2014; 3: 557-72 102. Hulbert, S., Ashburn, A., Roberts, L., Verheyden, G. Dance for Parkinson's-The effects on whole body co-ordination during turning around. Complementary Therapies in Medicine 2017; 0: 91-97 103. Jaywant, A., Ellis, T. D., Roy, S., Lin, C. C., Neargarder, S., Cronin-Golomb, A. Randomized Controlled Trial of a Home-Based Action Observation Intervention to Improve Walking in Parkinson Disease. Archives of Physical Medicine & Rehabilitation 2016; 5: 665-73 104. Joseph, C., Brodin, N., Leavy, B., Hagstromer, M., Lofgren, N., Franzen, E. Costeffectiveness of the HiBalance training program for elderly with Parkinson's disease: analysis of data from a randomized controlled trial. Clinical Rehabilitation 2019; 2: 222-232 105. Kadkhodaie, M., Sharifnezhad, A., Ebadi, S., Marzban, S., Habibi, S. A., Ghaffari, A., Forogh, B. Effect of eccentric-based rehabilitation on hand tremor intensity in Parkinson disease. Neurological Sciences 2020; 3: 637-643 106. Kalyani, H. H., Sullivan, K. A., Moyle, G. M., Brauer, S., Jeffrey, E. R., Kerr, G. K. Dance improves symptoms, functional mobility and fine manual dexterity in people with Parkinson disease: a quasi-experimental controlled efficacy study. European Journal of Physical and Rehabilitation Medicine 2020; 0: 107. Khalil, H., Busse, M., Quinn, L., Nazzal, M., Batyha, W., Alkhazaleh, S., Alomari, M. A. A pilot study of a minimally supervised home exercise and walking program for people with Parkinson's disease in Jordan. Neurodegenerative Disease Management 2017; 1: 73-84 108. Khallaf, Mohamed, Fathy, Heba Effect of treadmill training on activities of daily living and depression in patients with Parkinson's disease. Middle East Current Psychiatry 2011; 3: 144-148 109. King, L. A., Mancini, M., Smulders, K., Harker, G., Lapidus, J. A., Ramsey, K., Carlson-Kuhta, P., Fling, B. W., Nutt, J. G., Peterson, D. S., Horak, F. B. Cognitively Challenging Agility Boot Camp Program for Freezing of Gait in Parkinson Disease. Neurorehabilitation & Neural Repair 2020; 5: 417-427 110. King, L. A., Wilhelm, J., Chen, Y., Blehm, R., Nutt, J., Chen, Z., Serdar, A., Horak, F. B. Effects of Group, Individual, and Home Exercise in Persons With Parkinson Disease: A Randomized Clinical Trial. Journal of Neurologic Physical Therapy 2015; 4: 204-12 111. Klamroth, S., Gasner, H., Winkler, J., Eskofier, B., Klucken, J., Pfeifer, K., Steib, S. Interindividual Balance Adaptations in Response to Perturbation Treadmill Training in Persons With Parkinson Disease. Journal of Neurologic Physical Therapy 2019; 4: 224-232 112. Klamroth, S., Steib, S., Gasner, H., Gosler, J., Winkler, J., Eskofier, B., Klucken, J., Pfeifer, K. Immediate effects of perturbation treadmill training on gait and postural control in patients with Parkinson's disease. Gait & Posture 2016; 0: 102-108 113. Kunkel, D., Fitton, C., Roberts, L., Pickering, R. M., Roberts, H. C., Wiles, R., Hulbert, S., Robison, J., Ashburn, A. A randomized controlled feasibility trial exploring partnered ballroom dancing for people with Parkinson's disease. Clinical Rehabilitation 2017; 10: 1340-1350 114. Kurlan, Roger, Evans, Roye, Wrigley, Sandra, McPartland, Shannon, Bustami, Rami, Cotter, Ann Tai Chi in Parkinsonâ??s disease: a preliminary randomized, controlled, and rater-blinded study. Advances in Parkinson's Disease 2015; 1: 9 115. Kurt, E. E., Buyukturan, B., Buyukturan, O., Erdem, H. R., Tuncay, F. Effects of Ai Chi on balance, quality of life, functional mobility, and motor impairment in patients with Parkinson's disease. Disability & Rehabilitation 2018; 7: 791-797 116. Kurtais, Y., Kutlay, S., Tur, B. S., Gok, H., Akbostanci, C. Does treadmill training improve lower-extremity tasks in Parkinson disease? A randomized controlled trial. Clinical Journal of Sport Medicine 2008; 3: 289-91 117. Kwok, J. Y. Y., Kwan, J. C. Y., Auyeung, M., Mok, V. C. T., Lau, C. K. Y., Choi, K. C., Chan, H. Y. L. Effects of Mindfulness Yoga vs Stretching and Resistance Training Exercises on Anxiety and Depression for People With Parkinson Disease: A Randomized Clinical Trial. JAMA Neurology 2019; 0: 08 118. Landers, M. R., Hatlevig, R. M., Davis, A. D., Richards, A. R., Rosenlof, L. E. Does attentional focus during balance training in people with Parkinson's disease affect outcome? A randomised controlled clinical trial. Clinical Rehabilitation 2016; 1: 53-63 119. Landers, M. R., Navalta, J. W., Murtishaw, A. S., Kinney, J. W., Pirio Richardson, S. A High-Intensity Exercise Boot Camp for Persons With Parkinson Disease: A Phase II, Pragmatic, Randomized Clinical Trial of Feasibility, Safety, Signal of Efficacy, and Disease Mechanisms. Journal of Neurologic Physical Therapy 2019; 1: 12-25 [/fig]	None	https://academic.oup.com/ptj/article-pdf/102/4/pzab302/43491495/pzab302.pdf	Abstract A clinical practice guideline on Parkinson disease was developed by an American Physical Therapy Association volunteer guideline development group that consisted of physical therapists and a neurologist. The guideline was based on systematic reviews of current scientific and clinical information and accepted approaches for management of Parkinson disease. The Spanish version of this clinical practice guideline is available as a supplement (Suppl. Appendix 1).
e1412e589a55af36f30d24b6cd48a0215ffd8b22	pubmed	Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)	Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19) Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed.Methods:We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations.Results:The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy. # Introduction At the end of 2019, a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an acute respiratory illness epidemic in Wuhan, China [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref]. The World Health Organization (WHO) termed this illness Coronavirus Disease 2019 . By the time this guideline panel was assembled, the COVID-19 had become a pandemic and had affected over 120,000 individuals in more than 80 countries, and resulted in more than 5000 deaths worldwide. The WHO and the United States Center for Disease Control and Prevention (CDC) have issued preliminary guidance on infection control, screening and diagnosis in the general population, but there is limited guidance on the acute management of critically ill patients with severe illness due to COVID-19. ## Guideline scope This guideline provides recommendations to support hospital clinicians managing critically ill adults with COVID-19 in the intensive care unit (ICU). The target users of this guideline are frontline clinicians, allied health professionals, and policymakers involved in the care of patients with COVID-19 in the ICU. The guideline applies to both high and low-middle income settings. ## Guideline teams and structure The Surviving Sepsis Campaign (SSC) COVID-19 subcommittee selected panel members in such a way as to obtain a balance of topic expertise, geographic location and, as far as possible, gender. The SSC COVID-19 panel was assembled and worked within very tight timelines in order to issue recommendations in a timely manner. The panel included experts in guideline development, infection control, infectious diseases and microbiology, critical care, emergency medicine, nursing, and public health. The panel was divided into four groups: [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref] infection control and testing, (2) hemodynamic support, (3) ventilatory support, and (4) therapy. The Guidelines in Intensive Care Development and Evaluation (GUIDE) group provided methodological support throughout the guideline development process. ## Management of conflict of interests All panel members completed a conflict of interests (COI) form prior to joining the guideline panel [bib_ref] Conflicts of interest disclosure forms and management in critical care clinical practice..., Alhazzani [/bib_ref] [bib_ref] Understanding conflicts of interest, Vandvik [/bib_ref]. We used the GRADEpro guideline development tool (GDT) online software (http://gdt.guide lined evelo pment .org) to administer WHO COI disclosure forms to participating panel members. Direct financial and industry-related COIs were not permitted and were considered disqualifying. The development of this guideline did not include any industry input, funding, or financial or non-financial contribution. No member of the guideline panel received honoraria or remuneration for any role in the guideline development process. # Methods The guideline development process is summarized in [fig_ref] Figure 1: COVID-19 guideline development process [/fig_ref]. All actionable guideline questions were structured in the Population, Intervention, Control, and Outcome(s) (PICO) format, with explicit definitions, whereas descriptive questions were not. Content and methods experts in each group participated in developing the guideline questions. The PICO format provided the basis for defining inclusion and exclusion criteria for the literature searches (where performed) and for identification of relevant studies. To facilitate rapid development of recommendations, we did not perform a novel systematic prioritization of outcomes, but used the outcome prioritization informed by the ongoing SSC guideline 2020 work and expert input [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref]. Accordingly, we focused on hospital mortality and serious adverse event outcomes for most questions, and for some included other outcomes deemed critical for decision making. ## Literature search For some questions, with help of professional medical librarians, we electronically searched major databases, i.e. Cochrane Central and MEDLINE, to identify relevant systematic reviews, randomized controlled trials (RCTs), observational studies, and case series. These electronic searches were performed looking for studies published in English from inception to March 2020. To inform the recommendations on hemodynamic and ventilatory support, we used recently published systematic reviews and asked experts to identify any new relevant studies. ## Selection of studies and data abstraction For selected PICO questions, a pair of reviewers screened titles and abstracts retrieved from the bibliographic databases; for each PICO question, all potentially eligible studies were assessed for eligibility according to prespecified criteria. Content experts were asked to indicate any additional studies not identified by the search. Subsequently, pairs of reviewers independently abstracted relevant data on the corresponding PICO questions, and items relevant to risk of bias. We obtained intention-to-treat data whenever available; otherwise we used complete case data, i.e. ignoring missing data [bib_ref] Addressing dichotomous data for participants excluded from trial analysis: a guide for..., Akl [/bib_ref]. ## Quality of evidence We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] , i.e. our confidence in the estimate of the effect to support a recommendation [bib_ref] GRADE guidelines: 3. Rating the quality of evidence, Balshem [/bib_ref]. The quality of evidence was rated as high, moderate, low, or very low [bib_ref] GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation..., Andrews [/bib_ref]. We used the GDT online software (http://gdt.guide lined evelo pment .org) to generate the evidence profiles (evidence summaries) [bib_ref] GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes, Guyatt [/bib_ref]. ## Using indirect evidence Given the recent emergence of COVID-19, we anticipated that there would be a scarcity of direct evidence, and therefore used a predefined algorithm to decide whether indirect evidence could inform a specific question [fig_ref] Figure 1: COVID-19 guideline development process [/fig_ref]. The SSC COVID-19 panel decided which population to extrapolate evidence from based on the context of the recommendation, and the likelihood of the presence of an effect modifier . Accordingly, we used, as sources of indirect evidence, data on Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS), and other coronaviruses; in the same way, we considered, as indirect evidence, published data on supportive care in the ICU from studies on influenza and other respiratory viral infections, acute respiratory distress syndrome (ARDS) and sepsis. ## Recommendation formulation We used the principles outlined in the evidence to decision framework (EtD) to formulate recommendations, but because of the tight timelines we did not complete the online EtD tables [bib_ref] GRADE evidence to decision (EtD) frameworks for adoption, adaptation, and de novo..., Schunemann [/bib_ref]. The EtD framework covers the following domains: priority setting, magnitude of benefit and harm, certainty of the evidence, patient values, balance between desirable and undesirable effects, resources and cost, equity, acceptability and feasibility. Each of the four subgroups drafted the preliminary recommendations. We use the wording "we recommend" for strong recommendations and "we suggest" for suggestions (i.e. weak recommendations). The implications of the recommendation strength are presented in [fig_ref] Table 1: Implications of different recommendations to key stakeholders [/fig_ref]. The final list of recommendations was developed by panel discussion and consensus; voting on recommendations was not required. We present the guideline statements and recommendations in [fig_ref] Table 2: Recommendations and statementsFor intubated and mechanically ventilated adults with suspicion of COVID-19 [/fig_ref]. ## Updating the recommendations We will have periodic automated electronic searches sent to assigned panel members every week to identify relevant new evidence as it emerges. Accordingly, we will issue further guideline releases in order to update the recommendations, if needed, or formulate new ones. ## I. infection control ## Risk of sars-cov-2 transmission A recent report from the Chinese Center of Disease Control and Prevention described 72,314 cases of COVID-19 from China, of which 44,672 were laboratory confirmed. Among laboratory-confirmed cases, 1716 (3.8%) were healthcare workers, most of whom, 63% (1080 of 1716), acquired the infection in Wuhan. The report describes that 14.8% (247 of 1668) of infected healthcare workers had severe or critical illness, and that 5 died [bib_ref] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. In Italy, as of , there are 2026 documented COVID-19 cases among healthcare workers [bib_ref] Coronavirus Disease 2019 (COVID-19) in Italy, Livingston [/bib_ref]. Although incidence data is not available, these data point to a considerable burden of infection among healthcare workers. The risk of patient-to-patient transmission in the ICU is currently unknown, therefore, adherence to infection control precautions is paramount. Healthcare workers should follow the infection control policies and procedures already in place at their healthcare institutions. We provide the following recommendations and suggestions as considerations rather than a requirement to change institutional infection control policies. ## Recommendation 1. For healthcare workers performing aerosol-generating procedures* on patients with COVID-19 in the ICU, we recommend using fitted respirator masks (N95 respirators, FFP2, or equivalent), as opposed to surgical/medical masks, in addition to other personal protective equipment (i.e. gloves, gown,and eye protection, such as a face shield or safety goggles) Best practice statement. *Aerosol-generating procedures in the ICU include: endotracheal intubation, bronchoscopy, open suctioning, administration of nebulized treatment, manual ventilation before intubation, physical proning of the patient, disconnecting the patient from the ventilator, non-invasive positive pressure ventilation, tracheostomy, and cardiopulmonary resuscitation ## Rationale Respirator masks are designed to block 95-99% of aerosol particles. The N95 type conforms to United States Federal Drug Agency standards, and the FFP2 conforms to European standards-European Committee for Standards standards). Staff should be fit tested for each different type. Surgical masks (also known as medical masks) are designed to block large particles, droplets and sprays, but are less effective in blocking small particle aerosols (< 5 μm) [bib_ref] Influenza virus aerosols in human exhaled breath: particle size, culturability, and effect..., Milton [/bib_ref]. This recommendation is based on a consensus of recommendations from the CDC, WHO, and other public health organizations, along with epidemiologic data demonstrating that aerosol-generating procedures increased risk to healthcare workers during the SARS epidemic. Powered air purifying respirators (PAPRs) can be used by healthcare workers who failed N95 mask fit testing and when N95s are in limited supply. ## Rationale Negative pressure rooms are an engineering control intended to prevent the spread of contagious airborne pathogens from room to room (e.g. measles, and tuberculosis). The main goal is to avoid the accidental release of pathogens into a larger space and open facility, thereby protecting healthcare workers and patients in a hospital setting. Negative air pressure is created in the patient's room to keep the pathogen inside and avoid its diffusion. By adopting this precaution when aerosol-generating procedures like tracheal intubation, bronchoscopies, or non-invasive positive pressure ventilation (NIPPV) are performed within the room, there is a lower risk of crosscontamination among rooms and infection for staff and patients outside the room. Negative pressure is created and maintained by a ventilation system that allows extra air to enter the isolated room by differential pressure, and be exhausted directly to the outside or be filtered through a high-efficiency particulate air (HEPA) filter directly before recirculation. Moreover, the presence of unnecessary staff in the room should be avoided. Negative pressure rooms have proven to be an effective measure that helped to avoid cross-contamination during the SARS epidemic [bib_ref] Control measures for severe acute respiratory syndrome (SARS) in Taiwan, Twu [/bib_ref]. Accordingly, for aerosolgenerating procedures, the WHO guidance on COVID-19 recommends the use of negative pressure rooms with a minimum of 12 air changes per hour or at least 160 L/ second/patient in facilities with natural ventilation. Bronchoscopies are among the procedures at highest risk of aerosolization, and their use should be minimized. Non-invasive ventilation is also at high risk of aerosolization, and strategies have been described to contain the risk [bib_ref] Minimise nosocomial spread of 2019-nCoV when treating acute respiratory failure, Cabrini [/bib_ref] of virus spread, also according to a previous report on SARS infection [bib_ref] SARS: ventilatory and intensive care, Yam [/bib_ref]. Where this is not feasible, a portable HEPA filter should be used in the room wherever possible. A HEPA filter is a mechanical air filter, used for isolation where maximum reduction or removal of submicron particulate matter from air is required. HEPA filters have been demonstrated to reduce virus transmission in simulated settings [bib_ref] Particle removal efficiency of the portable HEPA air cleaner in a simulated..., Qian [/bib_ref]. ## Recommendations 3. For healthcare workers providing usual care for non-ventilated COVID-19 patients, we suggest using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protection, such as a face shield or safety goggles). Weak recommendation, low-quality evidence. 4. For healthcare workers who are performing non-aerosol-generating procedures on mechanically ventilated (closed circuit) patients with COVID-19, we suggest using surgical/medical masks, as opposed to respirator masks, in addition to other personal protective equipment (i.e. gloves, gown, and eye protection, such as a face shield or safety goggles). Weak recommendation, low-quality evidence. ## Rationale Our recommendations are in line with the WHO guidance, and with the current evidence, which suggests that surgical/medical masks are probably not inferior to N95 respirators for providing protection against laboratory confirmed seasonal respiratory viral infections (e.g. influenza, but not measles). We updated the most recent systematic review and meta-analysis of RCTs [bib_ref] Effectiveness of N95 respirators versus surgical masks in protecting health care workers..., Smith [/bib_ref] , and identified one new RCT [bib_ref] N95 respirators vs medical masks for preventing influenza among health care personnel:..., Radonovich [/bib_ref]. Overall, 4 RCTs (5549 individuals) randomized healthcare workers to N95 respirators or medical masks [bib_ref] N95 respirators vs medical masks for preventing influenza among health care personnel:..., Radonovich [/bib_ref] [bib_ref] Surgical mask vs N95 respirator for preventing influenza among health care workers:..., Loeb [/bib_ref] [bib_ref] A cluster randomized clinical trial comparing fit-tested and non-fit-tested N95 respirators to..., Macintyre [/bib_ref] [bib_ref] Efficacy of face masks and respirators in preventing upper respiratory tract bacterial..., Macintyre [/bib_ref] [bib_ref] A randomized clinical trial of three options for N95 respirators and medical..., Macintyre [/bib_ref]. The use of medical masks, as opposed to N95 respirators, did not increase laboratory-confirmed respiratory infection (OR 1.06, 95% CI 0. . Although the point estimates suggest that use of medical masks was associated with increased risk of influenza-like illness (OR 1.31, 95% CI 0.94, 1.85) and clinical respiratory infection (OR 1.49, 95% CI 0.98-2.28), the differences were not statistically significant. A No recommendation 48 There is insufficient evidence to issue a recommendation on the use of recombinant rIFNs, alone or in combination with antivirals, in critically ill adults with COVID-19 No recommendation 49 There is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19 No recommendation 50 There is insufficient evidence to issue a recommendation on the use of tocilizumab in critically ill adults with COVID-19 No recommendation recent systematic review and meta-analysis reached similar conclusions [bib_ref] Effectiveness of N95 respirators versus surgical masks against influenza: A systematic review..., Long [/bib_ref]. Only one RCT reported on coronavirus. On testing for seasonal coronavirus (OC43, HKU1, 229E, NL63) by means of PCR in this non-cluster RCT, 4.3% (9/212) of nurses in the medical mask group had RT-PCR confirmed coronavirus infection as compared with 5.7% in the N95 respirator group [bib_ref] Surgical mask vs N95 respirator for preventing influenza among health care workers:..., Loeb [/bib_ref]. When making these recommendations, the panel considered the lack of convincing evidence that N95 respirators improve clinical outcomes, the cost and resources associated with N95 mask use, and the need to preserve the N95 respirator supply for aerosol-generating procedures. Therefore, the panel issued a suggestion to use medical masks in this context. However, SARS-CoV-2 appears to be more easily transmissible and lethal than seasonal influenza. Specifically, an early estimate of the reproductive number (R 0 ) of SARS-CoV-2, the average number of people an infected person subsequently infects as a function of biological properties of the pathogen in combination with social and environmental factors, is 2.3 [bib_ref] Reporting, epidemic growth, and reproduction numbers for the 2019 novel coronavirus (2019-nCoV)..., Tuite [/bib_ref]. By comparison, the estimated average R 0 for the 1918 influenza pandemic that resulted in an estimated 50 million deaths globally was 1.8, and the estimated average R 0 for seasonal influenza is 1.28 [bib_ref] Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a..., Biggerstaff [/bib_ref]. Therefore, a minimum of a surgical/medical mask is recommended for healthcare workers caring for non-ventilated COVID-19 patients and for healthcare workers who are performing non-aerosol-generating procedures on mechanically ventilated (closed circuit) patients with COVID-19. When scarcity is not an issue, use of a fitted respirator use of a fitted respirator mask is a reasonable option. ## Recommendation ## For healthcare workers performing endotracheal intubation on patients with COVID-19, we suggest using video-guided laryngoscopy, over direct laryngoscopy, if available. Weak recommendation, low-quality evidence. ## Rationale There is no direct evidence comparing the use of videolaryngoscopy with direct laryngoscopy for intubation of patients with COVID-19. While SARS-CoV-2 appears to be predominantly spread by large respiratory droplets, intubation is likely a small particle (less than 5 μm) aerosol-generating procedure, which increases the risk of transmission to healthcare workers [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref]. Intubation is particularly risky given the close contact of healthcare workers with the patient's airway and respiratory secretions. Thus, techniques that can reduce the number of attempts at endotracheal intubation and the duration of the procedure and minimize the proximity between the operator and the patient, should be prioritized, potentially reducing the risk of complications in hypoxic COVID-19 patients. In a systematic review including 64 studies and 7044 patients, video-laryngoscopy reduced the risk of failed intubation (OR 0.35, 95% CI 0.19-0.65), without a significant impact upon the proportion of successful first-pass attempts (OR 0.79, 95% CI 0.48-1.3), hypoxia (OR 0.39, 95% CI 0.1-1.44), or time for tracheal intubation [bib_ref] Videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation: a Cochrane..., Lewis [/bib_ref] [bib_ref] Videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation, Lewis [/bib_ref]. In patients with difficult airways, the first-attempt success rate may be improved with video-laryngoscopy [bib_ref] Should the Glidescope video laryngoscope be used first line for all oral..., Russell [/bib_ref]. Thus, in settings where video-laryngoscopy is available and staff are skilled in its use, we suggest that it be used, in preference to direct laryngoscopy, to maximize the chances of success. Recognizing that not all centers will have rapid access to video-laryngoscopy or skilled users, this recommendation is conditional. ## Recommendation ## For covid-19 patients requiring endotracheal intubation, we rec- ommend that endotracheal intubation be performed by the healthcare worker who is most experienced with airway management in order to minimize the number of attempts and risk of transmission. Best practice statement. ## Rationale Similar to the reasoning above, factors that maximize the chances of first pass success should be used when intubating patients with suspected or confirmed COVID-19. Thus, we recommend that the healthcare operator with the most experience and skill in airway management should be the first to attempt intubation. ## Ii. laboratory diagnosis and specimens ## Indications for testing icu patients for sars cov-2 The WHO recently declared a COVID-19 pandemic. Accordingly, every critically ill patient arriving with evidence of respiratory infection should be considered potentially infected with SARS-CoV-2. Real-time polymerase chain reaction (RT-PCR) is the gold standard for similar viral infections, including SARS. Notably, COVID-19 poses several diagnostic challenges due to an extended incubation period (approximately 2 weeks) that includes a prolonged interval (approximately 5 days) of viral shedding prior to the onset of symptoms. Moreover, the duration of asymptomatic shedding is not only variable but may also differ based on the anatomic level (upper versus lower) of the infection in the respiratory system [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref] [bib_ref] Incubation period and other epidemiological characteristics of 2019 novel coronavirus infections with..., Linton [/bib_ref]. Accordingly, the performance of biomolecular assay may vary by site of sampling. ## Recommendations ## For intubated and mechanically ventilated adults with suspicion of covid-19: 7.1 For diagnostic testing, we suggest obtaining lower respiratory tract samples in preference to upper respiratory tract (nasopharyngeal or oropharyngeal) samples. Weak recommendation, low-quality evidence. 7.2 With regard to lower respiratory samples, we suggest obtaining endotracheal aspirates in preference to bronchial wash or bronchoalveolar lavage samples. Weak recommendation, low-quality evidence. ## Rationale COVID-19 diagnosis is based on RT-PCR testing of respiratory samples from nasopharyngeal and oropharyngeal swabs, and of lower respiratory tract samples whenever possible. Bronchoalveolar lavage should be limited and performed only if indicated and with adequate precautions, due to the risk of aerosolization and consequent exposure of healthcare professionals. Similarly, sputum induction should be avoided due to increased risk of aerosolization. Tracheal aspirate specimens appear to carry a lower risk of aerosolization, and can sometimes be obtained without disconnecting the patient from the ventilator. The procedures involved in laboratory RT-PCR testing for SARS-CoV-2 using a number of assays currently in use are well described [bib_ref] Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR, Corman [/bib_ref]. Despite the generally high sensitivity and specificity of RT-PCR-based assays [bib_ref] Molecular diagnosis of a novel coronavirus (2019-nCoV) causing an outbreak of pneumonia, Chu [/bib_ref] , it may not be enough to rely on oropharyngeal swabs specimens alone for SARS-CoV-2 diagnosis due to their low negative predictive value. In a recent study, only 9 out of 19 (47%) oropharyngeal swabs from COVID-19 patients tested positive by RT-PCR [bib_ref] Comparison of different samples for 2019 novel coronavirus detection by nucleic acid..., Xie [/bib_ref]. Similar data were reported using RT-PCR during the 2002-2003 SARS epidemic [bib_ref] Evaluation of reverse transcription-PCR assays for rapid diagnosis of severe acute respiratory..., Yam [/bib_ref]. Using seroconversion as the "gold standard" for SARS diagnosis, RT-PCR assays performed on nasopharyngeal and throat specimens were positive only 65 and 70% of the time, respectively. However, no false positives were observed indicating assay specificity of 100%. Similarly, in a study accounting for CT scan findings among suspected COVID-19 cases, 48% with negative oropharyngeal or nasal swabs were considered highly likely cases, and 33% were considered probable cases. Consequently, a single negative swab from the upper airway does not rule out SARS-CoV-2 infection and repeated sampling from multiple sites, including the lower airway, will increase diagnostic yield. Similarly, given that coinfection with other viral pathogens has been observed, a positive test for another respiratory virus does not rule out COVID-19, and should not delay testing if there is a high suspicion of COVID-19 [bib_ref] Co-infection with SARS-CoV-2 and influenza A virus in patient with pneumonia, Wu [/bib_ref]. Given this high specificity, a single positive swab confirms the diagnosis of COVID-19 and is enough to trigger infection control precautions and appropriate treatment of the patient. Lower respiratory tract specimens are considered to give a higher diagnostic yield than upper respiratory specimens in patients with pneumonia, consistent with what was observed for SARS, and should therefore be obtained whenever possible. ## Iii. supportive care a. hemodynamic support ## Shock and cardiac injury in covid-19 patients The reported prevalence of shock in adult patients with COVID-19 is highly variable (from 1 to 35%), depending on the patient population studied, the severity of illness, and the definition of shock. In a recent report summarizing the epidemiological characteristics of 44,415 Chinese patients with COVID-19, 2087 (5%) were diagnosed as critical cases, defined as severe hypoxemia and/or the presence of other organ failure, including shock [bib_ref] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. In another Chinese study of 1099 patients with COVID-19 with similar severity of illness, only 12 (1.1%) developed shock [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref]. In hospitalized patients, the incidence is likely higher [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [fig_ref] Table 3: Epidemiological characteristics in recent COVID-19 reportsCFR case fatality rate, ICU intensive care... [/fig_ref] , and may reach 20-35% among patients in the ICU [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Clinical characteristics of 138 Hospitalized patients With 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref]. Cardiac injury (elevation of cardiac injury biomarkers above the 99th percentile upper reference limit) has been reported in 7-23% of patients with COVID-19 in Wuhan, China [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Clinical characteristics of 138 Hospitalized patients With 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref]. While the prevalence of cardiac injury may correlate with the prevalence of shock, a lack of systematic screening for cardiac dysfunction in hemodynamically stable patients means that this association cannot be taken as certain [fig_ref] Table 3: Epidemiological characteristics in recent COVID-19 reportsCFR case fatality rate, ICU intensive care... [/fig_ref]. The prognosis of patients with COVID-19 and shock has not been systematically reported. In a study of 150 patients from 2 hospitals in Wuhan, China, shock was a major reason for death in 40%, and may, at least in part, be due to fulminant myocarditis [bib_ref] Clinical predictors of mortality due to COVID-19 based on an analysis of..., Ruan [/bib_ref]. Studies on risk factors associated with shock in patients with COVID-19 are lacking. The majority of those that are available report unadjusted estimates [bib_ref] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak..., Wu [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Clinical predictors of mortality due to COVID-19 based on an analysis of..., Ruan [/bib_ref]. Despite methodological limitations, these studies suggest that older age, comorbidities (especially diabetes and cardiovascular disease including hypertension), lower lymphocyte count, higher D-dimer level, and possibly cardiac injury are risk factors to consider. ## Fluid therapy Recommendation 8. In adults with COVID-19 and shock, we suggest using dynamic parameters skin temperature, capillary refilling time, and/or serum lactate measurement over static parameters in order to assess fluid responsiveness. Weak recommendation, low-quality evidence. ## Rationale There is no direct evidence addressing the optimal resuscitation strategy in patients with COVID-19 and shock, therefore the panel based this recommendation on indirect evidence drawn from critically ill patients in general. In a systematic review and meta-analysis of 13 RCTs (n = 1652) examining the effect of dynamic assessment of fluid therapy on important patient outcomes in adult ICU patients requiring fluid resuscitation [bib_ref] Incorporating dynamic assessment of fluid responsiveness into goal-directed therapy: a systematic review..., Bednarczyk [/bib_ref] , the use of dynamic assessment to guide fluid therapy was found to reduce mortality (RR 0.59, 95% CI 0.42-0.83), ICU length of stay (MD − 1.16 days, 95% CI − 1.97 to − 0.36) and duration of mechanical ventilation (− 2.98 h, 95% CI − 5.08 to − 0.89). Of note, only one trial focused on patients with septic shock. Dynamic parameters used in these trials included stroke volume variation (SVV), pulse pressure variation (PPV), and stroke volume change with passive leg raising or fluid challenge. Among the examined dynamic parameters, passive leg raising followed by PPV and SVV appears to predict fluid responsiveness with highest accuracy [bib_ref] Will this hemodynamically unstable patient respond to a bolus of intravenous fluids, Bentzer [/bib_ref]. The static parameters included components of early goal-directed therapy, e.g. central venous pressure (CVP) and mean arterial pressure (MAP). The use of serum lactate levels to guide resuscitation of patients with shock has been summarized in a systematic review and meta-analysis of 7 RCTs (n = 1301) [bib_ref] Relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients..., Pan [/bib_ref]. Compared with central venous oxygen saturation (ScVO2) guided therapy, early lactate clearance-directed therapy was associated with a reduction in mortality (RR 0.68, 95% CI 0.56-0.82), shorter ICU length of stay (MD 1.64 days, 95% CI − 3.23 to − 0.05), and shorter duration of mechanical ventilation (MD − 10.22 h, 95% CI − 15.94 to − 4.50). However, a high lactate level does not always indicate hypovolemia; it may also be caused by mitochondrial dysfunction, liver failure, beta-agonists, mesenteric ischemia, or epinephrine. In the ANDROMEDA-SHOCK trial, capillary refill testing (CRT) every 30 min was associated with a nonsignificant reduction in mortality (HR 0.75, 95% CI 0.55-1.02) compared with serum lactate measurement every 2 h. CRT is a simple and easy test that can be used in almost any setting. Given the possible improvements in mortality, length of stay, and duration of mechanical ventilation that they may produce, as well as their availability, we suggest using dynamic parameters skin temperature, capillary refilling time, and/or lactate measurement over static parameters to assess fluid responsiveness in patients with COVID-19 and shock. ## Recommendation ## 9. For the acute resuscitation of adults with COVID-19 and shock, we suggest using a conservative over a liberal fluid strategy. Weak recommendation, low-quality evidence. ## Rationale No direct evidence exists on patients with COVID-19 and shock, therefore the panel used indirect evidence from critically ill patients with sepsis and ARDS to inform this recommendation. A recent systematic review of 9 RCTs (n = 637 patients) comparing restricted versus liberal fluid volumes in the initial resuscitation of patients with sepsis found no statistically significant difference in mortality (RR 0.87, 95% CI 0.69-1.10) and serious adverse events (RR 0.91, 95% CI 0.78-1.05). However, all assessed outcomes favored conservative fluid therapy (lower volumes). Importantly, the quantity and quality of evidence were both judged to be very low, suggesting that more research is needed. Correspondingly, in a 2017 meta-analysis of 11 RCTs (n = 2051 patients), adults and children with ARDS or sepsis managed according to a conservative fluid strategy in the post-resuscitation phase of critical illness had more ventilator-free days and shorter ICU stays than patients managed according to a liberal fluid strategy [bib_ref] Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory..., Silversides [/bib_ref] (see section on respiratory support for more details). In 2011, a large RCT of 3141 febrile African children (FEAST) found that children randomized to fluid boluses with saline or albumin had increased mortality compared with children not receiving fluid boluses [bib_ref] Mortality after fluid bolus in African children with severe infection, Maitland [/bib_ref]. In the absence of data demonstrating a benefit of the use of liberal fluid strategies in critically ill patients with sepsis or ARDS, and considering that the majority of COVID-19 patients in the ICU develop ARDS, we suggest an initial conservative approach to fluid resuscitation in patients with COVID-19 and shock. ## Recommendation ## For the acute resuscitation of adults with covid-19 and shock, we recommend using crystalloids over colloids. Strong recommendation, moderate quality evidence. ## Rationale Since there exists no direct evidence on shock in patients with COVID-19, the panel based this recommendation on indirect evidence from critically ill patients in general. In a systematic review of 69 RCTs (n = 30,020 patients) that compared the use of crystalloids versus colloids in critically ill patients [bib_ref] Colloids versus crystalloids for fluid resuscitation in critically ill people, Lewis [/bib_ref] , no outcomes favored the use of colloids. Considering that some colloids are harmful (see below), all colloids are more costly than crystalloids, and availability of colloids is limited in some settings (e.g. some low-and middle-income countries), we recommend using crystalloids for fluid resuscitation in patients with COVID-19 and shock. ## Recommendation ## For the acute resuscitation of adults with covid-19 and shock, we suggest using buffered/balanced crystalloids over unbalanced crystalloids. Weak recommendation, moderate quality evidence. ## Rationale No direct evidence addresses this question in patients with COVID-19 and shock; the panel therefore based this recommendation on indirect evidence from critically ill patients in general. A systematic review and meta-analysis of 21 RCTs (n = 20,213 patients) comparing intravenous buffered (balanced) crystalloid solutions versus 0.9% saline for resuscitation of critically ill adults and children [bib_ref] Buffered solutions versus 09% saline for resuscitation in critically ill adults and..., Martin [/bib_ref] reported no significant differences in hospital mortality (OR 0.91, 95% CI 0.83-1.01) or acute kidney injury (OR 0.92, 95% CI 0.84-1.00) between the treatments. However, the point estimates for both outcomes suggest a potential for benefit from buffered crystalloid solutions. In the absence of apparent harm, and considering the roughly equivalent costs, we suggest using buffered crystalloid solutions over unbalanced crystalloid solutions for resuscitation of patients with COVID-19 and shock. In settings with limited availability of buffered solutions, 0.9% saline remains a reasonable alternative. ## Recommendation ## 12. For the acute resuscitation of adults with COVID-19 and shock, we recommend against using hydroxyethyl starches. Strong recommendation, moderate quality evidence. ## Rationale Given the absence of direct evidence on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. A systematic review of 69 RCTs (n = 30,020 patients) compared the use of crystalloids versus colloids in critically ill patients; 24 of these RCTs (n = 11,177 patients) compared the use of crystalloids with the use of starches [bib_ref] Colloids versus crystalloids for fluid resuscitation in critically ill people, Lewis [/bib_ref]. When the data were pooled, no statistically significant difference in mortality was observed at the end of follow-up (RR 0.97, 95% CI 0.86-1.09), within 90 days (RR 1.01, 95% CI 0.90-1.14), or within 30 days (RR 0.99, 95% CI 0.90-1.09). The authors, however, reported an increased risk of blood transfusion (RR 1.19, 95% CI 1.02-1.39) and renal replacement therapy (RRT) with starches (RR 1.30, 95% CI 1.14-1.48). Given the risk of clinically significant harm and of the apparent absence of benefits from the use of hydroxyethyl starches, we recommend against their use for resuscitation of patients with COVID-19 and shock. ## Recommendation ## For the acute resuscitation of adults with covid-19 and shock, we suggest against using gelatins. Weak recommendation, low-quality evidence. ## Rationale Since no study has evaluated this question in patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. In a systematic review of 69 RCTs (n = 30,020 patients) comparing crystalloid versus colloid use in critically ill patients, crystalloids were compared with gelatins in 6 RCTs (n = 1698) [bib_ref] Colloids versus crystalloids for fluid resuscitation in critically ill people, Lewis [/bib_ref]. No statistically significant difference in all-cause mortality was observed at the end of the follow-up (RR 0.89, 95% CI 0.74-1.08), within 90 days (RR 0.89, 95% CI 0.73-1.09), or within 30 days (RR 0.92, 95% CI 0.74-1.16), although point estimates favored the use of crystalloids. Considering the absence of any benefit of gelatins, and their higher costs, we suggest against using gelatins for resuscitation of patients with COVID-19 and shock. ## Recommendation ## 14. For the acute resuscitation of adults with COVID-19 and shock, we suggest against using dextrans. Weak recommendation, low-quality evidence. ## Rationale Given the absence of direct evidence on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. A systematic review and meta-analysis on crystalloid versus colloid use in critically ill patients identified 19 trials comparing crystalloids with dextrans (n = 4736) [bib_ref] Colloids versus crystalloids for fluid resuscitation in critically ill people, Lewis [/bib_ref]. It reported similar mortality rates at the end of follow-up (RR 0.99, 95% CI 0.88-1.11) and within 90 days (RR 0.99, 95% CI 0.87-1.12), but a possibly increased risk of blood transfusion in the dextran arm (RR 0.92, 95% CI 0.77-1.10). In view of a possible increased risk of blood transfusion (bleeding) and higher costs associated with dextrans, we suggest against their use for resuscitation of patients with COVID-19 and shock. ## Recommendation ## For the acute resuscitation of adults with covid-19 and shock, we suggest against the routine use of albumin for initial resuscitation. Weak recommendation, moderate quality evidence. ## Rationale Since there is no direct evidence on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. A systematic review and meta-analysis identified 20 RCTs (n = 13,047) comparing albumin with crystalloid use [bib_ref] Colloids versus crystalloids for fluid resuscitation in critically ill people, Lewis [/bib_ref]. It demonstrated no significant difference in all-cause mortality at the end of the follow-up (RR 0. [bib_ref] The application of low tidal volume pressure-controlled ventilation in patients with acute..., Wu [/bib_ref] In the absence of a benefit of albumin, and considering its cost and limited availability, we suggest against its routine use for the initial resuscitation of patients with COVID-19 and shock. ## Vasoactive agents Recommendation. For adults with COVID-19 and shock, we suggest using norepinephrine as the first-line vasoactive agent, over other agents. Weak recommendation, low-quality evidence. ## Rationale There is no direct evidence on patients with COVID-19 and shock, therefore the panel based this recommendation on indirect evidence from critically ill patients in general. A systematic review of 28 RCTs (n = 3497 patients) and a clinical practice guideline from 2016 summarized the available body of evidence on the best first-line vasopressor for patients with shock [bib_ref] Scandinavian SSAI clinical practice guideline on choice of first-line vasopressor for patients..., Moller [/bib_ref] [bib_ref] Vasopressors for hypotensive shock, Gamper [/bib_ref]. As norepinephrine is the most widely studied vasoactive agent with a low a priori risk of undesirable effects, we suggest using norepinephrine as the first-line vasoactive agent in patients with COVID-19 and shock. ## Recommendation 17. If norepinephrine is not available, we suggest using either vasopressin or epinephrine as the first-line vasoactive agent, over other vasoactive agents, for adults with COVID-19 and shock. Weak recommendation, low-quality evidence. ## Rationale In the absence of direct evidence on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. In a systematic review of 28 RCTs (n = 3497 patients) norepinephrine was compared with both vasopressin and epinephrine, but no trials directly compared the two options [bib_ref] Vasopressors for hypotensive shock, Gamper [/bib_ref]. If norepinephrine is not available, we suggest using either vasopressin or epinephrine, as both agents have been assessed in RCTs without showing clear evidence of harm. Factors determining the choice between vasopressin and epinephrine may include availability and contraindications to the two agents. With vasopressin, digital ischemia may be a concern; with epinephrine, tachycardia and excess lactate production may be considerations. ## Recommendation ## For adults with covid-19 and shock, we recommend against using dopamine if norepinephrine is available. Strong recommendation, high quality evidence. ## Rationale Because no direct evidence addresses this question in patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients. A 2016 Cochrane systematic review found 6 RCTs (n = 1400) comparing norepinephrine and dopamine in patients with shock [bib_ref] Vasopressors for hypotensive shock, Gamper [/bib_ref]. When pooled, the results showed no significant difference in all-cause mortality, but the point estimate favored norepinephrine (RR 1.07, 95% CI 0.99-1.16), and an increased risk of arrhythmias (RR 2.34, 95% CI 1.46-3.78) was found in the dopamine arm. On the basis of an increased risk of harm, including a possible increased risk of mortality in patients treated with dopamine, we recommend against using dopamine in patients with COVID-19 and shock where norepinephrine or alternatives are available (see recommendation 17). ## Recommendation ## 19. For adults with COVID-19 and shock, we suggest adding vasopressin as a second-line agent, over titrating norepinephrine dose, if target mean arterial pressure (MAP) cannot be achieved by norepinephrine alone. Weak recommendation, moderate quality evidence. ## Rationale In the absence of data on patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. In a recent clinical practice guideline, the use of vasopressin and vasopressin analogs in critically ill adults with distributive shock was assessed [bib_ref] Canadian Critical Care Society clinical practice guideline: the use of vasopressin and..., Honarmand [/bib_ref]. Analyzing 25 RCTS (n = 3737 patients), the authors found low certainty of a reduction in mortality (RR 0.91, 95% CI 0.85-0.99), high certainty of a reduction in atrial fibrillation (RR 0.77, 95% CI 0.67-0.88), and moderate certainty of an increased risk of digital ischemia (RR 2.56, 95% CI 1. with the addition of vasopressin or its analogs to catecholamines. Another recent systematic review reached similar conclusion [bib_ref] Association of vasopressin plus catecholamine vasopressors vs catecholamines alone with atrial fibrillation..., Mcintyre [/bib_ref]. In view of these findings, we suggest adding vasopressin as a second-line agent, over titrating norepinephrine dose, if target MAP cannot be achieved by norepinephrine alone in patients with COVID-19 and shock. ## Recommendation ## 20. For adults with COVID-19 and shock, we suggest titrating vasoactive agents to target a MAP of 60-65 mmHg, rather than higher MAP targets. Weak recommendation, moderate quality evidence. ## Rationale No direct evidence informs this recommendation; it is based on indirect evidence from critically ill patients. A recent individual patient-data meta-analysis of 2 RCTs (n = 894 patients) comparing higher versus lower blood pressure targets for vasopressor therapy in adult patients with shock reported no significant difference in [bib_ref] Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a..., Biggerstaff [/bib_ref] [bib_ref] Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy..., Lamontagne [/bib_ref]. The risk of arrhythmias was increased in patients allocated to the higher target group (OR 2.50, 95% CI 1. . Correspondingly, the recently published 65 trial reports an absolute risk difference in mortality of 3% (RR 0.93, 95% CI 0.85-1.03) in favor of a MAP target of 60-65 mmHg (lower target), as compared to a standard of care MAP target (higher target) [bib_ref] Effect of reduced exposure to vasopressors on 90-day mortality in older critically..., Lamontagne [/bib_ref]. With an indication of improved outcome with lower MAP targets (and no firm indication of harm), we suggest titrating vasoactive agents to a target of 60-65 mmHg. ## Recommendation ## 21. For adults with COVID-19 and shock with evidence of cardiac dysfunction and persistent hypoperfusion despite fluid resuscitation and norepinephrine, we suggest adding dobutamine, over increasing norepinephrine dose. Weak recommendation, very low-quality evidence. ## Rationale In the absence of direct evidence in patients with COVID-19 and shock, the panel used indirect evidence from critically ill patients to inform this recommendation. In a clinical practice guideline from 2018 assessing the optimal inotropic agent in patients with acute circulatory failure (shock), no RCTs comparing dobutamine vs. placebo or no treatment were identified [bib_ref] Scandinavian SSAI clinical practice guideline on choice of inotropic agent for patients..., Moller [/bib_ref]. Based on a physiological rationale, we suggest adding dobutamine, over no treatment, in patients with COVID-19 and shock with evidence of cardiac dysfunction and persistent hypoperfusion despite fluid resuscitation and high doses of norepinephrine. The use of dobutamine in shock, including in COVID-19 patients with shock, is a research priority. ## Recommendation ## 22. For adults with COVID-19 and refractory shock, we suggest using low-dose corticosteroid therapy ("shock-reversal"), over no corticosteroid therapy. Weak recommendation, very low-quality evidence. Remark: A typical corticosteroid regimen in septic shock is intravenous hydrocortisone 200 mg per day administered either as an infusion or intermittent doses. ## Rationale Since no data exist on the use of steroids in patients with COVID-19 and shock, the panel based this recommendation on indirect evidence from critically ill patients in general. As time to resolution of shock and length of stay (especially in ICU) are important cost considerations, we suggest using low-dose corticosteroid therapy in patients with COVID-19 and refractory shock. Below, we provide further guidance on patients with COVID-19 and respiratory failure in the absence of refractory shock. ## B. ventilatory support The prevalence of hypoxic respiratory failure in patients with COVID-19 is 19% [bib_ref] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. Recent reports from China showed that 4-13% of COVID-19 patients in these studies received non-invasive positive pressure ventilation (NIPPV), and that 2.3-12% required invasive mechanical ventilation [fig_ref] Table 3: Epidemiological characteristics in recent COVID-19 reportsCFR case fatality rate, ICU intensive care... [/fig_ref] [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref] [bib_ref] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak..., Wu [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Clinical characteristics of 138 Hospitalized patients With 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] [bib_ref] Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia..., Chen [/bib_ref]. Although the true incidence of hypoxic respiratory failure in patients with COVID-19 is not clear, it appears that about 14% will develop severe disease requiring oxygen therapy, and 5% will require ICU admission and mechanical ventilation [bib_ref] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. Another study reported on 52 critically ill COVID-19 patients; 67% of these patients had ARDS, 33 (63.5%) received high-flow nasal cannula (HFNC), 56% invasive mechanical ventilation, and 42% NIPPV [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. ## Risk factors for respiratory failure Risk factors associated with respiratory failure requiring mechanical ventilation are not clearly described in published reports, although from the limited available data, risk factors associated with a critical illness/ICU admission included older age (> 60 years), male gender, and the presence of underlying comorbidities such as diabetes, malignancy, and immunocompromised state [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref] [bib_ref] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak..., Wu [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Clinical characteristics of 138 Hospitalized patients With 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref]. The CDC reported an overall case-fatality rate (CFR) of 2.3%, with a CFR of 14.8% in patients aged 80 years or older. In critically ill patients, the CFR was 49.0%, and it was higher than 50% in those who received invasive mechanical ventilation. The presence of pre-existing comorbid conditions such as cardiovascular disease, diabetes, chronic respiratory disease, hypertension, and cancer were associated with higher risk of death [bib_ref] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. ## Recommendations ## 23. In adults with COVID-19, we suggest starting supplemental oxygen if the peripheral oxygen saturation (SpO 2 ) is < 92% (weak recommendation, low-quality evidence), and recommend starting supplemental oxygen if SpO 2 is < 90%. Strong recommendation, moderate quality evidence. [bib_ref] Efficacy of face masks and respirators in preventing upper respiratory tract bacterial..., Macintyre [/bib_ref]. In adults with COVID-19 and acute hypoxemic respiratory failure on oxygen, we recommend that SpO 2 be maintained no higher than 96%. Strong recommendation, moderate quality evidence. ## Rationale A recent study described the disease course of 1009 patients with COVID-19 in China and showed that 41% of all hospitalized patients and over 70% of those with severe disease required supplemental oxygen [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref]. In critically ill patients, hypoxia can be detrimental and is associated with poor outcomes [bib_ref] The search for optimal oxygen saturation targets in critically ill patients: observational..., Van Den Boom [/bib_ref]. There are no randomized or non-randomized studies on the use of oxygen in adults with COVID-19. However, the panel used indirect evidence from the acutely ill population to inform the recommendations. A systematic review and meta-analysis of 25 RCTs (16,037 patients) showed that a liberal oxygen strategy is associated with increased risk of hospital mortality (RR1.21, 95% CI 1.03-1.43) in acutely ill patients [bib_ref] Mortality and morbidity in acutely ill adults treated with liberal versus conservative..., Chu [/bib_ref]. Furthermore, a meta-regression showed a linear association between risk of death and higher SpO 2 targets [bib_ref] Mortality and morbidity in acutely ill adults treated with liberal versus conservative..., Chu [/bib_ref]. The median SpO 2 in the liberal oxygen group was 96% (IQR 96-98) across all trials. A recent clinical practice guideline recommended that SpO 2 be maintained no higher than 96% [bib_ref] Oxygen therapy for acutely ill medical patients: a clinical practice guideline, Siemieniuk [/bib_ref]. Subsequent trials provided further guidance on oxygenation targets. The ICU-ROX trial randomized 1000 critically ill patients to receive either conservative oxygen (based on a protocol to dial down oxygen) or usual care. This trial showed no difference in 180-day mortality between the two groups (OR 1.05, 95% CI 0.81-1.37) [bib_ref] Conservative oxygen therapy during mechanical ventilation in the ICU, Investigators I-R, The A ; G [/bib_ref]. The ICU-ROX trial did not compare hyperoxia with a conservative oxygen strategy; instead it compared usual care with a conservative oxygen strategy. The recent LOCO2 trial randomized patients with ARDS to a conservative oxygen arm (target SpO 2 88% to 92%) or a liberal oxygen arm (target SpO 2 ≥ 96%). The trial was stopped early for futility and possible harm after 61 deaths had occurred in 205 included patients for 28-day mortality [risk difference (RD) 7.8%, 95% CI; −4.8-20.6] [bib_ref] Investigators L, Network RR, Investigators L, Network RR (2020) Liberal or conservative..., Barrot [/bib_ref]. At 90 days, the conservative oxygen arm had a higher risk of death (RD 14.0%, 95% CI, 0.7-27.2). Considering the associated patient harm at the extremes of SpO 2 targets and the increased cost of liberal oxygen use, as well as the potential to reduce equity if oxygen resources are depleted, the panel issued a strong recommendation against using oxygen to target SpO 2 > 96%, and a strong recommendation to avoid lower values (SpO 2 < 90%). Therefore, a reasonable SpO 2 range for patients receiving oxygen is 92-96%. ## Recommendation ## For adults with covid-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, we suggest using HFNC over conventional oxygen therapy. Weak recommendation, low-quality evidence. ## Rationale As there is no direct evidence on patients with COVID-19, the panel used indirect evidence from the critically ill population to inform this recommendation. In an RCT comparing HFNC with conventional oxygen therapy in patients with acute hypoxic respiratory failure, HFNC resulted in reduced 90-day mortality (OR 0.42, 95% CI 0.21-0.85), but did not reduce the risk of intubation [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref]. A systematic review and meta-analysis of 9 RCTs (2093 patients) showed that HFNC reduces intubation compared with conventional oxygen (RR 0.85, 95% CI 0.74-0.99), but does not affect the risk of death or ICU length of stay [bib_ref] The effect of highflow nasal cannula in reducing the mortality and the..., Ni [/bib_ref] [bib_ref] Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic..., Ou [/bib_ref] [bib_ref] High flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic..., Rochwerg [/bib_ref]. Even though the evidence on mortality and length of stay was not as strong, the reduction in the need for intubation is an important finding, particularly from the perspective of pandemics such as COVID-19, where resources such as critical care beds and ventilators may become limited. In addition, in SARS, there are reports of increased transmission of disease to healthcare workers, especially nurses, during endotracheal intubation (OR 6.6, 95% Cl 2.3-18.9) [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] [bib_ref] Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation..., Raboud [/bib_ref] [bib_ref] Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation, Fowler [/bib_ref]. Although this is a finding based mostly on retrospective observational studies, HFNC does not seem to confer an increased risk of transmission of disease. In studies evaluating bacterial environmental contamination, HFNC presented a contamination risk similar to that of conventional oxygen [bib_ref] Comparison of high-flow nasal cannula versus oxygen face mask for environmental bacterial..., Leung [/bib_ref]. In SARS, healthcare workers exposed to HFNC were not at increased risk of developing disease [bib_ref] Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation..., Raboud [/bib_ref]. Finally, patients may find HFNC more comfortable than, or at least as comfortable as, conventional oxygen therapy [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref] [bib_ref] High flow nasal cannula compared with conventional oxygen therapy for acute hypoxemic..., Rochwerg [/bib_ref]. Although some authors advised avoiding the use of HFNC in patients with COVID-19 due to the fear of disease transmission, studies supporting this advice are lacking [bib_ref] Staff safety during emergency airway management for COVID-19 in Hong Kong, Cheung [/bib_ref]. Although some have proposed that patients wear face masks while on HFNC therapy, we are uncertain about the efficacy and safety of this approach. This question could be addressed in future studies. ## Recommendation ## In adults with covid-19 and acute hypoxemic respiratory failure, we suggest using HFNC over NIPPV. Weak recommendation, low-quality evidence. ## Rationale In adults with COVID-19 and acute respiratory failure, we suggest the use of HFNC over NIPPV. In an RCT comparing HFNC with NIPPV in patients with acute hypoxic respiratory failure, HFNC resulted in reduced mortality at 90 days (HR 2.50, 95% CI 1.31-4.78), but did not significantly affect the need for intubation (50% failure rate in NIPPV vs 47% in conventional oxygen and 40% in HFNC groups; p = 0.18) [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref]. Another meta-analysis comparing HFNC with NIPPV showed HFNC to decrease the need for intubation of patients, yet without significantly reducing mortality or ICU length of stay [bib_ref] The effect of highflow nasal cannula in reducing the mortality and the..., Ni [/bib_ref]. Additionally, patients may find HFNC more comfortable than NIPPV [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref]. Given the evidence for a decreased risk of intubation with HFNC compared with NIPPV in acute hypoxemic respiratory failure, and studies suggesting that NIPPV may carry a greater risk of nosocomial infection of healthcare providers, we suggest HFNC over NIPPV. However, any patients receiving HFNC or NIPPV should be monitored closely and cared for in a setting where intubation can be facilitated in the event of decompensation, as the failure rate may be high and emergency intubation in an uncontrolled setting may increase the risk of nosocomial infection of healthcare providers [bib_ref] Clinical course and outcomes of critically ill patients with Middle East respiratory..., Arabi [/bib_ref]. ## Recommendation ## In adults with covid-19 and acute hypoxemic respiratory failure, if HFNC is not available and there is no urgent indication for endotracheal intubation, we suggest a trial of NIPPV with close monitoring and short-interval assessment for worsening of respiratory failure. Weak recommendation, low-quality evidence. [bib_ref] Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a..., Biggerstaff [/bib_ref]. We were not able to make a recommendation regarding the use of helmet NIPPV compared with mask NIPPV. It is an option, but we are not certain about its safety or efficacy in COVID-19. 29. In adults with COVID-19 receiving NIPPV or HFNC, we recommend close monitoring for worsening of respiratory status, and early intubation in a controlled setting if worsening occurs. Best practice statement. ## Rationale In adults presenting with hypoxic respiratory failure from COVID-19, there is no direct evidence to support the use of NIPPV; furthermore, some prior studies suggested that it may be associated with an increased risk of infection transmission to healthcare workers. Metaanalyses of RCTs showed reductions in both intubation and mortality risks with NIPPV in hypoxic respiratory failure. However, these meta-analyses included studies focused on immunocompromised, acute cardiogenic pulmonary edema, or post-operative patients; their findings may therefore be less applicable to COVID-19 patients, in whom acute hypoxemic respiratory failure and ARDS are more common presentations. [bib_ref] Clinical characteristics of 138 Hospitalized patients With 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] [bib_ref] Noninvasive oxygenation strategies in immunocompromised patients with acute hypoxemic respiratory failure: a..., Zayed [/bib_ref] [bib_ref] noninvasive ventilation in acute hypoxemic nonhypercapnic respiratory failure: a systematic review and..., Xu [/bib_ref] [bib_ref] Noninvasive versus invasive mechanical ventilation for immunocompromised patients with acute respiratory failure:..., Wang [/bib_ref] In acute hypoxemic respiratory failure with an etiology other than cardiogenic pulmonary edema, NIPPV has a high failure rate. In one RCT, failure was reported in 49% of patients with hypoxic respiratory failure ventilated with NIPPV; these patients therefore required intubation [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref]. In addition, patients with hypoxic respiratory failure randomized to NIPPV had higher mortality (28%, 95% CI 21-37%) than those treated with conventional oxygen therapy (23%, 95% CI 16-33%) or HFNC (13%, 95% CI 7-20%) (p = 0.02). In a cohort of Middle East Respiratory Syndrome (MERS) patients, NIPPV was not associated with improved mortality or length of stay, compared with patients who were intubated without trying NIPPV. However, NIPPV was associated with a high failure rate (92.4%), leading to intubation. Patients who received NIPPV prior to intubation had increased inhaled nitric oxide requirements and increased mortality. Failure rates in other pandemics, such as influenza, H1N1 and SARS, range from 10 to 70%, while demonstrations of efficacy mainly come from case series and observational studies rather than RCTs, leading to practice variation. In China, the use of NIPPV for pandemic respiratory infection is common, whereas guidelines from Europe, Hong Kong, and the US advise against NIPPV as a first-line therapy in H1N1 [bib_ref] Noninvasive mechanical ventilation in high-risk pulmonary infections: a clinical review, Esquinas [/bib_ref]. There are additional concerns over the use of NIPPV in respiratory pandemics like COVID-19: NIPPV may aggravate severe forms of lung injury as a result of injurious transpulmonary pressures and large tidal volumes [bib_ref] Noninvasive ventilation for patients with hypoxemic acute respiratory failure, Brochard [/bib_ref] [bib_ref] Ventilator-induced lung injury, Slutsky [/bib_ref] , and may delay initiation of invasive mechanical ventilation, leading to emergency or more unstable intubations that can increase the risk of transmission to the healthcare team [bib_ref] Noninvasive ventilation for patients with hypoxemic acute respiratory failure, Brochard [/bib_ref]. In addition, NIPPV is an aerosol-generating procedure that can increase the risk of transmission of disease to healthcare workers [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref]. Several other studies and meta-analyses of SARS have also highlighted the risk of nosocomial spread of the disease with NIPPV [bib_ref] Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation, Fowler [/bib_ref] [bib_ref] Severe acute respiratory syndrome: historical, epidemiologic, and clinical features, Hui [/bib_ref]. The balance between benefit and harm when using NIPPV in adults with COVID-19 is unclear. If, in certain COVID-19 patients, other forms of respiratory failure, such as acute hypercapnic respiratory failure or acute cardiogenic pulmonary edema, are known to be the cause of respiratory failure, NIPPV may be beneficial [bib_ref] Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease, Brochard [/bib_ref] [bib_ref] Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure, Rochwerg [/bib_ref]. However, because limited experience with NIPPV in pandemics suggests a high failure rate, we recommend that any patient receiving NIPPV be monitored closely and cared for in a setting where intubation can be facilitated in the event of decompensation [bib_ref] Clinical course and outcomes of critically ill patients with Middle East respiratory..., Arabi [/bib_ref]. However, when resources become stretched, there may be insufficient ability to provide invasive ventilation, and even a moderate chance of success with NIPPV may justify its use. If NIPPV is used, helmet NIPPV is an attractive option, if available. A single-center RCT showed decreased intubation and improved mortality from NIPPV delivered by helmet in ARDS patients [bib_ref] Effect of noninvasive ventilation delivered by helmet vs face mask on the..., Patel [/bib_ref]. Of particular importance in the setting of a pandemic such as COVID-19, NIPPV by helmet has also been shown to reduce exhaled air dispersion, whereas face masks were insufficient [bib_ref] Exhaled air dispersion during noninvasive ventilation via helmets and a total facemask, Hui [/bib_ref]. However, helmet NIPPV is more expensive, and without direct evidence of benefit in COVID-19 patients, resources should not be utilized to acquire this equipment if is not already available. [fig_ref] Figure 2: Summary of recommendations on the initial management of hypoxic COVID-19 patients [/fig_ref] summarizes the recommendations on HFNC and NIPPV in patients with COVID-19. ## Invasive mechanical ventilation Recommendation [bib_ref] Videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation: a Cochrane..., Lewis [/bib_ref]. In mechanically ventilated adults with COVID-19 and ARDS, we recommend using low tidal volume (Vt) ventilation (Vt 4-8 mL/kg of predicted body weight), over higher tidal volumes (Vt > 8 mL/kg). Strong recommendation, moderate quality evidence. ## Rationale Currently there are no studies addressing mechanical ventilation strategies in COVID-19 patients. However, the panel of experts believes that mechanically ventilated patients with COVID-19 should be managed similarly to other patients with acute respiratory failure in the ICU. While mechanical ventilation is a potentially life-saving intervention, it can worsen lung injury and, through ventilator-induced lung injury (VILI), contribute to multiorgan failure in patients with ARDS [bib_ref] Ventilator-induced lung injury, Slutsky [/bib_ref]. One of the main ventilator strategies to minimize VILI is low Vt ventilation. A systematic review and meta-analysis of RCTs found an inverse association between larger Vt gradient and mortality [bib_ref] Low tidal volume versus non-volume-limited strategies for patients with acute respiratory distress..., Walkey [/bib_ref]. In addition, authors found that using a protocolized low Vt strategy with high PEEP (9 RCTs and 1629 patients) reduced the risk of death (RR, 0.80, 95% CI, 0.66-0.98) [bib_ref] Low tidal volume versus non-volume-limited strategies for patients with acute respiratory distress..., Walkey [/bib_ref]. Our analysis of 5 RCTs (1181 patients) showed a reduction in hospital mortality with low Vt ventilation (RR 0.73, 95% CI 0.63-0.85) [bib_ref] Effect of a protective-ventilation strategy on mortality in the acute respiratory distress..., Amato [/bib_ref] [bib_ref] A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome..., Villar [/bib_ref] [bib_ref] Ventilation with lower tidal volumes as compared with traditional tidal volumes for..., Respiratory Distress Syndrome [/bib_ref] [bib_ref] Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation..., Brower [/bib_ref] [bib_ref] Pulmonary function and health-related quality of life in survivors of acute respiratory..., Orme [/bib_ref] [bib_ref] The application of low tidal volume pressure-controlled ventilation in patients with acute..., Wu [/bib_ref]. On the basis of the available body of evidence, several guidelines recommended using low Vt (4-8 mL/kg of predicted body weight) in patients with ARDS [bib_ref] of Intensive Care Medicine/Society of critical care medicine clinical practice guideline: mechanical..., Fan [/bib_ref] [bib_ref] Surviving sepsis campaign: international guidelines for management of sepsis and septic shock-2016, Rhodes [/bib_ref]. The panel judged the magnitude of benefit to be moderate, the cost to be low, and the intervention to be acceptable and feasible to implement, and they therefore issued a strong recommendation to use low Vt (4-8 mL/ kg predicted body weight) when ventilating patients with ARDS . ## Practical considerations The ARDSNet study protocol set the initial Vt at 6 mL/kg which can be increased to 8 mL/kg if the patient is double triggering or if inspiratory airway pressure decreases below PEEP [bib_ref] Ventilation with lower tidal volumes as compared with traditional tidal volumes for..., Respiratory Distress Syndrome [/bib_ref]. Strict adherence to target Vt in spontaneously breathing patients with ARDS is a challenge; patient-ventilator dyssynchrony is not uncommon [bib_ref] Patientventilator asynchrony during assisted mechanical ventilation, Thille [/bib_ref]. ## Recommendation ## For mechanically ventilated adults with covid-19 and ards, we recommend targeting plateau pressures (Pplat) of < 30 cm H 2 O Strong recommendation, moderate quality evidence. ## Fig. 3 summary of recommendations on the management of patients with covid-19 and ards ## Rationale There are no clinical trials examining the effect of plateau pressure (Pplat) limitation on COVID-19 induced ARDS. However, there is a large body of indirect evidence in patients with ARDS. Along with low Vt ventilation, Pplat limitation is a lung protective strategy to limit VILI. A systematic review and meta-analysis of RCTs found that using a lung protective strategy including protocolized low Vt and Pplat < 30 cmH 2 O (9 RCTs and 1629 patients) reduced the risk of death (RR, 0.80, 95% CI 0.66-0.98) [bib_ref] Low tidal volume versus non-volume-limited strategies for patients with acute respiratory distress..., Walkey [/bib_ref]. A subsequent meta-analysis of RCTs comparing ventilatory strategies with low and high Pplat in patients with ARDS (15 studies) found that short-term mortality was higher in patients with Pplat > 32 cmH [bib_ref] of Intensive Care Medicine/Society of critical care medicine clinical practice guideline: mechanical..., Fan [/bib_ref] [bib_ref] Surviving sepsis campaign: international guidelines for management of sepsis and septic shock-2016, Rhodes [/bib_ref]. The panel judged the magnitude of benefit to be moderate, the cost to be low, the patients' values to be consistent, and the intervention to be acceptable and feasible to implement, and therefore, issued a strong recommendation to keep Pplat < 30 cmH 2 O when ventilating patients with ARDS. ## Practical considerations The ARDSNet study protocol set the initial Vt at 6 mL/kg, and then measured Pplat (after a 0.5 s inspiratory pause) [bib_ref] Ventilation with lower tidal volumes as compared with traditional tidal volumes for..., Respiratory Distress Syndrome [/bib_ref]. If the Pplat > 30 cmH 2 O, Vt could be reduced in 1 mL/kg (to 4 mL/kg) steps until Pplat was within range. ## Recommendation ## For mechanically ventilated adults with covid-19 and moderate to severe ARDS, we suggest using a higher PEEP strategy, over a lower PEEP strategy. Weak recommendation, low-quality evidence. Remarks: If using a higher PEEP strategy (i.e. PEEP > 10 cm H 2 O), clinicians should monitor patients for barotrauma. ## Rationale In ARDS, extrinsic PEEP is used to prevent repeated opening and closing of alveoli (i.e. atelectotrauma), and therefore to reduce VILI. In addition, PEEP increases and sustains alveolar recruitment, which improves oxygenation and reduces oxygen requirement. There are no clinical trials examining the effect of PEEP on coronavirus-induced ARDS. However, there is a large body of indirect evidence in patients with ARDS. An individual patient data meta-analysis (IPDMA) of the 3 largest trials (2299 patients) of high PEEP [bib_ref] Higher versus lower positive end-expiratory pressures in patients with the acute respiratory..., Brower [/bib_ref] [bib_ref] Lung Open Ventilation Study I (2008) Ventilation strategy using low tidal volumes,..., Meade [/bib_ref] [bib_ref] Expiratory Pressure Study G (2008) Positive end-expiratory pressure setting in adults with..., Mercat [/bib_ref] found no difference in in-hospital mortality in all patients (RR 0.94, 95% CI 0.86-1.04) [bib_ref] Higher vs lower positive end-expiratory pressure in patients with acute lung injury..., Briel [/bib_ref]. However, in patients with ARDS, a higher PEEP strategy resulted in lower ICU mortality (RR 0.85, 95% CI 0.76-0.95), lower in-hospital mortality (RR 0.90, 95% CI 0.81-1.0), and a reduction in the use of rescue therapies (RR 0.63, 95% CI 0.53-0.75), at the expense of a possible increase in the risk of pneumothorax [bib_ref] Higher vs lower positive end-expiratory pressure in patients with acute lung injury..., Briel [/bib_ref]. A recent systematic review and meta-analysis of 9 RCTs (3612 patients) examined the effect of a higher PEEP strategy on patient-important outcomes [bib_ref] Higher PEEP improves outcomes in ARDS patients with clinically objective positive oxygenation..., Guo [/bib_ref]. Overall, a higher PEEP strategy did not reduce hospital mortality (RR 0.92, 95% CI, 0.79-1.07). However, in a subgroup of trials that enrolled patients with oxygenation response to PEEP (6 RCTS, 1888 patients), the use of high PEEP significantly reduced in-hospital mortality, compared with a lower PEEP strategy (RR 0.83, 95% CI 0.69-0.98). Although the body of evidence suggests a beneficial effect of higher PEEP in selected patients, the results are likely to be confounded by the fact that low Vt ventilation was not used in the control arm of these trials [bib_ref] Higher PEEP versus lower PEEP strategies for patients with acute respiratory distress..., Walkey [/bib_ref]. There is no clear and agreed upon definition of higher PEEP; moreover, the optimal PEEP level in ARDS patients is unknown, and is likely to vary based on the extent of disease, lung compliance, and other factors. In the aforementioned IPDMA, the median PEEP level in the high PEEP arm was 15.3 and 13.3 cm H 2 O on days 1 and 3, respectively, compared with median values of 9 and 8.2 cm H 2 O on days 1 and 3 in the low PEEP arm [bib_ref] Higher vs lower positive end-expiratory pressure in patients with acute lung injury..., Briel [/bib_ref]. Although arbitrary, clinicians could consider PEEP levels > 10 cm H 2 O to constitute a higher PEEP strategy, and PEEP levels < 10 cm H 2 O as a lower PEEP strategy. ## Practical considerations Because the IPDMA combined different strategies to set higher PEEP, a reasonable starting point would be to implement a strategy used in the large RCTs that were included (i.e. ALVEOLI, LOV, and ExPRESS) [bib_ref] Higher versus lower positive end-expiratory pressures in patients with the acute respiratory..., Brower [/bib_ref] [bib_ref] Lung Open Ventilation Study I (2008) Ventilation strategy using low tidal volumes,..., Meade [/bib_ref] [bib_ref] Expiratory Pressure Study G (2008) Positive end-expiratory pressure setting in adults with..., Mercat [/bib_ref]. After increasing the PEEP level, clinicians should monitor their patients for evidence of barotrauma. Importantly, higher PEEP may result in higher Pplat, which is associated with its own risks and benefits when Pplat > 30 cmH 2 O. Clinicians can use the ARDS Network protocol strategies to determine the optimal PEEP level. Other available strategies include decremental PEEP strategy, the esophageal balloon technique, and electrical impedance tomography. However, the effect of using these techniques on clinical outcomes is unknown. ## Recommendation ## 33. For mechanically ventilated adults with COVID-19 and ARDS, we suggest using a conservative fluid strategy over a liberal fluid strategy. Weak recommendation, low-quality evidence. ## Rationale The optimal fluid strategy in COVID-19 is not known, however, it is plausible that these patients will respond to fluid similarly to other ARDS patients. The limited data available on COVID-19 show that cardiac failure, alone or in combination with respiratory failure, was the cause of 40% of COVID-19 deaths [bib_ref] Clinical predictors of mortality due to COVID-19 based on an analysis of..., Ruan [/bib_ref]. Another study showed that 44% of COVID-19 patients had arrhythmia [bib_ref] Clinical characteristics of 138 Hospitalized patients With 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref]. The data suggest the presence of myocardial injury in some patients with COVID-19. Few RCTs have been published that compare conservative or deresuscitative with liberal fluid strategies in ARDS. A recent systematic review included 5 RCTs enrolling 1206 patients with ARDS. The risk of death was similar in both groups: 28% in the conservative fluid strategy group and 31.1% in the liberal strategy group (RR 0.91, 95% CI 0.77-1.07) [bib_ref] Conservative fluid management or deresuscitation for patients with sepsis or acute respiratory..., Silversides [/bib_ref]. This study included RCTs in critically ill patients with or without ARDS, and the authors found that a conservative fluid strategy increased ventilator-free days (MD 1.82 days; 95% CI 0.53-3.10 days) and reduced ICU length of stay (MD − 1.88 days, 95% CI − 0.12 to − 3.64 days), compared with a liberal fluid strategy. There was no difference in harm, including renal failure between the two groups. The landmark trial in ARDS patients (FACTT) found a significant reduction in the duration of mechanical ventilation with a conservative fluid strategy [bib_ref] Comparison of two fluid-management strategies in acute lung injury, Wiedemann [/bib_ref]. Furthermore, the majority of patients with COVID-19 in the ICU are elderly, and may develop myocardial dysfunction that could limit their ability to handle large fluid volumes [bib_ref] Clinical predictors of mortality due to COVID-19 based on an analysis of..., Ruan [/bib_ref]. In view of the moderate benefit observed in other ARDS populations, the possible reduced cost of administering less fluids, and the feasibility of the intervention, the panel issued a weak recommendation favoring conservative fluid strategy in patients with COVID-19 and ARDS ## Recommendation ## For mechanically ventilated adults with covid-19 and moderate to severe ARDS, we suggest prone ventilation for 12-16 h, over no prone ventilation. Weak recommendation, low-quality evidence. ## Rationale In a series of 81 patients with COVID-19, radiographic features progressed over the first 1-2 weeks after symptom onset from predominant ground glass opacities to a mixed pattern of predominant basilar consolidation. This latter pattern may suggest a role for prone ventilation [bib_ref] Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a..., Shi [/bib_ref]. Prone positioning theoretically makes ventilation more homogeneous by decreasing ventral alveolar distention and dorsal alveolar collapse [bib_ref] Effects of prone positioning on lung protection in patients with acute respiratory..., Cornejo [/bib_ref]. This may reduce the difference between the dorsal and ventral transpulmonary pressures, in addition to reducing lung compression [bib_ref] The prone position eliminates compression of the lungs by the heart, Albert [/bib_ref] and improving perfusion [bib_ref] Lung ventilation and perfusion in prone and supine postures with reference to..., Nyren [/bib_ref]. A recent study that described the clinical course of COVID-19 in the ICU showed that prone ventilation was used in 11.5% of patients (6 out of 52) [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. However, there are no studies available that describe the clinical course of patients with COVID-19 who were ventilated in the prone position. A recent systematic review and meta-analysis of 9 RCTs (2129 patients) showed that prone ventilation for at least 12 h in patients with moderate to severe ARDS reduced mortality (5 RCTs; RR 0.74, 95% CI 0.56-0.99), but had no effect on mortality in studies that used prone ventilation for < 12 h (3 RCTs; RR 1.03, 95% CI 0. . On the other hand, prone ventilation increased the risks of pressure sores (RR 1.22, 95% CI 1.06-1.41) and endotracheal tube obstruction (RR 1.76, 95% CI 1.24-2.50) [bib_ref] Prone position for acute respiratory distress syndrome. A systematic review and meta-analysis, Munshi [/bib_ref]. Other systematic reviews reached similar conclusions [bib_ref] Prone position for acute respiratory failure in adults, Bloomfield [/bib_ref] [bib_ref] The effects of prone position ventilation in patients with acute respiratory distress..., Mora-Arteaga [/bib_ref] [bib_ref] The efficacy and safety of prone positional ventilation in acute respiratory distress..., Lee [/bib_ref]. We have moderate certainty that prone ventilation for more than 12 h in patients with moderate to severe ARDS reduces mortality, but may increase the risk of pressure sores and endotracheal tube obstruction. Healthcare workers proning patients with COVID-19 should be trained in the proper technique for proning and take infection control precautions in the event of accidental endotracheal tube disconnection from the ventilator. Proning itself is not associated with significant cost, and we believe that it may provide significant benefit. Further, proning can be implemented in low-and middle-income settings, and efforts should be made to provide the necessary training and education of healthcare workers to facilitate the practice (https ://www.youtu be.com/watch ?v=E_6jT9R 7WJs). ## Practical considerations A protocol for proning should be used at all institutions, based on the available resources and level of training. If prone ventilation is used, healthcare workers should be aware of complications such as pressure sores, vascular line and endotracheal tube displacement, facial edema, transient hemodynamic instability, corneal abrasions, brachial plexus injury, and hemodialysis vascular access flow issues. In addition, clinicians should be familiar with the absolute contraindications for prone ventilation, such as unstable spine, open abdomen or open chest (i.e. surgery or trauma). Enteral nutrition via nasogastric or nasoduodenal tube can be continued during proning [bib_ref] Enteral feeding in the critically ill: comparison between the supine and prone..., Van Der Voort [/bib_ref] [bib_ref] Oudemans-van Straaten HM, Function EWGoG (2017) Early enteral nutrition in critically ill..., Blaser [/bib_ref]. ## Rationale Several professional societies have issued recommendations on the use of NMBAs in ARDS [bib_ref] Surviving sepsis campaign: international guidelines for management of sepsis and septic shock-2016, Rhodes [/bib_ref] [bib_ref] Clinical practice guidelines for sustained neuromuscular blockade in the adult critically Ill..., Murray [/bib_ref] [bib_ref] New UK guidelines for the management of adult patients with ARDS, Griffiths [/bib_ref] [bib_ref] Scandinavian clinical practice guideline on fluid and drug therapy in adults with..., Claesson [/bib_ref] [bib_ref] Formal guidelines: management of acute respiratory distress syndrome, Papazian [/bib_ref]. Most issued recommendations favoring the use of an NMBA infusion in patients with moderate to severe ARDS. These recommendations were mostly based on the pooled estimates from 3 RCTs (431 patients) showing a reduction in 90-day mortality with an NMBA infusion as compared with no NMBA infusion [bib_ref] Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and..., Alhazzani [/bib_ref]. However, the results of the Re-evaluation of Systemic Early Neuromuscular Blockade (ROSE) trial challenged those of previous trials. The ROSE trial investigators randomized 1006 patients with moderate or severe ARDS to receive either an infusion of NMBA for 48 h or intermittent NMBA boluses on an as needed basis [bib_ref] Early neuromuscular blockade in the acute respiratory distress syndrome, Heart [/bib_ref]. The ROSE trial showed that a continuous infusion of cisatracurium did not improve any patient important outcomes. Due to differences in design between the ROSE trial and the earlier trials, we did not perform a meta-analysis for mortality outcome, although the pooled estimate for barotrauma favored continuous NMBA infusion (RR 0.55, 95% CI 0.35-0.85). The panel suggests that a continuous NMBA infusion should be reserved for patients who have an indication for ongoing paralysis in which intermittent dosing may not suffice, such as patients with persistent ventilator dyssynchrony, and patients needing ongoing deep sedation prone ventilation, or persistently high plateau pressures. The effect of NMBAs on longterm outcomes is unclear. ## Recommendations ## 36. In mechanically ventilated adults with COVID-19 ARDS, we recommend against the routine use of inhaled nitric oxide. Strong recommendation, low-quality evidence. [bib_ref] Comparison of different samples for 2019 novel coronavirus detection by nucleic acid..., Xie [/bib_ref]. In mechanically ventilated adults with COVID-19, severe ARDS and hypoxemia despite optimizing ventilation and other rescue strategies, we suggest a trial of inhaled pulmonary vasodilator as a rescuetherapy; if no rapid improvement in oxygenation is observed, the treatment should be tapered off. Weak recommendation, low-quality evidence. ## Rationale There are no studies that describe the use of pulmonary vasodilators in COVID-19 patients. A Cochrane review identified 13 RCTs (1243 patients) on inhaled nitric oxide in ARDS; this treatment showed no significant effect on mortality (RR 1.04, 95% CI 0.9-1.19), and was associated with an increased risk of acute kidney injury (RR 1.59, 95% CI 1.17-2.16). Inhaled nitric oxide results in a transient improvement in oxygenation. The subgroup of studies reporting PaO 2 /FiO 2 (mm Hg) values up to 24 h after the intervention showed a statistically significant difference in favor of inhaled nitric oxide, which was not present beyond 24 h. No study assessed the use of inhaled nitric oxide as a "rescue" therapy [bib_ref] Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and..., Gebistorf [/bib_ref]. Because of the possible harm from inhaled nitric oxide and the absence of a clear mortality benefit, the panel issued a strong recommendation against its routine use in patients with ARDS. However, in view of the finding of improved oxygenation, a trial of inhaled nitric oxide as a "rescue" therapy, after trying other options, is reasonable if available. If inhaled nitric oxide is used without a good response in terms of oxygenation, it should be tapered off to avoid rebound the pulmonary vasoconstriction that can occur with prolonged use and abrupt discontinuation. No adequately powered RCTs have evaluated inhaled prostacyclins such as ilioprost, therefore, we could not recommend against or for their use in severe ARDS. ## Recommendations ## For mechanically ventilated adults with covid-19 and hypoxemia despite optimizing ventilation, we suggest using recruitment maneuvers, over not using recruitment maneuvers. Weak recommendation, low-quality evidence. 39. If recruitment maneuvers are used, we recommend against using staircase (incremental PEEP) recruitment maneuvers. Strong recommendation, low-quality evidence. ## Rationale No studies have assessed the role of recruitment maneuvers (RMs) in patients with ARDS secondary to COVID-19. RMs aim to improve oxygenation by increasing transpulmonary pressure to open atelectatic alveoli [bib_ref] Lung recruitment in patients with the acute respiratory distress syndrome, Gattinoni [/bib_ref]. However, exposure to high levels of positive pressure may lead to barotrauma, as well as cause transient hypotension in already critically ill and unstable patients. We assessed 8 indirect RCTs assessing RMs in ARDS patients, including patients with sepsis due to bacterial or viral pneumonia. Varying strategies were used to help recruit atelectatic lungs, however two strategies, in particular, were common in the 8 RCTs included in this meta-analysis. Traditional RMs are described as prolonged inspiratory holds for a set duration of time on higher levels of CPAP, most commonly 35-40 cm H 2 O for 40 s [bib_ref] Effect of a protective-ventilation strategy on mortality in the acute respiratory distress..., Amato [/bib_ref] [bib_ref] Lung Open Ventilation Study I (2008) Ventilation strategy using low tidal volumes,..., Meade [/bib_ref] [bib_ref] Open lung approach for the acute respiratory distress syndrome: a pilot, randomized..., Kacmarek [/bib_ref] [bib_ref] Clinical efficacy and safety of recruitment maneuver in patients with acute respiratory..., Xi [/bib_ref]. Incremental PEEP titration RMs are described as incremental increases in PEEP from 25 to 35 to 45 cm H 2 0 for 1-2 min each [bib_ref] A randomised controlled trial of an open lung strategy with staircase recruitment,..., Hodgson [/bib_ref] [bib_ref] Maximal recruitment open lung ventilation in acute respiratory distress syndrome (PHAR-LAP). A..., Hodgson [/bib_ref] [bib_ref] Efficacy of positive end-expiratory pressure titration after the alveolar recruitment manoeuvre in..., Huh [/bib_ref]. In a systematic review and meta-analysis of 6 RCTs (1423 patients), RMs reduced mortality and the use of rescue interventions, and improved oxygenation at 24 h without increasing the risk of barotrauma [bib_ref] Lung recruitment maneuvers for adult patients with acute respiratory distress syndrome. A..., Goligher [/bib_ref]. Similarly, we identified 8 RCTs (2544 patients) that reported on in-hospital mortality. In these studies, RMs were not associated with reduced mortality (RR 0.90, 95% CI 0.78-1.04). However, subgroup analyses suggested that traditional RMs significantly reduced mortality (RR 0.85, 95% CI 0.75-0.97), whereas incremental PEEP titration RMs increased mortality (RR 1.06, 95% CI 0. . While the effects of RMs on oxygenation may be transient, the studies showed a significant improvement in oxygenation after 24 h. Trials used different PEEP strategies in intervention and control arms; RMs are best combined with a higher PEEP strategy. Patients with severe ARDS and hypoxemia may benefit from traditional recruitment maneuvers along with higher levels of PEEP, but evidence specific to COVID-19 is needed. Patients receiving RMs should be monitored closely for severe desaturation, hypotension or barotrauma. RMS should be stopped if they lead to patient deterioration. ## Recommendation ## In mechanically ventilated adults with covid-19 and refractory hypoxemia despite optimizing ventilation, use of rescue therapies, and proning, we suggest using venovenous (VV) ECMO if available, or referring the patient to an ECMO center. Weak recommendation, low-quality evidence. Remark: Due to the resource-intensive nature of ECMO, and the need for experienced centers and healthcare workers, and infrastructure, ECMO should only be considered in carefully selected patients with COVID-19 and severe ARDS. ## Rationale There are no clinical trials of ECMO in COVID-19 patients. A recent report from China suggested that 11.5% of COVID-19 cases in the ICU received ECMO [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] , but the clinical courses and the outcomes of these patients have not been reported yet. The Ministry of Health in Saudi Arabia established an ECMO program during the MERS-CoV epidemic. In a retrospective cohort study of 35 patients with MERS-CoV and refractory hypoxemia, the group of patients who received VV ECMO had lower in-hospital mortality (65 vs. 100%, p = 0.02) [bib_ref] Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus, Alshahrani [/bib_ref]. However, this cohort study is at high risk of selection bias given its retrospective design. Only two RCTs have evaluated ECMO vs. conventional mechanical ventilation in severe ARDS. Guidelines published in 2017 were unable to provide specific guidance on the use of ECMO, and further research was recommended [bib_ref] of Intensive Care Medicine/Society of critical care medicine clinical practice guideline: mechanical..., Fan [/bib_ref]. Although the most recent RCT (EOLIA) was stopped early for futility [bib_ref] Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome, Combes [/bib_ref] , a re-analysis of this trial using a Bayesian approach provided a more favorable interpretation, suggesting lower mortality with ECMO in severe ARDS [bib_ref] Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome and posterior probability..., Goligher [/bib_ref]. A recent systematic review including two RCTs (429 patients) found a reduction in 60-day mortality with ECMO (RR 0.73, 95% CI 0.58-0.92), but the risk of major bleeding was higher with ECMO [bib_ref] Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review..., Munshi [/bib_ref]. ECMO is a resource-intensive technique restricted to specialized centers, and it remains an extremely limited resource. Therefore, its use as a rescue therapy should be reserved for carefully selected patients [bib_ref] Preparing for the most critically ill patients with COVID-19: the potential role..., Maclaren [/bib_ref]. Future studies describing the outcomes of COVID-19 patients on ECMO and the mechanisms of death will advance our understanding and guide practice. ## Iv. covid-19 therapy In this section we will discuss possible treatment options for SARS CoV-2 and its complications, including antiviral agents, immunosuppressive agents, immunomodulators and other therapies. ## Cytokine storm syndrome Cytokine storm syndrome is a hyperinflammatory state that is characterized by fulminant multi-organ failure and elevation of cytokine levels. A recent study from China showed that COVID-19 is associated with a cytokine elevation profile that is reminiscent of secondary hemophagocytic lymphohistiocytosis (HLH). Some authors even suggest that we screen critically ill COVID-19 patients for secondary HLH using the Hscore [bib_ref] Development and validation of the HScore, a score for the diagnosis of..., Fardet [/bib_ref] , and that corticosteroids and other immunosuppressive agents can be used in patients with a high likelihood of HLH. More evidence is needed before we can make recommendations on the treatment options for cytokine storm. ## Recommendations ## 41. In mechanically ventilated adults with COVID-19 and respiratory failure (without ARDS), we suggest against the routine use of systemic corticosteroids. Weak recommendation, low-quality evidence. [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. In mechanically ventilated adults with COVID-19 and ARDS, we suggest using systemic corticosteroids, over not using corticosteroids. Weak recommendation, low-quality evidence. Remark: The majority of our panel support a weak recommendation (i.e. suggestion) to use steroids in the sickest patients with COVID-19 and ARDS. However, because of the very low-quality evidence, some experts on the panel preferred not to issue a recommendation until higher quality direct evidence is available. ## Rationale There are no controlled clinical trials on the use of corticosteroids in COVID-19 patients or other coronaviruses. A published, but not peer-reviewed, report of 26 patients with severe COVID-19 reports that the use of methylprednisolone at 1-2 mg/kg/day for 5-7 days was associated with shorter duration of supplemental oxygen use (8.2 days vs. 13.5 days; p < 0.001) and improved radiographic findings. Although interesting, we judged these preliminary reports to be an insufficient basis for formulating recommendations, due to the risk of confounding. Therefore, we used indirect evidence from community acquired pneumonia, ARDS, and other viral infections to inform our recommendation. There are several RCTs on the use of systemic corticosteroids in hospitalized patients with community-acquired pneumonia, mostly non-ICU patients, some with sepsis or septic shock. A systematic review and meta-analysis of RCTs showed that using corticosteroids may reduce the need for mechanical ventilation (5 RCTs; 1060 patients; RR 0.45, 95% CI 0.26-0.79), ARDS (4 RCTs; 945 patients; RR 0.24, 95% CI 0.10-0.56) and the duration of hospitalization (6 RCTs; 1499 patients; MD − 1.00 day, 95% CI, − 1.79 to − 0.21), but increase the risk of hyperglycemia requiring treatment [bib_ref] Corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and..., Siemieniuk [/bib_ref]. However, these trials included different populations, the effect on mortality outcome was unclear, and they used different drugs and dosing regimens. In addition, there are some concerns about corticosteroid use in viral pneumonias. Therefore, the results may not be generalizable to the COVID-19 population. There are many published observational studies on the use of steroids in viral pneumonias (i.e. influenza virus, coronaviruses, and others), but they are prone to confounding, as sicker patients usually receive corticosteroids. We updated a recent Cochrane review on the use of corticosteroids in influenza [bib_ref] Corticosteroids as adjunctive therapy in the treatment of influenza, Lansbury [/bib_ref] and searched for studies on other coronaviruses. We included a total of 15 cohort studies on influenza and 10 on coronaviruses. Our meta-analysis of adjusted ORs showed an association between corticosteroid use and increased mortality (OR 2.76, 95% CI 2.06-3.69), but the effect in the patients with other coronaviruses was unclear (OR 0.83, 95% CI 0. . Also, these studies are limited by significant heterogeneity. We found significant homogeneity between observational studies on the use of corticosteroids in ARDS caused by coronaviruses and in general viral ARDS (I 2 = 82% and 77% respectively). Furthermore, in both cases, the summary statistic tended toward harm with the use of steroids. We updated a recent Cochrane review [bib_ref] Pharmacological agents for adults with acute respiratory distress syndrome, Lewis [/bib_ref] and identified an additional RCT [bib_ref] Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled..., Villar [/bib_ref] dealing with ARDS. Overall, we included 7 RCTs enrolling 851 patients with ARDS. The use of corticosteroids reduced mortality (RR 0.75, 95% CI 0.59-0.95) and duration of mechanical ventilation (MD − 4.93 days, 95% CI − 7.81 to − 2.06). However, these trials were not focused on viral ARDS, which limits the generalizability of their results to COVID-19 patients. In addition, we reviewed observational studies on corticosteroid use in viral ARDS, and identified 4 cohort studies. Although the point estimate showed increased mortality, the CI included substantial harm and benefit (OR 1.40, 95% CI 0. . In a recent RCT (INTEREST trial), the use of recombinant interferon β1b (rIFN β1ba) did not reduce mortality in ARDS patients, but in the subgroup of patients receiving corticosteroids, rIFN β1ba use was associated with increased mortality (OR, 2.53, 95% CI 1.12-5.72) [bib_ref] Group IS (2020) Effect of Intravenous Interferon beta-1a on death and days..., Ranieri [/bib_ref]. The only direct evidence comes from a retrospective cohort study of 201 patients with COVID-19 pneumonia. This study showed an association between corticosteroid use and lower mortality in patients with COVID-19 and ARDS (HR 0.38, 95% CI 0.20-0.72). However, the estimate was not adjusted for confounding factors [bib_ref] Risk factors associated with acute respiratory distress syndrome and death in patients..., Wu [/bib_ref]. The effect of corticosteroids in COVID-19 patients with sepsis or septic shock may be different. Recent systematic reviews and meta-analyses of RCTs in sepsis showed small improvements in mortality and faster resolution of shock with corticosteroid use, compared with not using corticosteroids [bib_ref] Low-dose corticosteroids for adult patients with septic shock: a systematic review with..., Rygard [/bib_ref] [bib_ref] Corticosteroids in sepsis: an updated systematic review and meta-analysis, Rochwerg [/bib_ref] [bib_ref] Reevaluating the role of corticosteroids in septic shock: an updated meta-analysis of..., Lian [/bib_ref] (see the previous section on hemodynamic support). It is widely recognized that corticosteroids have a range of adverse effects. In viral pneumonia in the ICU, several studies showed increase in viral shedding with corticosteroid use [bib_ref] Corticosteroid therapy for critically ill patients with middle east respiratory syndrome, Arabi [/bib_ref] [bib_ref] Systemic corticosteroid therapy may delay viral clearance in patients with middle east..., Hui [/bib_ref] [bib_ref] Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in..., Lee [/bib_ref] , potentially indicating viral replication, but the clinical implication of increased viral shedding is uncertain. Considering the above, the panel issued a suggestion against the routine use of systemic corticosteroids for respiratory failure in COVID-19, and a suggestion to use corticosteroids in the sicker population of COVID-19 with ARDS. If clinicians use corticosteroids in ARDS, they should use lower dosing and shorter treatment courses. ## Recommendation ## In mechanically ventilated patients with covid-19 and respiratory failure, we suggest using empiric antimicrobials/antibacterial agents, over no antimicrobials. Weak recommendation, low-quality evidence. Remark: if the treating team initiates empiric antimicrobials, they should assess for de-escalation daily, and re-evaluate the duration of therapy and spectrum of coverage based on the microbiology results and the patient's clinical status. ## Rationale There are no controlled clinical trials evaluating the use of empiric antimicrobials in COVID-19 patients or other coronaviruses. This recommendation is therefore based upon extrapolation of data from other viral pneumonias, particularly influenza [bib_ref] Update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenzaa, Uyeki [/bib_ref]. Identifying bacterial coinfection or superinfection in patients with COVID-19 is challenging, as the symptoms may be similar to those of the underlying viral infection. The diagnostic difficulty is reflected in high rates of intravenous antibiotics administered in Wuhan: 53% with non-severe disease and > 90% of patients admitted to hospital or the ICU [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] [bib_ref] Clinical characteristics of 138 Hospitalized patients With 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref]. Data on the prevalence of bacterial superinfection in patients with COVID-19 are limited, as in larger case studies clinicians were often too overwhelmed to systematically obtain high-quality samples [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref]. In critically ill patients with MERS, 18% had bacterial and 5% viral co-infections [bib_ref] Saudi Critical Care Trials G (2017) Critically ill patients with the middle..., Arabi [/bib_ref]. Co-infection with Staphylococcus aureus is common with influenza pneumonia and can be especially virulent [bib_ref] Update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenzaa, Uyeki [/bib_ref]. Recent clinical practice guidelines recommend initiating empiric antibacterial therapy in adults with community-acquired pneumonia who test positive for influenza [bib_ref] Update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenzaa, Uyeki [/bib_ref]. Data from critically ill patients demonstrate secondary infection in about 11% of cases, although the numbers are small. Isolated organisms included gram-negative organisms such as K. pneumoniae, P. aeruganosa, and S. marcescens. On the basis of these limited data it is difficult to determine patterns of superinfection, including the risk of S. aureus infection, commonly seen in influenza. In patients with COVID-19 and hypoxic respiratory failure requiring mechanical ventilation, the panel suggest empiric antimicrobial treatment, on the basis that superinfection is reasonably common in this population and may to lead to a substantial increase in mortality, as in pandemic influenza [bib_ref] Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in..., Rice [/bib_ref] [bib_ref] Pandemic influenza A (H1N1): pathology and pathogenesis of 100 fatal cases in..., Shieh [/bib_ref] [bib_ref] Do specific virus-bacteria pairings drive clinical outcomes of pneumonia?, Mccullers [/bib_ref]. Therefore, critically ill patients with suspected or confirmed COVID-19 should be treated with empiric antimicrobial therapy in accordance with the clinical syndrome (e.g. community-acquired or hospital-acquired pneumonia). Secondary infections occur in patients with COVID-19, but the incidence is unknown given the very limited data [bib_ref] Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis, Rodriguez-Morales [/bib_ref]. These infections should be treated according to clinical and microbiological data. ## Recommendation ## 44. For critically ill adults with COVID-19 who develop fever, we suggest using acetaminophen/paracetamol for temperature control, over no treatment. Weak recommendation, low-quality evidence. ## Rationale The majority of patients with COVID-19 develop fever during hospitalization (92% of those with severe disease). In the largest report from China, the median temperature across 1099 patients was 38.3 °C (IQR 37.8-38.9) [bib_ref] China Medical Treatment Expert Group for C (2020) Clinical characteristics of Coronavirus..., Guan [/bib_ref]. Data from critically ill patients in general are available. We reviewed the literature and identified 12 RCTs (1785 patients) that examined the effect of fever control in the critically ill population, excluding neurological indication for temperature control [bib_ref] The effect of antipyretic therapy upon outcomes in critically ill patients: a..., Schulman [/bib_ref] [bib_ref] Acetaminophen for fever in critically ill patients with suspected infection, Young [/bib_ref] [bib_ref] Effect of ibuprofen in patients with severe sepsis: a randomized, doubleblind, multicenter..., Haupt [/bib_ref] [bib_ref] The effects of ibuprofen on the physiology and survival of patients with..., Bernard [/bib_ref] [bib_ref] Is it worth treating fever in intensive care unit patients? Preliminary results..., Gozzoli [/bib_ref] [bib_ref] Effects of lornoxicam on the physiology of severe sepsis, Memis [/bib_ref] [bib_ref] Fever control using external cooling in septic shock: a randomized controlled trial, Schortgen [/bib_ref] [bib_ref] Assessment of the safety and feasibility of administering antipyretic therapy in critically..., Niven [/bib_ref] [bib_ref] Body temperature control in patients with refractory septic shock: too much may..., Yang [/bib_ref] [bib_ref] Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis Study G..., Janz [/bib_ref] [bib_ref] Respective impact of lowering body temperature and heart rate on mortality in..., Schortgen [/bib_ref] ; active temperature management (pharmacologic or non-pharmacologic) did not reduce the risk of death (RR 1.03, 95% CI 0.81-1.31), ICU length of stay (MD − 0.07 days, 95% CI − 0.70-0.56), but it was effective in reducing body temperature (MD − 0.36 °C, 95% CI − 0.42 lower to − 0.29). Given the safety of acetaminophen and lack of harm in the body of evidence, increasing patient comfort through fever management maybe important. Therefore, we issued a suggestion for clinicians to consider using pharmacologic agents for controlling fever in COIVD-19 patients. The use of non-steroidal anti-inflammatory drugs to treat fever in patients with COVID-19 continues to be debated. Until more evidence is available, we suggest using acetaminophen/paracetamol to treat fever. ## Recommendation ## 45. In critically ill adults with COVID-19, we suggest against the routine use of standard intravenous immunoglobulins (IVIG). Weak recommendation, low-quality evidence. ## Rationale The use of intravenous immunoglobulin (IVIG) has been reported in several series of COVID-19 patients, but no efficacy data are available [bib_ref] Clinical characteristics of imported cases of COVID-19 in Jiangsu Province: a multicenter..., Wu [/bib_ref]. In the absence of adequate titers of neutralizing antibodies, standard intravenous immunoglobulin is unlikely to have a biologic effect in COVID-19. While IVIG may have immunomodulatory actions, its use can, rarely, also be associated with an increased risk of serious adverse events including anaphylactic reactions, aseptic meningitis, renal failure, thromboembolism, hemolytic reactions, transfusion-related lung injury, and other late reactions [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref]. Preparations of anti-SARS-CoV-2 polyclonal or monoclonal antibodies are being developed. However, data from recent trials on the use of antibody-based therapies (immune plasma, hyperimmune globulin, monoclonal antibody to hemagglutinin stalk) [bib_ref] Adverse effects of human immunoglobulin therapy, Stiehm [/bib_ref] in hospitalized seasonal influenza patients did not demonstrate improvement in outcomes [bib_ref] Critical care management of adults with community-acquired severe respiratory viral infection, Arabi [/bib_ref]. ## Recommendation ## 46. In critically ill adults with COVID-19, we suggest against the routine use of convalescent plasma. Weak recommendation, low-quality evidence. ## Rationale Convalescent plasma obtained from patients who have recovered from COVID-19 has been suggested as a potential therapy that may provide passive immunity from SARS-CoV2-specific antibodies [bib_ref] The convalescent sera option for containing COVID-19, Casadevall [/bib_ref]. Convalescent plasma has been used to treat several other viral infections, including those caused by SARS coronavirus, avian influenza A (H5N1) virus, and influenza A (H1N1) pdm09 virus [bib_ref] Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients..., Hung [/bib_ref] [bib_ref] SARS: systematic review of treatment effects, Stockman [/bib_ref] [bib_ref] Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A..., Hung [/bib_ref] [bib_ref] Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?, Luke [/bib_ref] [bib_ref] Successful treatment of avian influenza with convalescent plasma, Kong [/bib_ref]. A recent meta-analysis of observational studies using passive immunotherapy for the treatment of severe acute respiratory infections of viral etiology suggests that convalescent plasma therapy was associated with reduction in mortality (OR 0.25, 95% CI 0.14-0.45) [bib_ref] The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of..., Mair-Jenkins [/bib_ref]. During the current outbreak in China, convalescent plasma was used in some patients with COVID-19. However, data on the efficacy and safety of convalescent plasma are limited, and the target for sufficient levels of neutralizing antibody titers against SARS-CoV-2 is unknown. A study on MERS concluded that use of convalescent plasma might be feasible but was challenging due to a small pool of potential donors with sufficiently high antibody titers [bib_ref] Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia, Arabi [/bib_ref]. An RCT in patients with confirmed Ebola virus disease showed that convalescent plasma, with unknown levels of neutralizing antibodies, was not associated with improvement in survival [bib_ref] Evaluation of convalescent plasma for ebola virus disease in Guinea, Van Griensven [/bib_ref]. Another RCT in patients with seasonal influenza treated with high-titer versus low-titer anti-influenza immune plasma was terminated for futility because of the lack of effect on the primary outcome measured by a 6-point ordinal scale of clinical status on Day 7 [bib_ref] Anti-influenza immune plasma for the treatment of patients with severe influenza A:..., Beigel [/bib_ref]. Given the lack of convincing evidence from RCTs and the uncertainty surrounding the optimal preparation of convalescent plasma and its safety, we suggest that it should not be routinely used in treating patients with COVID-19 until more evidence is available. ## Recommendation ## 47. In critically ill adults with COVID-19: 47.1. We suggest against the routine use of lopinavir/ritonavir (weak recommendation, low-quality evidence). ## 47.2. There is insufficient evidence to issue a recommendation on the use of other antiviral agents in critically ill adults with COVID-19. ## Rationale The prolonged detection of SARS-CoV-2 RNA in the respiratory tract and sometimes other sites of seriously ill COVID-19 patients provides the rationale for administration of antiviral agents to reduce replication in efforts to improve clinical outcomes. At present, no direct-acting antivirals have been proven to inhibit replication or provide clinical benefit in COVID-19 or MERS patients. A considerable number of agents approved for other indications have been proposed for use, but the comments below address the most promising ones. Several others are undergoing testing (e.g. arbidol , favipiravir, ribavirin, traditional Chinese medicines, inhaled interferons), alone or in combinations, and in one or more countries. Lopinavir is an antiretroviral protease inhibitor used in combination with ritonavir to ensure adequate lopinavir exposure for the treatment of human immunodeficiency virus (HIV) infection [bib_ref] Efficacy and biological safety of lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients:..., Huang [/bib_ref]. Because it was found to show in vitro activity against SARS-CoV, lopinavir/ritonavir was administered, in combination with high-dose oral ribavirin and a tapering course of systemic corticosteroids, in a cohort of 41 patients with SARS, and was found to be associated with significantly fewer adverse clinical outcomes (ARDS or death) compared with ribavirin alone used in 111 historical controls that received ribavirin and corticosteroids [bib_ref] Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical..., Chu [/bib_ref]. In a high-throughput screening for antiviral compounds, lopinavir inhibited replication of MERS-CoV in vitro [bib_ref] Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle..., De Wilde [/bib_ref]. In an animal model of MERS-CoV infection, treatment with lopinavir/ritonavir or IFN-β1b was associated with virologic, histologic and clinical improvement versus placebo [bib_ref] Treatment With lopinavir/ritonavir or interferon-beta1b improves outcome of MERS-CoV infection in a..., Chan [/bib_ref]. Lopinavir/ritonavir in combination with interferon beta 1-b is being tested in an RCT in MERS-CoV patients [bib_ref] Critical Care Trials g (2020) Treatment of Middle East respiratory syndrome with..., Arabi [/bib_ref]. This combination was considered the second candidate in a WHO research prioritization list of therapeutic agents. The drug has a generally good safety profile, but may have interactions with many drugs commonly used in critically ill patients (http://www.covid 19-drugi ntera ction s.org/). A recent RCT compared the use of lopinavir/ritonavir to usual care in 199 hospitalized patients with COVID-19 in China [bib_ref] A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19, Cao [/bib_ref]. In this trial, lopinavir/ritonavir did not significantly reduce 28-day mortality (RD − 5.8%; 95% CI − 17.3 to 5.7) or time to clinical improvement (MD 1.31 days, 95% CI 0. . In addition, lopinavir/ritonavir was associated with more adverse events [bib_ref] A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19, Cao [/bib_ref]. This trial is the only available direct evidence on the use of lopinavir/ritonavir in patients with COVID-19, however, it has several limitations. The trial was unblinded and it enrolled a small number of patients (n = 199) with a small number of events (44 deaths in total), which limits our confidence in its results. Nevertheless, the routine use of lopinavir/ritonavir in critically ill patients is probably not warranted, and a weak recommendation against the routine use of lopinavir/ritonavir in critically ill COVID-19 patients is reasonable. Lopinavir/ritonavir is one of the arms in a planned WHO core treatment protocol for hospitalized patients with COVID-19, and in the REMAP-CAP (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia) trial (NCT02735707) The results of ongoing trials will help increase the precision of estimates and the certainty in the evidence. Remdesivir is the prodrug of an adenosine analog, which incorporates into nascent viral RNA chains and results in premature termination. It was considered the most promising drug in an informal consultation on research prioritization of candidate therapeutic agents by WHO. Currently, there are published case reports but no published trials on the use of remdesivir in COVID-19. Remdesivir demonstrated effective inhibition of SARS-CoV-2, MERS-CoV, and SARS-CoV in in vitro studies [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref]. Furthermore, studies in animal models of MERS-CoV showed that it was more effective than control and superior to lopinavir/ritonavir combined with systemic IFN-β [bib_ref] Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta..., Sheahan [/bib_ref] [bib_ref] Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of..., De Wit [/bib_ref]. Although intravenous remdesivir appears to adequately tolerated, a recent RCT showed that it was less effective than several antibody therapies in Ebola virus disease [bib_ref] A randomized, Mulangu [/bib_ref]. There are several ongoing RCTs that aim to examine the efficacy and safety of intravenous remdesivir for severe COVID-19 (clinicaltrials.gov NCT04257656) and for mild and moderate COVID-19 (clinicaltrials.gov NCT04252664). Another trial sponsored by the National Institute of Allergy and Infectious Diseases is recruiting patients in USA (clinicaltrials.gov NCT04280705). We will update our guidelines as new evidence emerges. ## Recommendation ## 48. There is insufficient evidence to issue a recommendation on the use of recombinant rIFNs, alone or in combination with antivirals, in critically ill adults with COVID-19. ## Rationale Recombinant interferon, often combined with ribavirin therapy, has been used in patients with MERS and SARS [bib_ref] SARS: systematic review of treatment effects, Stockman [/bib_ref] [bib_ref] Inhibition of novel beta coronavirus replication by a combination of interferon-alpha2b and..., Falzarano [/bib_ref] [bib_ref] Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques, Falzarano [/bib_ref] [bib_ref] Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)-possible lessons from a..., Momattin [/bib_ref]. Different preparations of recombinant rIFNs (rIFN-α2a, rIFN-α2b, rIFN-β1a and rIFN-β1b) have shown activity against MERS-CoV in Vero and LLC-MK2 cells, and in a rhesus macaque model of MERS-CoV infection [bib_ref] Inhibition of novel beta coronavirus replication by a combination of interferon-alpha2b and..., Falzarano [/bib_ref] [bib_ref] Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques, Falzarano [/bib_ref] [bib_ref] Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome..., Hart [/bib_ref]. The largest cohort of critically ill patients with MERS showed that rIFN-α2a, rIFN-α2b, rIFN-β1a and ribavirin were not associated with lower mortality (OR 1.03, 95% CI . or reduced viral clearance when adjusted for time-varying covariables [bib_ref] Ribavirin and interferon therapy for critically ill patients with middle east respiratory..., Arabi [/bib_ref]. The relative effectiveness of different interferons against SARS-CoV-2 is unknown at this point. In vitro data showed that rIFN-β displayed the strongest MERS-CoV inhibition among different rIFN preparations [fig_ref] Figure 2: Summary of recommendations on the initial management of hypoxic COVID-19 patients [/fig_ref] , rIFN-β), at 41 times lower than the previously reported 50% inhibitory concentration (IC50) of rIFN-α2b [bib_ref] Interferon-beta and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome..., Hart [/bib_ref] [bib_ref] Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus, Chan [/bib_ref]. An RCT to examine the effect of a combination of lopinavir/ritonavir and rIFN-β-1b on mortality of hospitalized patients with MERS is currently recruiting patients [bib_ref] Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and..., Arabi [/bib_ref]. Unpublished data indicate that IFN-β inhibits SARS-C0V-2 in cell culture, and IFNs have been prioritized for study in COVID-19 by the WHO. ## Recommendation ## 49. There is insufficient evidence to issue a recommendation on the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19. ## Rationale Chloroquine and its metabolite, hydroxychloroquine, are antimalarial agents that have demonstrated antiviral effects on SARS-CoV and SARS-CoV-2 in vitro [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref] [bib_ref] Chloroquine is a potent inhibitor of SARS coronavirus infection and spread, Vincent [/bib_ref] [bib_ref] In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine..., Yao [/bib_ref]. Prior studies found inhibitory effects of chloroquine for multiple RNA viruses in vitro, but RCTs in treatment of dengue and chikungunya virus infections and of influenza prophylaxis failed to demonstrate antiviral or clinical benefits [bib_ref] Of chloroquine and COVID-19, Touret [/bib_ref]. In one non-human primate model of chikungunya infection, it was shown that chloroquine's immunomodulatory effects were associated with delayed immune responses, higher levels of viral replication, and worse illness. A news briefing suggested that its use in more than 100 patients showed "that it was superior to the control in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus negative conversion, and shortening the disease course", but the data have not been published yet [bib_ref] Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated..., Gao [/bib_ref]. A recent consensus document recommended chloroquine phosphate 500 mg twice daily for minimum of 5 days, with dose modifications if severe gastrointestinal side effects occur . Since chloroquine is not available in some countries, hydroxychloroquine is an alternative. A recent study in China explored various dosing regimens of chloroquine and hydroxychloroquine using physiologicallybased pharmacokinetic models [bib_ref] In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine..., Yao [/bib_ref]. The study found hydroxychloroquine to be more potent than chloroquine in inhibiting SARS-CoV-2 in vitro. Based on these models, a hydroxychloroquine loading dose of 400 mg twice daily followed by 200 mg twice daily for 4 days was recommended [bib_ref] In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine..., Yao [/bib_ref]. A recent systematic review found no published studies in COVID-19 patients [bib_ref] A systematic review on the efficacy and safety of chloroquine for the..., Cortegiani [/bib_ref]. Pending the results of ongoing trials, we were unable to issue a recommendation for or against chloroquine. ## Recommendation ## 50. There is insufficient evidence to issue a recommendation on the use of tocilizumab in critically ill adults with COVID-19. ## Rationale Tocilizumab is a humanized immunoglobulin that functions in the immune response and blocks IL-6 receptor binding to IL-6. It has been approved for CRS and other inflammatory conditions related to IL-6 related inflammation, such as rheumatoid arthritis and juvenile idiopathic arthritis [bib_ref] Two years of sarilumab in patients with rheumatoid arthritis and an inadequate..., Genovese [/bib_ref] [bib_ref] Efficacy and safety of tocilizumab in patients with systemiconset juvenile idiopathic arthritis:..., Yokota [/bib_ref] [bib_ref] FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced..., Le [/bib_ref]. Severely ill patients with COVID-19 may have an extreme immune response leading to severe respiratory failure. In such cases, inhibition of IL-6 may help attenuate the cytokine release syndrome by reducing cytokine concentrations and acute phase reactant production. Ongoing trials of tocilizumab will help address the safety and efficacy of this therapy in COVID-19. From the rheumatoid arthritis literature, a systematic review and meta-analysis of 6 RCTs (3 with 8/mg dose and 3 with 4 mg/kg dose) showed an increased risk of adverse events compared with control treatment (OR 1.53, 95% CI 1.26-1.86), and an increased risk of infections (OR 1.30, 95% CI 1.07-1.58) [bib_ref] Risk of adverse events including serious infections in rheumatoid arthritis patients treated..., Campbell [/bib_ref]. Another systematic review and meta-analysis of RCTs on tocilizumab in rheumatoid arthritis found an increased risk of infectious respiratory adverse events (RR 1.53, 95% CI 1.04-2.25) [bib_ref] Tocilizumab and the risk of respiratory adverse events in patients with rheumatoid..., Geng [/bib_ref]. Since we have no data on the safety or efficacy of tocilizumab in COVID-19, we were unable to issue a recommendation. ## Other agents Nafamostat is a synthetic serine protease inhibitor and a potent inhibitor of MERS CoV. Nitazoxanide is an antiprotozoal agent with antiviral potential against several respiratory viruses including influenza, parainfluenza, respiratory syncytial virus, and rhinovirus. An in vitro study showed that both nafamostat and nitazoxanide inhibited SARS-CoV-2 [bib_ref] Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in..., Wang [/bib_ref]. An RCT in patients with acute uncomplicated influenza demonstrated that the use of nitazoxanide reduced the duration of symptoms [bib_ref] Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a..., Haffizulla [/bib_ref]. However, in hospitalized patients with severe acute respiratory infection in Mexico, nitazoxanide was not found to be superior to placebo [bib_ref] Mexico Emerging Infectious Diseases Clinical Research N (2019) Efficacy and safety of..., Gamino-Arroyo [/bib_ref]. ## Compliance with ethical standards ## Conflicts of interest Dr. Yaseen Arabi is the principal investigator on a clinical trial for lopinavir/ ritonavir and interferon in Middle East respiratory syndrome (MERS) and he was a nonpaid consultant on antiviral active for MERS-coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is an investigator on REMAP-CAP trial and is a Board Members of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Dr. Eddy Fan declared receiving consultancy fees from ALung Technologies and MC3 Cardiopulmonary. Dr. Maurizio Cecconi declared consultancy work with Edwards Lifesciences, Directed Systems, and Cheetah Medical. Dr. Lennie Derde is the NVIC (Dutch National ICU society) chair of Taskforce Infectious Diseases (standing committee), member of ESICM Coronavirus Taskforce (started with this outbreak), chair ESICM Clinical Training Committee, all are unpaid positions. Dr. Frederick Hyden is non-compensated consultant to Gilead Sciences (antivirals for RVIS including remdesivir), Regeneraon (monoclonals for RVIs including MERS), and SAB Biotherapeutics (polyclonal antibodies for RVIs including MERS). Other authors declared no conflict of interest. ## Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. [fig] Figure 1: COVID-19 guideline development process [/fig] [fig] Figure 2: Summary of recommendations on the initial management of hypoxic COVID-19 patients [/fig] [table] Table 1: Implications of different recommendations to key stakeholders [/table] [table] Table 2: Recommendations and statementsFor intubated and mechanically ventilated adults with suspicion of COVID-19: With regard to lower respiratory samples, we suggest obtaining endotracheal aspirates in preference to bronchial wash or bronchoalveolar lavage samples In adults with COVID-19 and shock, we suggest using dynamic parameters skin temperature, capillary refilling time, and/or serum lactate measurement over static parameters in order to assess fluid responsiveness Weak 9For the acute resuscitation of adults with COVID-19 and shock, we suggest using a conservative over a liberal fluid strategy Weak 10 For the acute resuscitation of adults with COVID-19 and shock, we recommend using crystalloids over colloids Weak11 For the acute resuscitation of adults with COVID-19 and shock, we suggest using buffered/balanced crystalloids over unbalanced crystalloids Weak 12 For the acute resuscitation of adults with COVID-19 and shock, we recommend against using hydroxyethyl starches Strong 13 For the acute resuscitation of adults with COVID-19 and shock, we suggest against using gelatins Weak 14 For the acute resuscitation of adults with COVID-19 and shock, we suggest against using dextrans Weak 15 For the acute resuscitation of adults with COVID-19 and shock, we suggest against the routine use of albumin for initial resuscitation Weak 16 For adults with COVID-19 and shock, we suggest using norepinephrine as the first-line vasoactive agent, over other agents Weak 17 If norepinephrine is not available, we suggest using either vasopressin or epinephrine as the first-line vasoactive agent, over other vasoactive agents, for adults with COVID-19 and shock Weak 18 For adults with COVID-19 and shock, we recommend against using dopamine if norepinephrine is available Strong 19 For adults with COVID-19 and shock, we suggest adding vasopressin as a second-line agent, over titrating norepinephrine dose, if target mean arterial pressure (MAP) cannot be achieved by norepinephrine alone Remark: A typical corticosteroid regimen in septic shock is intravenous hydrocortisone 200 mg per day administered either as an infusion or intermittent doses [/table] [table] Table 3: Epidemiological characteristics in recent COVID-19 reportsCFR case fatality rate, ICU intensive care unit, NIPPV non-invasive positive pressure ventilation [/table]	None	https://link.springer.com/content/pdf/10.1007/s00134-020-06022-5.pdf	None
2474ecaced635e91cde8daf933dffcb42ca56757	pubmed	Training Guidelines for Endovascular Ischemic Stroke Intervention: An International multi-society consensus document	Training Guidelines for Endovascular Ischemic Stroke Intervention: An International multi-society consensus document # Background Ischemic stroke is a leading cause of death and disability worldwide. Much of the long-term disability occurs in patients with Emergent Large Vessel Occlusion (ELVO). In fact, in these patients, occlusion of a major intracerebral artery results in a large area of brain injury often resulting in death or severe disability. [bib_ref] Prognosis of untreated strokes due to anterior circulation proximal intracranial arterial occlusions..., Lima [/bib_ref] Until recently, intravenous tissue plasminogen activator (t-PA) was the only proven treatment for ELVO. However, the landscape of stroke treatment has changed with the publication of five randomized multicenter controlled clincal trials. These trials provide Class 1, Level A evidence that endovascular thrombectomy (ET) is the standard of care for patients with ELVO. In particular, thrombectomy results in significantly better clinical outcomes compared to best medical therapy in patients with acute occlusion of the intracranial internal carotid artery (ICA) and/or M1 segment of the middle cerebral artery (MCA). [bib_ref] A randomized trial of intraarterial treatment for acute ischemic stroke, Berkhemer [/bib_ref] [bib_ref] Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke, Goyal [/bib_ref] [bib_ref] Thrombectomy within 8 hours after symptom onset in ischemic stroke, Jovin [/bib_ref] [bib_ref] Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke, Saver [/bib_ref] [bib_ref] Endovascular therapy for ischemic stroke with perfusion-imaging selection, Campbell [/bib_ref] These results have led to guideline recommendations advocating for endovascular treatment in addition to t-PA for patients with ELVO. In addition, ET is now offered as first line therapy for patients that are not eligible for intravenous thrombolysis. 7-9 However, achieving the best possible clinical outcomes with endovascular stroke treatment mandates structured training and education of those physicians who are providing endovascular stroke treatment. On this regard, a recent meta-analysis of these five clinical trials showed that the vast majority of thrombectomies were performed by experienced neurointerventionalists. These include interventional neuroradiologists, endovascular neurosurgeons, and interventional neurologists who routinely perform neuroendovascular procedures. [bib_ref] Endovascular Thrombectomy for Acute Ischemic Stroke: A Meta-analysis, Badhiwala [/bib_ref] None of the studies allowed physicians without previous experience in mechanical thrombectomy to enroll patients. The centers participating in these trials offered endovascular stroke therapy 24 hours a day (with the exception of those in the EXTEND-IA trial) with expertise in vascular neurology and neurocritical care in a comprehensive stroke center. On-site expertise in vascular neurology and neurocritical care is paramount to achieving good clinical outcomes. Geographical limitations to rapid access to acute stroke centers providing mechanical thrombectomy have led some to suggest physicians without prior experience or formal neuroendovascular training should consider providing coverage for these procedures. A multidisciplinary British Intercollegiate Stroke Working Party put forth a document outlining the safe delivery of mechanical thrombectomy, which highlights that operators should not normally carry out procedures with which they are unfamiliar and that they should recognize ad-hoc arrangements are not in the best interest of patients.It is also important to recognize that modern endovascular stroke therapy focuses on direct clot removal with mechanical devices, as compared with previous paradigms where intra-arterial thrombolytic infusion was an acceptable treatment option for large vessel occlusions. [bib_ref] Endovascular therapy after intravenous t-PA versus t-PA alone for stroke, Broderick [/bib_ref] The technical skills needed to safely deliver devices into the intracranial circulation are significantly more involved than simply placing a catheter for medication infusion. Catheter skills from other circulations do not replace the need for formal training in safe intracranial microcatheter navigation and device placement. Acute ischemic stroke is a complex disease and successful endovascular treatment is based on the comprehensive ability to rapidly integrate multiple pieces of information, including: the patient's history, clinical examination, neuroradiological studies, and to subsequently formulate a treatment plan. Both patient selection and procedural expertise are critical to achieve a good clinical outcome. Hence, there is a clear rationale for formal training in both clinical neuroscience and interventional neuroradiology. The purpose of this document is to define what constitutes adequate training for physicians who can provide endovascular treatment for acute ischemic stroke patients. These training guidelines are modeled after prior standards of training documents such as the training, competency and credentialing standards for diagnostic cerebral angiography, carotid stenting and cerebrovascular intervention 13 and the performance and training standards for endovascular ischemic stroke treatment, [bib_ref] Performance and training standards for endovascular ischemic stroke treatment, Meyers [/bib_ref] written and endorsed by multispecialty groups. In addition, the importance of organ specific training, rigorous quality improvement benchmarks, and minimum volume requirements needed to maintain high quality care has been extensively described for acute myocardial infarction, an analogous time sensitive disease. [bib_ref] Update of the Clinical Competence Statement on Coronary Artery Interventional Procedures: a..., Harold [/bib_ref] This document represents the cumulative work of the societies listed below, and represents an international consensus on adequate training to safely and effectively perform these procedures: [formula] American [/formula] ## Physician qualifications Physicians providing intra-arterial treatment for acute stroke are required to have appropriate training and experience for the performance of neuroangiography and interventional neuroradiology. We recognize that the specific training pathways may differ across nations, but the consensus is to mandate adequate training to perform emergent endovascular stroke intervention. These cognitive requirements consist of baseline training and qualifications as well as ongoing professional education, which are essential for safe and efficient patient management. It is also important to point out that these qualifications are for new practitioners who are not currently performing acute stroke intervention with mechanical thrombectomy. We understand that there are current practitioners (who are board certified or board eligible in radiology, neurology or neurosurgery) who may have trained prior to the establishment of formal training pathways, and have acquired the necessary skills listed below to safely and effectively treat these complex patients. We would still expect the same requirements for maintenance of qualifications as listed below. ## I. baseline training and qualifications 1. Residency training (in radiology, neurology or neurosurgery) which should include documented training in the diagnosis and management of acute stroke, the interpretation of cerebral arteriography and neuroimaging under the supervision of a board-certified neuroradiologist, neurologist or neurosurgeon with subsequent board eligibility or certification. The residency program and supervising physicians should be accredited according to national standards as they pertain to the countries involved. Those physicians who did not have adequate such training during their residencies must spend an additional period (at least one year) by training in clinical neurosciences and neuroimaging, focusing on the diagnosis and management of acute stroke, the interpretation of cerebral arteriography and neuroimaging prior to their fellowshsip in neuroendovascular interventions. ## And ## Dedicated training in interventional neuroradiology (also termed Endovascular Neurosurgery or Interventional Neurology) under the direction of a Neurointerventionalist (with neuroradiology, neurology or neurosurgical training background), at a high-volume center. It is preferred that this is a dedicated time (minimum of one year), which occurs after graduating from residency (i.e., a fellowship). A training program accredited by a national accrediting body is also strongly preferred but not required. Published standards exist for various countries. [bib_ref] WFITN recommendations for certification and maintenance of competence in interventional neuroradiology. (Therapeutic..., Picard [/bib_ref] [bib_ref] Japanese society of neuro-endovascular treatment specialist qualification system. Six years' experience and..., Hyogo [/bib_ref] [bib_ref] Training of future interventional neuroradiologists: the European approach, Flodmark [/bib_ref] Within these programs, specific training for intra-arterial therapy for acute ischemic stroke should be performed, including obtaining appropriate access even in challenging anatomy, microcatheter navigation in the cerebral circulation, knowledge and training of the use of stroke specific devices and complication avoidance and management. While various national standards will have differing procedure requirements, we encourage practitioners to meet their national minimum procedural and training standards. Fellowships which are not accredited by national credentialing bodies should still have adequate training to meet their local minimum procedure requirements. In addition, we expect that minimum training numbers for stroke thrombectomy may increase in future revisions of these standards given the recent developments in the field. ## Ii. maintenance of physician qualifications It is vital that the physician have ongoing stroke specific continuing medical education. A minimum of 16 hours of stroke specific education every 2 years is suggested. Individual physician outcomes should conform to national standards and institutional requirements. In addition, the physician should participate in an ongoing quality assurance and improvement program. The goals of this quality assurance program for stroke therapy would be to monitor outcomes both in the periprocedural period and at 90 days. The quality assurance program must review all emergency interventional stroke therapy patients. In addition, participation in a national quality improvement registry, when available, is also encouraged. Outcomes should be tracked and recorded. While threshold levels for recanalization, complication rates, etc. have yet to be established, we suggest the following as a minimum: ## Hospital requirements Successful treatment of the ELVO patient does not occur in a vacuum, but rather with the framework of a multi-disciplinary team. As such, we feel it is critical that the patients be treated in a center, which has 24/7 access to the following: ## Summary We, as a group of international multi-disciplinary NeuroInterventional societies involved in the endovascular management of acute ischemic stroke, have put forth these training guidelines. We believe that a neuroscience background, dedicated neurointerventional training, and stringent peer review and quality assurance processes are critical to ensuring the best possible patient outcomes. Well-trained neurointerventionalists are a critical component of an organized and efficient team needed to deliver clinically effective mechanical thrombectomy for acute ischemic stroke patients. [table] 1: Angiography suites suitably equipped to handle these patients, as well as equipment and capability to handle the complications. 2. Dedicated stroke and intensive care units (preferably dedicated neuro-intensive care unit), staffed by physicians with specific training in those fields. 3. Vascular neurology and Neurocritical care expertise. 4. Neurosurgery expertise, including vascular neurosurgery 5. All relevant neuroimaging modalities (CT/CTA, MR/MRA, Trans-cranial Doppler [TCD]), including 24/7 access to CT and MRI. [/table]	None	https://journals.sagepub.com/doi/pdf/10.1177/1591019916636801	Contributors American Academy of Neurological Surgeons/ Congress of Neurological Surgeons (AANS/CNS): S.D. Lavine, K Cockroft, B Hoh, N Bambakidis, AA Khalessi, H Woo, H Riina. A. Siddiqui American Society of Neuroradiology (ASNR): J. A. Hirsch Asian Australasian Federation of Interventional and Therapeutic Neuroradiology (AAFITN): W. Chong Australian and New Zealand Society of Neuroradiology - Conjoint Committee for Recognition of Training in Interventional Neuroradiology (CCINR) representing the RANZCR (ANZSNR), ANZAN and NSA: H. Rice, J Wenderoth, P Mitchell, A Coulthard, TJ Signh, C Phatorous, M Khangure Canadian Interventional Neuro Group (CING): P. Klurfan, K. Terbrugge, D Iancu, T. Gunnarsson European Society of Neuroradiology (ESNR); O. Jansen, M. Muto European Society of Minimally Invasive Neurologic Therapy (ESMINT): I. Szikora L. Pierot P. Brouwer J. Gralla, S. Renowden, T. Andersson, J. Fiehler, F. Turjman, P. White, AC Januel, L Spelle, Z Kulcsar, R Chapot, L Spelle, A Biondi, S Dima, C Taschner, M Szajner, A Krajina Japanese Society for Neuroendovascular therapy (JSNET): N.Sakai, Y. Matsumaru, S. Yoshimura Sociedad Ibero Latino Americana de Neuroradiologica (SILAN): O.Diaz, P.Lylyk Society of NeuroInterventional Surgery (SNIS): M.V. Jayaraman, A. Patsalides, C. D. Gandhi, S.K.Lee, T. Abruzzo, B. Albani, S. A. Ansari, A.S. Arthur, B.W. Baxter, K.R.Bulsara, M. Chen, J.E.Delgado-Almandoz, J.F.Fraser, D.V. Heck, S.W. Hetts, M.S.Hussain, R.P. Klucznik, T.M. Leslie-Mawzi, W.J.Mack, R.A.McTaggart, P.M.Meyers, J. Mocco, C.J.Prestigiacomo, G.L.Pride, P.A.Rasmussen, R.M.Starke, P.J.Sunenshine, R.W.Tarr, D.F.Frei Society of Vascular and Interventional Neurology (SVIN): M.Ribo, R.G.Nogeuira, O.O. Zaidat, T. Jovin, I. Linfante, D. Yavagal, D. Liebeskind, R. Novakovic World Federation of Interventional and Therapeutic Neuroradiology (WFITN): S. Pongpech, G Rodesch, M Soderman, K ter Brugge, A. Taylor, T Krings, D Orbach, A. Biondi, L Picard, D C Suh, M. Tanaka, HQ Zhang
19b32d9ff8462cf395207921efc43b40b6375d59	pubmed	None	Coronavirus disease 2019 is an emerging infectious disease caused by a novel SARS-CoV-2 pathogen. Its capacity for human-to-human transmission through respiratory droplets, coupled with a high-level of population mobility, has resulted in a rapid dissemination worldwide. Healthcare workers have been particularly exposed to the risk of infection and represent a significant proportion of COVID-19 cases in the worst affected regions of Europe.Recommendations for interventional pulmonology during COVID-19 outbreak 387 procedures to ensure safety of both patients and staff. Several recommendation documents were published at the beginning of the pandemic, but as the situation evolves, our thoughts should not only focus on the present, but should also reflect on how we are going to deal with the presence of the virus in the community until there is a vaccine or specific treatment available. It is in this sense that this document aims to guide interventional pulmonology throughout this period, providing a set of recommendations on how to perform bronchoscopy or pleural procedures safely and efficiently. # Introduction Coronavirus Disease 2019 (COVID-19), a new infectious disease that emerged in early December 2019 in Wuhan (China), 1 is triggered by a novel pathogen with phylogenetic similarity to what caused the severe acute respiratory syndrome (SARS) outbreak in 2003, and was called SARS-CoV-2. [bib_ref] A novel coronavirus from patients with pneumonia in China, Zhu [/bib_ref] Its capacity for human-to-human transmission and international air travel facilitated the rapid dissemination on an unprecedented scale to the rest of the world. [bib_ref] Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins..., Lu [/bib_ref] In Italy, the latest figures reported that 9% of COVID-19 cases were health care workers (HCW), while in Spain the rate of medical staff infected reached 26%, the highest in Europe.In Portugal, by 12th May 2020, 11.3% of infections occurred in HCW. There are at least two explanations for such a high number of infected personnel. First, the lack of proper personal protective equipment (PPE) at the beginning of the epidemic, when assisting both confirmed and suspected patients with COVID-19. Second, the duration of exposure to infected patients undergoing aerosol-generating procedures, such as non-invasive ventilation (NIV) and bronchoscopy, directly resulting in a significant increase in the risk of transmission to HCW. The Portuguese Society of Pulmonology recently issued a set of recommendations for bronchoscopic procedures, 7 shortly after the diagnosis of the first cases in Portugal. The document aimed to guarantee the protection of both patients and medical practicioners, and to ensure that the healthcare workforce would be conserved to fullfill their mission throughout the period. Since then, a significant amount of scientific evidence has been accumulated; so, the present document gives an update of the available literature, providing practical suggestions for pulmonologists undergoing bronchoscopy or pleural procedures in the setting of the current and post-pandemic phases. ## Risk of transmission Respiratory droplets comprise the main route of SARS-CoV-2 transmission, although airborne transmission is also possible through aerosol-generating procedures, such as bronchoscopy. [bib_ref] Airborne transmission of severe acute respiratory syndrome coronavirus-2 to healthcare workers: a..., Wilson [/bib_ref] One study during the H1N1 pandemic provided experimental evidence that bronchoscopic procedures increases more than 4 times the viral copy number per litre in positive air samples. [bib_ref] Influenza aerosols in UK hospitals during the H1N1 (2009) pandemic----the risk of..., Thompson [/bib_ref] While the heavy droplets rapidly settle, aerosol particles are much smaller (<5−10 m) and are dispersed in the air over extensive distances, posing a considerable risk of infection in enclosed spaces, specially if poorly ventilated. [bib_ref] Recognition of aerosol transmission of infectious agents: a commentary, Tellier [/bib_ref] The contribution of asymptomatic carriers has also been subject of debate. [bib_ref] Estimating the asymptomatic proportion of coronavirus disease 2019 (COVID-19) cases on board..., Mizumoto [/bib_ref] A significant proportion of them have lung abnormalities on chest CT scans [bib_ref] SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients, Zou [/bib_ref] and a high level of viral shedding may be detected in presymptomatic patients, [bib_ref] SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients, Zou [/bib_ref] so it is likely that transmission occurs in the early stages of infection when patients are either minimally symptomatic or asymptomatic. Unrecognized patients pose a real challenge to infection control and, when not promptly handled with appropriate airborne precautions, are one of the most critical factors for SARS-CoV-2 infection spread in the healthcare setting. # Methods The Portuguese Pulmonology Society appointed FG to chair this consensus group. Seven national IP specialists were selected based on their clinical expertise and different settings (university vs. non-university hospitals; state vs. private hospitals; pulmonologists vs. critical care specialists; ...). At the first online consensus meeting, attended by all members, a primary draft with several sections was created. This was shared online and further improved by written comments and suggestions. Then, each IP specialist was assigned a specific section presented in this document and was responsible for reviewing and evaluating the relevant available literature related to the topic. Electronic databases (Pubmed, OVID Medline and Embase, Web of Science, Cochrane Central Register of Controlled Trials) were used to search for the terms ''COVID-19'' OR ''SARS-CoV-2'' AND (''bronchoscopy'' OR ''interventional pulmology'' OR ''thoracentesis'' OR ''thoracocentesis'' OR ''pleural effusion'' OR ''pneumothorax'' OR ''rigid bronchoscopy'' OR ''thoracoscopy'' OR ''chest drain''). Position papers from major health organizations (US Centers for Disease Control and Prevention, European Centre for Disease Prevention and Control and World Health Organization) and important scientific societies (European Respiratory Society, European Association for Bronchology and Interventional Pulmonology, American Association for Bronchology and Interventional Pulmonology, World Association for Bronchology and Interventional Pulmonology and British Thoracic Society) were also reviewed. In a second online conference the complete draft was evaluted by all team members and two working groups were created. They were responsible for discussing and revising different sections, and editing the text for consistency. Afterwards, the final manuscript was distributed to the consensus group members and assessed for final approval. ## Adaptations of the interventional pulmonology (ip) department Although there is still some heterogeneity in the definition and scope of of ''interventional pulmonology'' (IP), it has become the most widely accepted term to describe the use of techniques for the diagnosis and treatment of a growing number of thoracic disorders.In the context of this document, the term IP is used to encompass the concepts of bronchoscopy (diagnostic or therapeutic), advanced bronchoscopy (flexible or rigid bronchoscopy and all its associated techniques), pleuroscopy (rigid or semi-flexible) and other simpler pleural techniques (such as thoracentesis, placement of thoracic drainage systems and indwelling pleural catheters). Though we acknowledge this wider definition of IP may be controversial, it covers all technical domains that most Portuguese pulmonologists need to address, and for the purpose of this document, it positions us to issue general recommendations. In the following subsections, specific scenarios of different technical specializations will be addressed in order to overcome this broader definition and to apply it better to individual settings. The IP department is a high-risk area, given the type of procedures that are performed with airway manipulation and with multiple staff involved. Although this setting is generally designed to deal with occasional airborne infectious diseases, such as tuberculosis, it is not prepared to systematically assess high-risk cases that need additional resources, diminish productivity and effectiveness and generate a huge workload. Thus, each IP unit must rethink their administrative and logistic circuits in different areas, as well as the type and timing of performed procedures, to protect both HCW and patients. Moreover, as international health associations advocate, an infection-control program in healthcare settings should be implemented, consisting of a threelevel hierarchy, including administrative, environmental and engineering controls, and personal protection equipment (PPE).In the following subsections, each of the above listed hierachic levels are briefly presented. ## Administrative and organizational issues Administrative and logistic measures are crucial to ensuring safety while still maintaining IP activity.In patients with a positive RT-PCR SARS-CoV-2, the decision to procede with the intervention will be based on the urgency of the procedure (Chart 1 and . -The IP unit should keep a record of deferred patients to reschedule their procedures according to the COVID-19 outbreak situation, as proposed in. ## Environmental and engineering control physical space preparation The design of strategies to minimize risks and a protocol fitting the characteristics of each specific Unit are crucial. [bib_ref] Recommendations for day case bronchoscopy services during the COVID-19 pandemic, Baldwin [/bib_ref] -Reception, administrative, clinical and waiting areas should separate confirmed/high-risk patients from negative/low-risk ones. In addition, inpatients should be segregated from outpatients, either by time or physical location, to prevent cross infection. -Specific circuits and written workflow plans must be prepared, covering the pre-procedural area, procedural room, post-procedural area, decontamination and reprocessing. The implementation of a flowchart with different areas and walking paths using a visual colour zone system can be useful: 1) red zone for contaminated areas; 2) yellow zone for transition areas, and 3) green zone for non-COVID-19 safe areas [fig_ref] Figure 1: A [/fig_ref]. These need to be formulated by internal elements from the IP unit with the cooperation of a multidisciplinary team of hospital members, including administration, engineers, and infection control board. -A specific place to store and retrieve all items required for PPE should be defined inside the Unit. -A designated area in the Unit should be selected, close to the procedural suite, for gowning and removal of all PPE, according to hospital protocol and standards, in order to reduce exposure to contaminated particles and droplets. When an anteroom is available, it may be used as an area for donning and doffing of PPE [fig_ref] Figure 1: A [/fig_ref]. -Stations should be created to facilitate frequent hand hygiene and to distribute waste containers according to local infectious control recommendations. Posters and other visual aids should be placed at strategic locations around the intervention suite to act as reminders. -Emergency procedures in COVID-19 positive patients should preferably be performed within the ICU enviroment, with controlled airway through cuffed endotracheal tube and assisted ventilation. Chart 1 Proposed triage of IP procedures during the COVID-19 outbreak. Priorization of IP exams according to SARS-CoV-2 status and procedure urgency. . Nevertheless, these procedures should still be performed in a dedicated negative pressure room (see below, ventilation requirement) with strict isolation precautions and sufficient ventilation to avoid aerosol contamination. [bib_ref] A case study evaluating the risk of infection from middle eastern respiratory..., Adhikari [/bib_ref] If these requirements are not met in the bronchoscopy suite, then in a different venue, such as an operating theatre, isolation room or the ICU with negative pressure, if available. -If negative pressure rooms are unavailable througout the instituition, a specific and dedicated room with adequate natural ventilation (see requirement below) may be an alternative, provided that appropriate intervals between procedures are reserved and that the suspected COVID-19 cases be programmed after all planned non-COVID daily activity, so that the unit can be carefully cleaned (following the disinfection policy) and ventilated. -Keep the endoscopy room for procedures only (all other activities, such as planning, reporting and laboratory requisition should take place elsewhere). -Suspected and confirmed cases of COVID-19 must be placed in an airborne infection isolation room with negative pressure before and after the procedure. Low-risk and negative patients can remain in the pre-procedural and recovery area, if there is adequate room ventilation, protective equipment (e.g. surgical mask) and physical distance (>2 m) from other negative patients. ## Ventilation -Patient source control strategies, such as wearing a mask should be encouraged. -Whenever feasible, it is recommended procedures are pereformed in a room that meets the ventilation requirements for Airborne Infection Isolation (AII), ensuring the dilution and removal of contaminated air. The preferred system is a negative pressure room with at least 12 air changes per hour (ACH) with airflow direction control (single-pass or recirculation systems with HEPA filtration). Alternatively, natural ventilation with an airflow of at least 160 L/s is an option.,21 -Enough time should be allowed to ensure that contaminated air is removed from the room before performing another procedure in the same room (depending on ACH and disinfection methods, but at least 30 min). Local adaptations must be considered according to the characteristics of the IP unit. ## Cleaning and disinfecting patient care equipment and rooms Endoscopes are considered semi-critical medical instruments according to the Spaulding classification. [bib_ref] Disinfection of endoscopes: review of new chemical sterilants used for high-level disinfection, Rutala [/bib_ref] Recommendations from the Centers for Disease Control and Prevention (CDC) on reprocessing procedures should be followed. These include pre-cleaning, leak-testing, manual cleaning and visual inspection followed by disinfection/sterilization. -A high-level manual disinfection or using an automated endoscope reprocessor is recommended. -Proper storage and documentation are also an integral part of the reprocessing workflow. -A pathway of contaminated equipment must be defined, as well as adequate packaging to minimize exposure (for example, a hermetic box). -If available, disposable bronchoscopes are recommended for confirmed COVID-19 patients with clear advantages in portability, post-procedural handling and cross contamination risk. 23 -Floors and surfaces of the endoscopy suite must be disinfected after each procedure. -Intermediate level disinfectants with proven activity against enveloped viruses include 0.1% sodium hipochlorite, 62---71% ethanol, 0.5% hydrogen peroxide and quaternary ammonium compounds. [bib_ref] Biosafety in the preparation and processing of citology specimens with potential coronavirus..., Chen [/bib_ref] Personal protective equipment IP procedures are considered to be consistently subjected to the highest risk of exposure. In this setting, full precautions must be taken to cover all different possible types of transmission (contact, droplet and airborne). [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] Personnel involved in the reprocessing procedure must also wear protective equipment consisting of eye protection, respiratory mask FP2, long sleeved gown and double gloves. [bib_ref] Society for advanced bronchoscopy consensus statement and guidelines for bronchoscopy and airway..., Pritchett [/bib_ref] The recommendations for the use of PPE are shown in [fig_ref] Table 3: Specifications for personal protective equipment during IP procedures [/fig_ref]. ## Specimen transportation Samples from the upper and lower respiratory tract, including pleural effusion, are deemed to be the most potentially infectious. Consequently, they should be handled as Category 3 pathogen and double-bagged (first the specimen must be bagged in the patient's room and then taken out of the room and placed in a separate pre-labeled specimen bag). All specimens must be manually delivered. [bib_ref] Society for advanced bronchoscopy consensus statement and guidelines for bronchoscopy and airway..., Pritchett [/bib_ref] ## Safety rules for staff and patients It is also important to define proper new rules for both HCW and patients circulating in the IP unit, as listed below: ## Health professionals -The IP Unit should reduce and prioritise the allocation of human resources according to the outbreak evolution and hospital needs. The minimum number of staff required to ensure a correct operation must be clearly defined. -It is essential that all personnel follow, train and maintain competency in effective hand hygiene and every aspect of PPE (theoretical, training and simulation sessions) so that everyone is familiar with their role. -All interactions with patients, including informed consent, should be done with appropriate PPE and frequent hand washing. The staff should not reduce the level of awareness and protection, and the idea that patients with suspected COVID-19 should be handled in the same manner as confirmed cases must be reinforced. -A core team that includes only essential HCW should perform the procedure on SARS-CoV-2 positive patients. The most experienced staff should be responsible for the exam to reduce time and deal effectively with possible complications. Other healthcare personnel, such as residents, medical students and visitors should not be inside the unit and the examination room before, during or after the procedure. -Of note, the scheduled exams must be done during normal working hours (avoiding an emergency basis or setting) and in an appropriate, designated room that fulfils all the standards required for care. ## Patients and other personel -Respiratory and contact isolation should be standard and mandatory for all patients. Outpatients and inpatients should always enter the IP Unit with a suitable face mask and keep it on at all times (until the beginning and after the end of the procedure) to minimize the risk of transmission. No unnecessary personal items should be brought into the IP unit. -Family members and caregivers should not stay in the IP waiting rooms. In case of children or patients in need of support, the Unit can allow a single relative to enter the preparation area to provide aid. -The entry into the Unit of suppliers and medical devices sales representatives must be restricted. ## Prioritization of procedures Scheduled elective procedures should be reviewed and cancelled if potentially delayable, until local control of the outbreak is achieved. After flattening the infectious curve, many elective IP procedures will have to be performed, as they are essential to provide a definitive diagnosis and effective treatment. At this time, it is advisable to evaluate the delayed requests and to optimize the procedure planning based on clinical needs and operational capability. A suggested rational approach for stratification of procedures is provided in , but we recognize that, in certain cases, the indication may not be straightforward, and the risk-benefit must be weighted on an individual basis by the IP team.Although rescheduling certain procedures is obvious in other cases it may not be desirable or ethical. It is important to note that these indications may change according to local epidemiological conditions and the response capabilities of the healthcare system. Several societies have recommended different levels of procedure stratification. [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] [bib_ref] Management of lung nodules and lung cancer screening during the COVID-19 pandemic, Mazzone [/bib_ref] Briefly, what is recommended is a stepwise reopening of elective IP procedures according to the national and local COVID-19 outbreak situation, depending on the number of new confirmed cases, hospital admitted cases (ward and ICU), availability of equipment and healthcare staff, time elapse and number of postponed IP cases. Some authors [bib_ref] Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial..., Hellyer [/bib_ref] have proposed a summary of the elective endoscopic procedure by phases, as shown in. Anyway, it should be noted that the evolving procedural criteria should always be communicated to other physicians who refer patients for invasive respiratory procedures and to the hospital administration. ## Recommendations for bronchoscopy bronchoscopy under spontaneous ventilation The following reccomendations are expert opinion-based and should be adapted to local regulations and guidelines. In an optimal scenario, it is safer to perform elective bronchoscopy under general anesthesia and orotracheal intubation, clinical conditions permitting. If this is not possible, bronchoscopy can be performed under spontaneous ventilation. Some recommendations are listed below: -Operator should be standing behind the patient's head to reduce direct exposure. Oxygen supplementation should be done without the use of humidification, either through a nasal cannula or preferably with an oxygen mask with an entrance to the bronchoscope . -For flexible bronchoscopy, a transnasal approach should be preferred, and a surgical mask should be placed over the patient's mouth to minimize droplet emission . -In hypoxemic patients, bronchoscopy can be performed under NIV, using a closed circuit ventilation (double circuit with viral filters in both arms) and non-ventilated masks with a dedicated bronchoscope entrance . High performance NIV ventilators with FiO 2 regulation are preferable. From the end of the procedure, NIV should be continued for 1−2 h, titrating the FiO 2 to obtain an SpO 2 of around 94---95%. -Bronchoscopy under nasal high-flow oxygen therapy is not reccomended and thus should be avoided. -Nebulized medications should be avoided before or after the procedure. -Proper sedation should be used to minimize cough reflex and to increase patient cooperation. -An oral aspiration cannula should be available during the procedure . -A transparent protective box may enhance safety by containing dispersal of droplet particles . The box is placed over the patient's head prior to bronchoscopy, with the anesthesia equipment already in place. The bronchoscope is inserted through the covered opening behind the patient . ## Bronchoscopy in the intubated patient The following recommendations are directed for patients under mechanical ventilation in an ICU setting due to respiratory failure. As reported, 5% of COVID-19 patients can develop respiratory failure and will need ventilatory support 32 ; moreover, associated bacterial, viral and fungal co-infection should not be negleted. [bib_ref] The clinical characteristics of pneumonia patients co-infected with 2019 novel coronavirus and..., Ding [/bib_ref] In critically ill patients under invasive ventilation, ventilator-associated pneumonia occurs in up to 30% and lobar collapse is frequent and multifactorial. [bib_ref] Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial..., Hellyer [/bib_ref] The same adaptations apply to elective procedures under general anesthesia, performed in the Bronchoscopy Unit or Operating Theatre. -A cuffed endotracheal tube is preferred over supraglotic devices, such as a laryngeal mask; cuff pressure should be maintained between 25---30 cmH 2 O. 35 -General anesthesia with muscle relaxant is recommended to reduce the aerosol production. -FiO 2 should be adjusted to 100%. -Volume control, pressure-limited mode is preferable and PEEP should be kept at the same level during the procedure. Adjustments can be made dynamically, with a prior assessment of the anticipated risks (e.g., lung derecruitment and desaturation, arrhythmias, pneumothorax). -To avoid aerosol dispersion, a simple and appropriate maneuver consists of clamping the ventilation circuit just before introduction of bronchoscope, repeating the same step just before withdrawal. ## Figure 2 Strategies to minimize droplets dispersal during bronchoscopy. A. The bronchoscope may be introduced through an opening made at the oxygen mask, in this case with an additional plastic sheet covering the patient's head. B. Transnasal approach, with oxygen supplementation through nasal cannula and a surgical mask placed over the patient's mouth and the oral aspiration canulla. C. Bronchoscopy can be performed under ventilatory support, using a closed circuit ventilation and non-ventilated masks with a dedicated bronchoscope entrance. D. Transparent protective box may contain droplet particles inside. E. Protective box placed over the patient's head during endobronchial ultrasound. F. Rigid bronchoscopy with rubber caps on the ports of the scope and a plastic covering. -Bronchoscope removal and reinsertion should be avoided during the procedure. -In hypoxemic patients, if bronchoalveolar lavage is needed for diagnostic purposes, the volume used should be reduced to a minimum. If a SARS-Cov-2 diagnosis is needed, a minimum of 2−3 mL of recovered lavage is enough. 26 ## Rigid bronchoscopy Rigid bronchoscopy is used for diagnostic and therapeutic purposes, in procedures where flexible bronchoscopy would be deemed difficult or even impossible, like obtaining larger samples of endobronchial lesions, foreign body removal, management of central airway obstruction (including ablative techniques, like electrocautery, argon plasma coagulation, laser, cryotherapy, among others, and placement of airway stents) or massive hemoptysis. [bib_ref] Indications and complications of rigid bronchoscopy, Batra [/bib_ref] There are different ventilation strategies used during rigid bronchoscopy, although manual jet ventilation and high frequency jet ventilation are much the most frequent. [bib_ref] Ventilation and anesthetic approaches for rigid bronchoscopy, Pathak [/bib_ref] Common to these two techniques is the fact that the proximal end of the bronchoscope is open to allow the passage of instruments, thus ventilation is achieved providing 100% oxygen under high pressure (usually 50 psi) through an open system. [bib_ref] Protocol incorporating airway CT decreases negative bronchoscopy rates for suspected foreign bodies..., Ahmed [/bib_ref] [bib_ref] New bronchoscopic instrumentation: a review and update in rigid bronchoscopy, Yarmus [/bib_ref] The use of these ventilation techniques means that aerosols are released into the room, making it a highrisk procedure. In patients with suspected or confirmed COVID-19 diagnosis, rigid bronchoscopy should be avoided, except for urgent cases . Clinical scenarios are mostly therapeutic, like acute foreign body aspiration, massive hemoptysis (when there is no place for embolization), severe symptomatic central airway obstruction (either benign or malignant) and migrated stents. In a clinically stable patient, upon suspicion of foreign body aspiration, one should consider non-contrast computerized tomography (CT) to confirm the presence of a foreign body before rigid bronchoscopy, to avoid unnecessary exams. [bib_ref] The use of CT-scan in foreign body aspiration in children: a 6..., Pitiot [/bib_ref] [bib_ref] Protocol incorporating airway CT decreases negative bronchoscopy rates for suspected foreign bodies..., Ahmed [/bib_ref] In some centers, the rigid scope is used to perform other techniques, like Endobronchial Ultrasound-Transbronchial Needle Aspiration (EBUS-TBNA) or transbronchial cryobiopsy; this provides comfort to the operator and safety in case of major bleeding. The authors recommend performing these diagnostic procedures through cuffed endotracheal tube to minimize the risk of exposure. However, the operator must be ready to convert to rigid bronchoscopy, if necessary. In a patient undergoing rigid bronchoscopy, it is recommended that: -Rigid bronchoscopy should always be performed in a negative pressure room. -Controlled ventilation is preferred, with the rigid bronchoscope used like an endotracheal tube. -Air leaks should be reduced using rubber caps on the ports of the rigid scope, as well as using a plastic covering or filling the mouth with gauze. [bib_ref] New bronchoscopic instrumentation: a review and update in rigid bronchoscopy, Yarmus [/bib_ref] While this strategy is more appealing to minimize aerosol spread, the operator may find it challenging to handle instruments through the working channel. ## Recommendations for pleural techniques Pleural effusion does not appear to be a prominent feature of COVID-19. It occurs in 5.3---5.8% of patients, according to two recent meta-analyses. [bib_ref] CT imaging features of 4,121 patients with COVID-19: a meta-analysis, Zhu [/bib_ref] [bib_ref] Coronavirus disease 2019 (covid-19): a systematic review of imaging findings in 919..., Salehi [/bib_ref] There have been occasional reports of bilateral effusion that resolved spontaneously. [bib_ref] Asymptomatic novel coronavirus pneumonia patient outside Wuhan: the value of CT images..., Lin [/bib_ref] As bacterial superinfection is common in severe patients, they can also develop complicated effusions or empyema, requiring targeted treatment. There have been a few anecdotal reports of spontaneous pneumothorax and pneumomediastinum in severe COVID-19 pneumonia, requiring drainage. [bib_ref] Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia..., Chen [/bib_ref] [bib_ref] Mediastinal emphysema, giant bulla, and pneumothorax developed during the course of covid-19..., Sun [/bib_ref] This may be more frequent in critical patients on invasive ventilation, which can lead to bronchopleural fistulae. [bib_ref] Management of persistent pneumothorax with thoracoscopy and blebs resection in covid-19 patients, Aiolfi [/bib_ref] It is, therefore, plausible that pleural drainage may be necessary in some COVID-19 patients, either in the ICU or in the ward, and indications for drainage do not differ from the standard clinical guidelines. However, as with any invasive procedure in confirmed COVID-19 patients, all precautions regarding the full use of protective equipment should be taken. The procedure must be performed by trained and dedicated staff to reduce its duration and to minimize the risk of complications. In other situations, the use of ultrasound may be very helpful with COVID-19 patients. [bib_ref] Findings of lung ultrasonography of novel corona virus pneumonia during the 2019---2020..., Peng [/bib_ref] Besides its wide availability, safety and low cost, it is easy to use at the bedside and allows medical staff to detect small pleural effusions and to guide pleural fluid collection and drainage, if needed. On the other hand, even patients without suspected COVID-19 can have assymptomatic infection; so, any procedure should be considered as a possible COVID-19 case and precautions should be taken. Indeed, although some procedures may be postponed, in many situations they should not be deferred, especially in suspected or confirmed cancer patients. It is crucial that cancer patients do not experience delays in diagnostic or therapeutic procedures due to the present contingency.Few societies have published guidelines addressing pleural procedures during COVID-19 pandemic. The British Thoracic Society has issued guidance on pleural services provision, 49 mainly to minimize hospital visits and admissions and to ensure both patient and staff safety. Nonetheless, although we recognize lack of published evidence supporting these reccomendations, this document will adopt some of them. First of all, despite pleural procedures not being listed as Aerosol Generating Procedure (AGP) in the CDC updated reccomendations, 50 they should be considered so and Level 2 PPE should be worn, as described above. Other societies have considered potential AGP as any procedure ''likely to induce coughing, that should be performed cautiously and avoided if possible''. ## Pneumothorax -Spontaneous primary pneumothorax can be managed in outpatient care if the risk assessment allows and if there is local team experience; needle aspiration and discharge should be considered if the patient is minimally symptomatic. -When pleural drainage placement is necessary, if there is local expertise and the patient is at low risk, the use of pleural vent systems should be considered, thus allowing the patient to be managed at home. ## Chest drainage placement and care -Extra care must be taken when placing the chest tubes, in order to avoid open communication with the pleural space and the potentialemission of droplets and aerossols. -When chest tubes are placed in ventilated patients, consideration should be given to clamping the ventilator circuit before assessing the pleural cavity, so that positive pressure spreading of pleural air or fluid can be prevented. -Whenever possible, the use of non-wired pleural drainage should be considered; it can be connected to the drainage system before insertion into the pleural cavity (closed circuit). -When pleuroscopy is required, the use of one way valve trocars should be preferred to assess the pleural cavity and properly seal the entrance port of the pleuroscope. -In case of prolonged air-leaks, the use of wall suction should be weighted to create a closed system. ## Concluding remarks As with other societal consensus papers, this document was developed by a restricted panel of experts from the Portuguese Society of Pulmonology; individual clinical judgment and local resources may lead to alternative perspectives. This guidance was based on the current knowledge of COVID-19, but, as new data appears, this statement should be revised in the future to accommodate updated recommendations. At present, one of the controversial assumptions is that, every patient, even if asymptomatic, should be assumed as potentially infected with SARS-CoV-2. Therefore, it is mandatory that contact precautions and proper training on donning and doffing of PPE be provided to all HCWs involved in IP. Another key element is to plan in advance and keep each IP Unit well-organized [fig_ref] Table 4: IP Unit checklist during COVID-19 outbreak [/fig_ref]. Although the reduction in the number of elective procedures represents one of the central strategies to improve safety, it is crucial that patients do not suffer unnecessary delays in diagnostic or therapeutic procedures due to the current contingency. Taken together, our ultimate intention is to bring full attention to this and future outbreaks or other emerging medical situations. [fig] Figure 1: A. Implementation of specific circuits with colour visual zone system to distinguish contaminated (1, red zone), transition (2, yellow zone) and safe cleaned areas (3, green zone). B. Designated area for donning and doffing of PPE, where posters and other visual aids were placed strategically to act as reminders. [/fig] [table] Table 3: Specifications for personal protective equipment during IP procedures. [/table] [table] Table 4: IP Unit checklist during COVID-19 outbreak. [/table]	None	None	None
84496bf81a8c11d652840ea7b5075e8e9d4ba131	pubmed	AACC Practical Recommendations for Implementing and Interpreting SARS-CoV-2 EUA and LDT Serologic Testing in Clinical Laboratories	AACC Practical Recommendations for Implementing and Interpreting SARS-CoV-2 EUA and LDT Serologic Testing in Clinical Laboratories BACKGROUND: The clinical laboratory continues to play a critical role in managing the coronavirus pandemic. Numerous FDA emergency use authorization (EUA) and laboratory developed test (LDT) serologic assays have become available. The performance characteristics of these assays and their clinical utility continue to be defined in real-time during this pandemic. The American Association for Clinical Chemistry (AACC) convened a panel of experts from clinical chemistry, microbiology, and immunology laboratories, the in vitro diagnostics (IVD) industry, and regulatory agencies to provide practical recommendations for implementation and interpretation of these serologic tests in clinical laboratories. CONTENT: The currently available EUA serologic tests and platforms, information on assay design, antibody classes including neutralizing antibodies, and the humoral immune responses to SARS-CoV-2 are discussed. Verification and validation of EUA and LDTs are described along with quality management approach. Four indications for serologic testing are outlined. Result interpretation, reporting comments, and the role of orthogonal testing are also recommended. SUMMARY: This document aims to provide a comprehensive reference for laboratory professionals and healthcare workers to appropriately implement SARS-CoV-2 serologic assays in the clinical laboratory and interpret test results during this pandemic.Given the more frequent occurrence of outbreaks associated with either vector-borne or respiratory pathogens, this document will be a useful resource in planning for similar scenarios in the future.Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. # Introduction Coronavirus disease 2019 , caused by severe acute respiratory syndrome (SARS) coronavirus (CoV)-2 has resulted in millions of deaths worldwide and is continuing to spread at the time of this publication. The Secretary of Health and Human Services (HHS) issued a public health emergency declaration for SARS-CoV-2 on January 31 st , 2020 which allowed the FDA to grant emergency use authorization (EUA) of unapproved medical products or devices. While the FDA immediately required EUA for SARS-CoV-2 molecular tests, EUA was not required for serologic assays until May 4 th , 2020. As of January 8, 2021, over 200 SARS-CoV-2 serologic tests are available, of which 64 have obtained EUA. As a result of the limited FDA review process for EUA approval, numerous available tests, varied performance characteristics, and incomplete understanding of the humoral immune response in COVID-19, questions have arisen on how to best utilize and interpret these tests. Interim guidelines were published by several professional organizations [bib_ref] IFCC interim guidelines on serological testing of antibodies against SARS-CoV-2, Bohn [/bib_ref] [bib_ref] Canadian society of clinical chemists (CSCC) interim consensus guidance for testing and..., Bailey [/bib_ref] , but no guidance to date provides comprehensive and practical recommendations for the selection, validation, implementation, and quality management of EUA or laboratory developed test (LDT) serologic tests. To provide assistance on these topics, a panel of clinical diagnostic laboratory and industry experts from AACC reviewed the current literature and developed this guidance and recommendation document. This manuscript provides the most up-to-date understanding of host immune responses to SARS-CoV-2, the associated antibody kinetics, and the currently available EUA assays. Clinical utility and limitations are discussed to help laboratories select appropriate test(s) for their purposes and targeted population needs. The processes and considerations to verify or validate either EUA or LDT serologic tests in a clinical setting are described. In addition, quality management, test interpretation, and orthogonal testing strategies are outlined. 2. SARS-CoV-2 and the Humoral Immune Response 2.1. Antigenic Targets SARS-CoV-2 encodes four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N), among which the S and N proteins are most commonly used for SARS-CoV-2 serologic assays [bib_ref] SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human..., Gupta [/bib_ref] [bib_ref] Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein, Walls [/bib_ref]. The S protein is divided into S1 and S2 subunits, S1 contains the receptor binding domain (RBD), which binds the human angiotensin-converting enzyme 2 (ACE2) receptor, mediating host cell entry, and S2 facilitates fusion of the viral and host membranes [bib_ref] Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein, Walls [/bib_ref]. Distal regions of the S protein (S1, RBD) are the least conserved among members of Beta-CoV (e.g., SARS-CoV, MERS-CoV) and are likely to induce a SARS-CoV-2 specific antibody response. Overall, the SARS-CoV-2 S protein shares 76% homology with SARS-CoV-1 and only about 30% homology with seasonal Beta-CoVs (e.g., OC43 and HKU1) [bib_ref] Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease Patients, Okba [/bib_ref]. The N protein is the most abundantly expressed immuno-dominant protein among CoVs, functioning to stabilize viral RNA [bib_ref] Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease Patients, Okba [/bib_ref] [bib_ref] Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses, Jiang [/bib_ref] [bib_ref] Comparative computational analysis of SARS-CoV-2 nucleocapsid protein epitopes in taxonomically related coronaviruses, Tilocca [/bib_ref] [bib_ref] Performance characteristics of five immunoassays for SARS-CoV-2: a head-tohead benchmark comparison, Ainsworth [/bib_ref]. It is highly conserved between SARS-CoV-2 and SARS-CoV with approximately 90% identity [bib_ref] Comparative computational analysis of SARS-CoV-2 nucleocapsid protein epitopes in taxonomically related coronaviruses, Tilocca [/bib_ref] but shares only 33% identity with seasonal Beta-CoVs (12). ## Antibody classes Commercial SARS-CoV-2 serologic assays are available for detection of total antibodies, specific antibody subclasses (IgG, IgM, or IgA), or neutralizing antibodies (nAbs) using qualitative or semi-quantitative methods. There is no clear evidence to support the clinical utility of standalone IgM testing. IgA-based assays have been reported to suffer from lower specificity as compared to IgG-based assays [bib_ref] Severe Acute Respiratory Syndrome Coronavirus 2-Specific Antibody Responses in Coronavirus Disease Patients, Okba [/bib_ref] , and are currently not recommended for use by either the Centers for Disease Control and Prevention (CDC) or the Infectious Diseases Society of America (IDSA). Detection of total antibodies may enhance sensitivity [bib_ref] Performance characteristics of five immunoassays for SARS-CoV-2: a head-tohead benchmark comparison, Ainsworth [/bib_ref] [bib_ref] The early antibody response to SARS-Cov-2 Infection, Dittadi [/bib_ref] [bib_ref] Comparison of the Clinical Performance of the Abbott Alinity IgG, Abbott Architect..., Harley [/bib_ref] [bib_ref] Interpreting Diagnostic Tests for SARS-CoV-2, Sethuraman [/bib_ref]. The antibody response to a virus can be split into two broad categories -binding and neutralizing. While binding antibodies inactivate the virus through mechanisms such as complement activation or opsonization, neutralizing antibodies (nAbs) inhibit by binding to regions of the virus that directly interact with host cell receptors, effectively blocking viral entry and inhibiting replication. Unlike the detection of binding antibodies, the detection of nABs requires functional assays. The "gold" standard is the plaque reduction neutralization test (PRNT), which is technically challenging to perform, requires live viral and cellular culture, has a prolonged turnaround time (days to weeks), and for SARS-CoV-2, requires biosafety level (BSL) 3 facilities. To overcome these challenges, alternative methods have been developed, including pseudovirus-based live-cell neutralization assays or blockade-of-binding (BoB) immunoassays. Pseudovirus neutralization assays can be performed at BSL2 [bib_ref] Evaluation of Neutralizing Antibodies Against Highly Pathogenic Coronaviruses: A Detailed Protocol for..., Almahboub [/bib_ref] , though these assays are still complex, associated with significant analytical variability and challenging to support in most clinical laboratories. BoB immunoassays can be performed in a 96-well format and can be automated on different immunoassay processing platforms for high throughput analysis [bib_ref] Performance characteristics of five immunoassays for SARS-CoV-2: a head-tohead benchmark comparison, Ainsworth [/bib_ref]. nAb assays have played an important role in the development and assessment of SARS-CoV-2 vaccines and in research studies probing the host immune response to infection.Given the challenges associated with assay maintenance, lack of standardization, and the currently unknown correlation of nAb titers with protective immunity, their role in the clinical laboratory will likely be limited. ## Antibody kinetics Understanding the kinetics of the antibody response to SARS-CoV-2 is a prerequisite for test selection and accurate result interpretation. The current understanding of the kinetics of the antibody responses against SARS-CoV-2 are depicted in [fig_ref] 1: Ensure testing personnel are properly trained and qualified based on test complexity... [/fig_ref]. Of note, antibody kinetics in specific sub-populations, including immunosuppressed patients, cancer patients, and other sub-groups, may differ and continue to be studied. Unlike viral RNA and antigens, detection of antibodies during the incubation phase is unlikely. Multiple published studies demonstrate that most individuals develop an IgM/IgA/IgG response within 7-14 days of symptom onset, with over 90% of individuals seropositive after three weeks [bib_ref] Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019, Zhao [/bib_ref] [bib_ref] Antibody Detection and Dynamic Characteristics in Patients with COVID-19, Xiang [/bib_ref]. IgM/IgA peak and decline earlier than IgG, often within weeks of symptom onset [bib_ref] Kinetics of SARS-CoV-2 specific IgM and IgG responses in COVID-19 patients, Sun [/bib_ref] [bib_ref] Longitudinal Change of Severe Acute Respiratory Syndrome Coronavirus 2 Antibodies in Patients..., Zhang [/bib_ref] [bib_ref] Molecular and Serological Assays for SARS-CoV-2: Insights from Genome and Clinical Characteristics, Shi [/bib_ref] [bib_ref] SARS-CoV-2 (COVID-19) serology: implications for clinical practice, laboratory medicine and public health, Van Caeseele [/bib_ref]. IgG antibodies correlate with disease severity, decline at varying rates, and may be detectable for months following infection [bib_ref] The laboratory's role in combating COVID-19, Fang [/bib_ref] [bib_ref] Magnitude and Kinetics of Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Responses..., Lynch [/bib_ref] [bib_ref] Differences in Antibody Kinetics and Functionality Between Severe and Mild Severe Acute..., Rijkers [/bib_ref] [bib_ref] SARS-CoV-2 neutralizing antibody responses are more robust in patients with severe disease, Wang [/bib_ref] [bib_ref] Antibody responses to SARS-CoV-2 in patients with COVID-19, Long [/bib_ref] [bib_ref] Neutralizing Antibody Production in Asymptomatic and Mild COVID-19 Patients, in Comparison with..., Ko [/bib_ref] [bib_ref] Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low Prevalence Communities and Reveal..., Ripperger [/bib_ref] [bib_ref] Mapping Neutralizing and Immunodominant Sites on the SARS-CoV-2 Spike Receptor-Binding Domain by..., Piccoli [/bib_ref]. Notably, approximately 4-10% of the population with confirmed SARS-CoV-2 infection may have either an undetectable or delayed antibody response [bib_ref] Humoral Immune Response to SARS-CoV-2 in Iceland, Gudbjartsson [/bib_ref]. Regarding antibody longevity, some studies indicate that up to 40% of confirmed individuals become IgG seronegative by the early convalescent phase [bib_ref] Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections, Long [/bib_ref] while others have demonstrated that antibodies decline, yet remain detectable for months postinfection [bib_ref] Humoral Immune Response to SARS-CoV-2 in Iceland, Gudbjartsson [/bib_ref] [bib_ref] Robust neutralizing antibodies to SARS-CoV-2 infection persist for months, Wajnberg [/bib_ref] [bib_ref] Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection, Dan [/bib_ref]. Given these inconsistencies, the precise kinetics of the SARS-CoV- ## Eua serologic tests ## Assay designs Several assay formats for detection of SARS-CoV-2 antibodies have received EUA. Lateral flow assays (LFAs) utilize immunochromatographic chemistry to detect antibodies, usually at the point-of-care. Manual or semi-automated 96-well enzymelinked immunosorbent assays (ELISAs) are also available [bib_ref] Are we underestimating seroprevalence of SARS-CoV-2?, Burgess [/bib_ref] [bib_ref] COVID-19 and the Path to Immunity, Stephens [/bib_ref] , as well as chemiluminescent immunoassays/chemiluminescent microparticle immunoassays (CIAs/CMIAs) for fully automated, high-throughput platforms. These methods are illustrated in . . The majority detect IgG, followed by IgM/IgG, total antibody, and IgM-only. All EUA assays use serum, some accept plasma, and less frequently, whole-blood or dried blood spots. Currently, serologic testing is not recommended for other sample types such as saliva and cerebrospinal fluid. The most frequent antigen targeted in these assays is the RBD, followed by S (including full S, S1, and S2), and N. Currently, only one assay uses all three antigens. Most current EUA assays are qualitative with a few being semi-quantitative. ## Characteristics of eua serologic tests Assessing the relative performance characteristics of each EUA assay is complicated, as the approach, the sample size, sample collection time, and disease prevalence in the population tested by each manufacturer vary widely. Clinical laboratory professionals should take these variables into consideration when evaluating assay performance. ## Utility and limitations of sars-cov-2 serology SARS-CoV-2 serologic testing is not recommended as the primary approach for diagnosis of SARS-CoV-2 infection. However, it can be used for: 1) supportive diagnosis of COVID-19, 2) manufacture of convalescent plasma, 3) epidemiologic and seroprevalence studies, and 4) vaccine response and efficacy studies (5,6,15) . ## Supporting diagnosis of covid-19 Serologic testing may be helpful to diagnose COVID-19 in symptomatic patients presenting later in disease (e.g., >9-14 days post symptom onset), who test negative by a molecular assay, with optimal assay sensitivity occurring at least 2-3 weeks post symptom onset [bib_ref] Diagnostics for SARS-CoV-2 detection: A comprehensive review of the FDA-EUA COVID-19 testing..., Ravi [/bib_ref]. Total antibody or IgG testing may be more useful for evaluating patients presenting later in the disease course [bib_ref] Comparison of the Clinical Performance of the Abbott Alinity IgG, Abbott Architect..., Harley [/bib_ref] [bib_ref] Quantitative SARS-CoV-2 Serology in Children With Multisystem Inflammatory Syndrome (MIS-C), Rostad [/bib_ref] [bib_ref] Clinical and laboratory evaluation of SARS-CoV-2 lateral flow assays for use in..., Flower [/bib_ref] [bib_ref] Diagnostic accuracy of serological tests for covid-19: Systematic review and meta-analysis, Bastos [/bib_ref] [bib_ref] Distinct antibody responses to SARS-CoV-2 in children and adults across the COVID-19..., Weisberg [/bib_ref]. Serologic testing, alongside RT-PCR, has been recommended to support the diagnosis of multisystem inflammatory syndrome in children (MIS-C), including for hospitalized individuals <21 years presenting with fever, inflammation, and multi-system organ involvement following exclusion of other potential diagnoses [bib_ref] Clinical Characteristics of 58 Children with a Pediatric Inflammatory Multisystem Syndrome Temporally..., Whittaker [/bib_ref] [bib_ref] Clinical characteristics of children and young people admitted to hospital with covid-19..., Swann [/bib_ref] [bib_ref] Multisystem inflammatory syndrome associated with COVID-19 from the pediatric emergency physician's point..., Junior [/bib_ref]. Serologic testing should precede intravenous immunoglobulin or blood product administration as these therapies may influence serologic results. ## Convalescent plasma donor identification and manufacturing Identification of potential convalescent plasma (CP) donors for COVID-19 CP therapy, which has received FDA EUA, is a recognized application of serologic testing. The FDA continues to refine donor eligibility criteria, identify serologic assays for the manufacture of COVID-19 CP units, and define acceptable antibody thresholds. Originally, the FDA recommended that the qualitative Ortho Clinical Diagnostics SARS-CoV-2 IgG CIA be used in the manufacturing of CP, with signal/cutoff (S/CO) threshold values >12 considered "high titer" and preferred for infusion. Given that most currently available serologic assays are qualitative, there are limited mechanisms for distinguishing donors with high versus low titers. Recently, the FDA updated their COVID-19 CP EUA to include nine serologic assays for manufacture of CP, including two semi-quantitative assays (53). ## Epidemiologic and seroprevalence studies Determination of seroprevalence is important to characterize the epidemiology of COVID-19 in the community and support public health efforts [bib_ref] Humoral Immune Response to SARS-CoV-2 in Iceland, Gudbjartsson [/bib_ref] [bib_ref] Are we underestimating seroprevalence of SARS-CoV-2?, Burgess [/bib_ref] [bib_ref] COVID-19 and the Path to Immunity, Stephens [/bib_ref] [bib_ref] Prevalence of SARS-CoV-2 antibodies in a large nationwide sample of patients on..., Anand [/bib_ref]. However, serologic assays have limitations that may lead to an underestimate of the true seroprevalence. First, most commercial assays were developed using symptomatic patients with moderate to severe disease. It is unknown whether the cutoffs based on these populations will detect antibodies in asymptomatic or mild disease cases. Second, a small proportion of the population may never develop detectable antibodies following infection. Third, the accuracy of this approach is dependent on the prevalence of the disease in the community, as the positive predictive value may be low in regions with little disease, even if using a highly specific assay [bib_ref] SARS-CoV-2 (COVID-19) serology: implications for clinical practice, laboratory medicine and public health, Van Caeseele [/bib_ref] [bib_ref] SARS-CoV-2 Serology: Much Hype, Little Data, Farnsworth [/bib_ref]. ## Vaccine response and efficacy Available and developing vaccines range from inactivated or live platforms to more novel DNA or RNA based preparations, such as the two recently authorized vaccines in the US: Moderna and Pfizer/BioNTech [bib_ref] SARS-CoV-2 vaccines in development, Krammer [/bib_ref]. Because the primary target of neutralizing antibodies is the S protein, the majority of the vaccines target the S protein [bib_ref] Safety and immunogenicity of an rAd26 and rAd5 vectorbased heterologous prime-boost COVID-19..., Logunov [/bib_ref] [bib_ref] Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy..., Zhu [/bib_ref] [bib_ref] An mRNA Vaccine against SARS-CoV-2 -Preliminary Report, Jackson [/bib_ref]. Vaccine trials have assessed vaccine efficacy by using endpoint outcome measures such as prevention of moderate or severe disease due to SARS-CoV-2 infection in the placebo vs. vaccinated populations. Vaccine trials have also used several different approaches to assess vaccine response, including binding antibody ELISAs, and both PRNT and pseudovirus-based neutralization assays to determine that the majority of vaccinated individuals developed a robust antibody response, including neutralizing antibodies [bib_ref] Neutralizing Antibodies against SARS-CoV-2 and Other Human Coronaviruses, Jiang [/bib_ref] [bib_ref] Comparative computational analysis of SARS-CoV-2 nucleocapsid protein epitopes in taxonomically related coronaviruses, Tilocca [/bib_ref] [bib_ref] SARS-CoV-2 Serology: Much Hype, Little Data, Farnsworth [/bib_ref] [bib_ref] SARS-CoV-2 vaccines in development, Krammer [/bib_ref] [bib_ref] Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy..., Zhu [/bib_ref] [bib_ref] An mRNA Vaccine against SARS-CoV-2 -Preliminary Report, Jackson [/bib_ref]. To date, only one assay has received EUA for detection of nAbs. It is important to note that, although a detectable antibody response in a vaccinated individual (including immunosuppressed persons) indicates that an antibody response has developed in response to vaccination, there is no threshold on any assay that is indicative of vaccine efficacy. Therefore, at this point in time, even semi-quantitative or quantitative assays against S protein that can quantify the magnitude of the antibody response to vaccines should not be used to determine vaccine efficacy and protective immunity. This is true not only for binding antibody ELISAs but also for neutralization assays. Currently, there are no recommendations from any professional societies in the US for monitoring or assessing vaccine response in any population, including immunosuppressed individuals. As the S/RBD protein is primarily used for vaccines, the availability of antibody assays that detect N-versus S-specific antibodies may also be useful to distinguish between naturally infected versus vaccinated individuals but further studies are needed to understand the merits and limitations of this approach. ## Performance verification of eua assays Verification studies for non-waived EUA assays are the same as those for FDAapproved/cleared assays. However, waived EUA tests should be verified in a similar manner as moderately complex, non-waived tests. Further resources for detailed method verification protocols are available through the Clinical & Laboratory Standards Institute (CLSI) (online Supplemental [fig_ref] Table 2: Relationship of P/NPV with Sensitivity and Specificity in OTA Given 2% Population... [/fig_ref]. ## Regulatory and accreditation requirements Clinical laboratories in the United States are required by CLIA to verify assay performance of unmodified, FDA-approved/cleared and EUA assays, and must adhere to manufacturer instructions. Several accreditation organizations are available; labs should refer to the specific requirements. The College of American Pathology (CAP) is used as an example to discuss some specific requirements for EUA verification. 2. Perform testing as outlined in the EUA without modification; a. Any deviation from instructions for use will render the assay an LDT, which needs to be validated (Section 6). 3. Verify test method performance following the CAP's All Common Checklist: a. COM.40300 -The laboratory must assess analytical accuracy, analytical precision, and reportable range (as appropriate). b. COM.40475 -Laboratory director must sign the laboratory's written assay assessment. c. COM.40500 -Laboratory understands analytical interferences for each test and has a plan of action when present.. Update the laboratory's activity menu. Here, we consolidate and expand on prior recommendations to provide a systematic approach for EUA assay verification (62-64). ## Sample collection Sample type, target population (e.g., symptomatic, asymptomatic, ambulatory, hospitalized, pediatric, pregnant patients), and number of positive samples may be difficult to discern early on in a public health emergency. Below are recommended strategies. ## Accuracy Accuracy is verified by assessing the result concordance with either another EUA assay or clinical correlate, reflecting assay clinical sensitivity and specificity. Below are recommendations for accuracy assessments. ## Single analyte or total analyte A minimum of 10 negative and 10 positive samples per sample type should be used. For total antibody tests, it is optimal to use known positive patient samples from each antibody class. ## Multiple differentiated analytes Accuracy verification must be demonstrated with known positive samples for each antibody class that could be reported. Combinations of a minimum of 20 samples (e.g., IgM-/IgG+, IgM+/IgG-, IgM+/IgG+, IgM-/IgG-) should be used to assess class specific positive and negative agreement and to verify clinical specificity. For SARS-CoV-2, it may be challenging to identify IgM+/IgG-samples due to concurrent seroconversion. ## Precision The reproducibility and repeatability of an EUA assay around the positive cutoff must be verified. For qualitative assays, a positive and negative sample can be used, with the positive sample near the cutoff. Semi-quantitative assays should be evaluated as quantitative assays, and samples should span low, mid, and high S/CO, with at least one sample near the cutoff. The intra-day and inter-day precision experiments should test both positive and negative samples over 10 replicates on the same day or over 10 runs on a minimum of five days and over multiple shifts, respectively. Precision for single use LFAs should be assessed for inter-day only over five days with multiple testing operators. ## Reportable range For semi-quantitative or quantitative serologic assays with EUA, the reportable range must be verified. Verification should be done by using non-diluted, known standards of anti-SARS-CoV-2 antibodies, such as the recently available standard from the World Health Organization (68), or if unavailable, an alternate calibrator lot or patient samples that span the analytical measuring range. Future standardization of quantitative assays to a single international standard will be essential for accurate assessment of antibody levels once a protective immunity threshold is established. ## Validation of laboratory developed tests (ldts) An in vitro diagnostic test that is designed and used in a clinical setting by a single laboratory is considered an LDT. Clinical laboratories authorized to perform highcomplexity testing under CLIA must perform thorough LDT validation studies before patient testing. This section will discuss minimum validation requirements of LDTs that go beyond those necessary for EUA assay verification with respect to sensitivity and specificity, the establishment of assay result cutoffs, class specificity, and carryover. ## Regulatory and accreditation requirements Typically, following HHS declaration of a public health emergency, any clinical test used to diagnose that condition, regardless of type (i.e., molecular or serologic or antigen), requires EUA. On August 19 th , 2020, the EUA requirement for COVID-19 laboratory assays was removed to ease regulatory burdens placed on high-complexity CLIA laboratories capable of developing LDTs. The CAP and other accreditation organizations provide specific requirements for clinical laboratories that must be used in the implementation of LDTs (70). ## Sample collection Generally, LDTs require additional samples to establish assay performance as compared to EUA assays that require verification only. The FDA recommends at least 30 positive and 75 antibody negative (or pre-COVID-19) samples in their guidance for EUA applications (4). In situations where an assay using 75 negative specimens does not demonstrate greater than 95% specificity, or if 75 specimens are not available, the FDA recommends specific cross-reactivity studies with samples known to be positive for a variety of potentially cross-reactive antibodies or those directed against other respiratory pathogens. It is also our recommendation to collect at least 30 positive (with known days from symptom onset) and 75 negative samples (ideally 100-200). ## Analytical sensitivity and specificity 6.3.1 sensitivity Assay sensitivity can be evaluated with well characterized RT-PCR-positive samples, ideally with chart data that indicate the days from a patient's symptom onset. In this way, assay sensitivity as a function of time can be assessed. It is also valuable to compare performance with another EUA assay, if available. ## Specificity, cross-reactivity, and interfering substances Samples from patients with known acute respiratory infections should be included for any LDT assay assessing the serologic response to SARS-CoV-2. Ideally, these would include samples from patients infected with one of the circulating seasonal human CoVs (NL63, OC43, HKU1, 229E), although data indicating that these are not a source of significant cross-reactivity on SARS-CoV-2 serologic tests have begun to accumulate. A disclaimer to the effect that cross-reactivity cannot be ruled out should be included if such samples were not evaluated in the validation [bib_ref] Patients with common cold coronaviruses tested negative for igg antibody to sars-cov-2, Brecher [/bib_ref] [bib_ref] Head-to-Head Comparison of Two SARS-CoV-2 Serology Assays, Merrill [/bib_ref]. Additionally, samples from those diagnosed with other infectious and autoimmune conditions known to give false positive results in immunoassays (e.g., syphilis, Lyme disease, cytomegalovirus, rheumatoid arthritis, etc.) should be included. Investigation of other interfering substances is another core component to determine an assay's analytical specificity (e.g., hemoglobin, lipids, bilirubin). For laboratories validating an LDT, it is necessary to investigate potential interferences based on assay design and devise interference validation studies. ## Establishing assay cutoffs Cutoffs for a qualitative/semi-quantitative LDT can be established with limit of blank studies using known negative samples tested repeatedly over several runs (e.g., 20 known negative samples tested by multiple operators on five separate runs). The mean optical density (OD) (or equivalent readout) and standard deviations from the mean should be calculated, with the assay threshold determined as the mean readout plus 3 to 5 times the standard deviations (SD). Further refinement of cutoffs can be performed using Receiver-Operating Characteristic (ROC) analysis to optimize sensitivity and specificity. Alternatively, if risk assessment dictates an overriding concern, then cutoffs can be set accordingly (e.g., for 100% specificity). Assays that report quantitative results, as well as those that indicate neutralization levels, are less commonly used in clinical laboratories, and require additional layers of validation. Once a cutoff is established, it is also recommended to verify the cutoff as required by the respective accreditation agencies. ## Antibody class specificity If a claim about antibody class specificity is made for an LDT, it must be validated. Methods for this include the use of a detection or capture antibody with a known class specificity or class-specific antibody depletion of the sample. As an alternative, the FDA recommends treating samples with dithiothreitol (DTT) (74) which effectively removes IgM-class antibodies (4). ## Carryover Clinical laboratories should perform an assessment to verify that a positive result was not due to positivity from a nearby high-titer positive sample (e.g., for probe-based instruments). This is commonly performed by alternating testing of a negative sample before and after a positive sample with a high index or S/CO value. If carryover cannot be eliminated from the assay, it is recommended to assess the impact on accuracy of a positive and negative result. Carryover should not exceed 20% of the lower limit of quantitation according to the FDA and additional details are available through CLSI EP10-A3-AMD (online Supplemental [fig_ref] Table 2: Relationship of P/NPV with Sensitivity and Specificity in OTA Given 2% Population... [/fig_ref] and CAP. ## Other eua assay implementation considerations ## Quality management QC must be identified, verified, and implemented for routine SARS-CoV-2 testing based on test complexity and manufacturer's instructions. A minimum of two levels of quality control (positive and negative) should be included with each run of the specified assay. For qualitative and semi-quantitative assays, a negative QC and a positive QC near the cutoff must be run at least daily. For SARS-CoV-2 serologic assays, controls may be provided as part of the assay kit or may need to be sourced separately. For the latter, laboratories can purchase separate controls provided by the assay manufacturer or third-party vendors or use pooled patient samples. Use of assay calibrator material to create assay controls is discouraged, but if needed, the calibrator material must be from a different kit lot. QC material should also match the analyte detected by the specific assay and patient matrix. Typically, 20 QC data points on separate days are used to determine the target control mean and SD to establish the range. For vendor material with assigned QC ranges, the laboratory should verify the product. QC performance should be monitored in real-time to identify shifts and trends. Laboratories should participate in proficiency testing (PT) either using vendor products or an alternative assessment program. Finally, because EUA assays were not extensively evaluated, laboratories may implement a more rigorous quality management system until assay reliability is established. This may include analysis of additional QC material, performing additional lot-to-lot comparisons, and identifying a partner laboratory for more frequent sample exchanges than the bi-annual PT requirement. ## Pre-analytical considerations Pre-analytical variables should be noted for SARS-CoV-2 antibody tests and thoroughly reviewed to determine possible limitations. These include sampling time, sample stability, as well as potential endogenous and exogenous interferences (e.g., hemoglobin). Time of sample collection is important when selecting positive samples for verification studies. In order to verify test performance at the optimal reported sensitivity for most current EUA assays, samples collected ≥14 days post symptom onset / PCR positivity should be used for verification. The limitation of test performance in patients tested <14 days prior to symptom onset/ PCR positivity should be clearly stated. For LDTs, clinical sensitivity relative to days from symptom onset needs to be determined during the validation (Section 6). If an assay is performed with several sample types, including dried blood spots, laboratories should define and specify collection device, transportation, and preanalytical requirements prior to patient testing. ## Interpretation of serologic test results The majority of SARS-CoV-2 serologic assays are qualitative in design and generally, positive results indicate recent or prior SARS-CoV-2 infection. Negative results indicate that SARS-CoV-2 antibodies were not present or are below defined detection limits. Negative results cannot rule out active or prior infection. Results should be interpreted in the context of antibody class(es) detected (Section 4.1) and antigenic target(s), time of sample collection (Section 2.3), disease severity, and assay analytical performance characteristics (Section 6.3). Understanding the clinical sensitivity, clinical specificity, and disease prevalence are also key considerations for interpretation of serologic test results. ## Impact of clinical sensitivity, specificity and disease prevalence To minimize potential false positives and to be of clinical value, the CDC and IDSA have suggested using tests with clinical sensitivity and specificity of 99.5% or greater. Positive (or negative) predictive values (PPV/NPV) depend on disease prevalence in the target population and on assay clinical sensitivity and specificity. They indicate the percent probability that a positive (or negative) test result will correctly identify individuals with (or without) antibodies in a given population. An assay with 95% sensitivity and 90% to 99% specificity was used to illustrate this relationship [fig_ref] Figure 3: The relationship between assay sensitivity, specificity, disease prevalence, and positive and negative... [/fig_ref]. The PPV increases as specificity increases. Using these sensitivity and specificity values, the PPV increases very rapidly with increased disease prevalence until it plateaus at ≥20% prevalence. The NPV, however, changes minimally with different levels of assay specificity and drops markedly when disease prevalence increases. A test that has 95% sensitivity and 95% specificity within a population of 20% or 5% antibody prevalence (2000 or 500 individuals have antibodies assuming a population of 10,000, respectively) is used as an example to show the impact of disease prevalence on PPV/NPV [fig_ref] Figure 3: The relationship between assay sensitivity, specificity, disease prevalence, and positive and negative... [/fig_ref]. In a population with 20% prevalence, the test would ## Orthogonal testing If a desired PPV cannot be achieved using a single assay, the CDC recommends use of an orthogonal testing algorithm (OTA), a two-step testing strategy where all initially positive results are tested with a second independent serologic test. Studies on the effectiveness of this approach are still scarce [bib_ref] Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low Prevalence Communities and Reveal..., Ripperger [/bib_ref]. ## Ota test selection Both tests should ideally have high sensitivities (>90%, ideally > 95%). The test with higher specificity should be selected as the first-line test to minimize the number of discordant results while still retaining optimal PPV. OTA may include tests that use different methods/same antigenic target, same methods/same antigenic target but different domains or methods that detect antibodies against different antigenic targets [bib_ref] Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low Prevalence Communities and Reveal..., Ripperger [/bib_ref]. OTAs incorporating IgM or IgA serologic tests are not recommended as there is a higher likelihood of discordant results. The relationship of PPV/NPV and discordant rate in different OTA designs is illustrated in [fig_ref] Table 2: Relationship of P/NPV with Sensitivity and Specificity in OTA Given 2% Population... [/fig_ref] with a 2% disease prevalence. If evaluated by a single test (test 1) with specificity of 98%, about 50% false positive results would be expected. Adding a sequential test (test 2) with specificity of 95% will, however, result in PPV of >90% [fig_ref] Figure 4: Effect of an Orthogonal Testing Algorithm [/fig_ref]. OTA1 and OTA2 represents different designs from test 1 and test 2. Both OTA1 and OTA2 have the same combined PPV of 95%. However, OTA1, which uses the highest specificity test first, results in a lower discordant rate without affecting combined PPV/NPV. ## Ota result reporting and interpretation If the initial result is negative, the second test is not needed and a negative report is issued; if both tests are positive, a positive report is issued. The interpretive challenge arises when the first result is positive and second is negative, granting discordant or indeterminate results (online Supplemental . In this case, OTA results should be interpreted in the context of disease prevalence, sensitivity and specificity of each test, assay methodology, and antigenic targets. If different antigenic targets are used, a discordant result may be attributed to 1) initial false-positive, 2) early recovery and/or differences in antibody kinetics, 3) skewed immune response towards one antigen, or 4) waning immunity. To rule out the contribution of differences in antibody kinetics, retesting in 2-4 weeks may be attempted. # Conclusions and perspectives Though not recommended as first-line testing for diagnosis of SARS-CoV-2, Many studies are underway to gain deeper and broader understanding of SARS-CoV-2 and the tests used to detect and manage the infection will continue to improve. Clinical laboratory professionals, in collaboration with their clinical colleagues, will continue to play an indispensable role in reviewing the evolving scientific literature and adjusting testing strategies to best serve patient and public health needs during this pandemic. Serologic testing may be offered as an approach to support diagnosis of COVID-19 illness in symptomatic patients and late phase negative molecular testing or for patients presenting with late complications such as multisystem inflammatory syndrome in children (MIC-C). ## Serologic testing can help identify people who may have been infected with or have recovered from the sars-cov-2 infection. Serologic testing can be used to screen potential convalescent plasma donors and in the manufacture of convalescent plasma. ## Serologic testing can be used for epidemiology and seroprevalence studies. Serologic testing can be used for vaccine response and efficacy studies. # Limitations False positive results may occur. ## Negative results do not preclude acute sars-cov-2 infection or viral shedding. ## Serologic tests may not differentiate between natural infection and vaccine response. The durability and kinetics of the humoral immune response continue to be elucidated. ## Serologic results should not be used for Determining individual protective immunity Return to work decisions Cohorting individuals in congregate settings Assessment of convalescent plasma recipients Use of Personal Protective Equipment Placement of high-risk job functions sensitivity, 95%; specificity, 98%. Test 2: sensitivity, 99%; specificity, 95%) and their combined performance. Regardless of the order in which the tests are performed, sequential testing can increase PPV in testing populations with low disease prevalence. [fig] 1: Ensure testing personnel are properly trained and qualified based on test complexity authorized by the FDA; [/fig] [fig] Figure 3: The relationship between assay sensitivity, specificity, disease prevalence, and positive and negative predictive values (PPV/NPV). (A) PPV, the proportion of true positives, is strongly influenced by the specificity of an assay when a disease is low prevalence. NPV, the proportion of true negatives, declines as disease prevalence increases. (B) A visual comparison of PPV for the same assay (sensitivity, 95%; specificity, 95%) performed in two test populations of 10,000 people with high (20%, PPV = 82.6%) and low (5%, PPV = 50.0%) disease prevalence (upper and lower panels). [/fig] [fig] Figure 4: Effect of an Orthogonal Testing Algorithm (OTA) on Positive Predictive Value (PPV). Shown is the performance of two tests with different characteristics (Test 1: [/fig] [table] Table 2: Relationship of P/NPV with Sensitivity and Specificity in OTA Given 2% Population Disease PrevalenceT1: Test 1 with sensitivity of 95% and specificity of 98% T1: Test 2 with sensitivity of 99% and specificity of 95% PPV/NPV, Positive/Negative Predictive Value; OTA, Orthogonal Testing Algorithm An online calculator from the FDA (https://www.fda.gov/media/137612/download) is a helpful tool to assess the combined PPV/NPV. [/table]	None	https://academic.oup.com/clinchem/article-pdf/67/9/1188/40242031/hvab051.pdf	Abstract BACKGROUND The clinical laboratory continues to play a critical role in managing the coronavirus pandemic. Numerous FDA emergency use authorization (EUA) and laboratory developed test (LDT) serologic assays have become available. The performance characteristics of these assays and their clinical utility continue to be defined in real-time during this pandemic. The American Association for Clinical Chemistry (AACC) convened a panel of experts from clinical chemistry, microbiology, and immunology laboratories, the in vitro diagnostics (IVD) industry, and regulatory agencies to provide practical recommendations for implementation and interpretation of these serologic tests in clinical laboratories. CONTENT The currently available EUA serologic tests and platforms, information on assay design, antibody classes including neutralizing antibodies, and the humoral immune responses to SARS-CoV-2 are discussed. Verification and validation of EUA and LDTs are described along with quality management approach. Four indications for serologic testing are outlined. Result interpretation, reporting comments, and the role of orthogonal testing are also recommended. SUMMARY This document aims to provide a comprehensive reference for laboratory professionals and healthcare workers to appropriately implement SARS-CoV-2 serologic assays in the clinical laboratory and interpret test results during this pandemic. Given the more frequent occurrence of outbreaks associated with either vector-borne or respiratory pathogens, this document will be a useful resource in planning for similar scenarios in the future.
1cfcbe82eb3b08c73c09257ad0a82bd6190b1b6d	pubmed	The Saudi Critical Care Society extracorporeal life support chapter guidance on utilization of veno-venous extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome and special considerations in the era of coronavirus disease 2019	The Saudi Critical Care Society extracorporeal life support chapter guidance on utilization of veno-venous extracorporeal membrane oxygenation in adults with acute respiratory distress syndrome and special considerations in the era of coronavirus disease 2019 ‫الدموية‬ ‫للدورة‬ ‫ا‬ ً Extracorporeal membrane oxygenation (ECMO) is considered as a supportive treatment that provides circulatory and ventilatory support and can be thought off as a bridge to organ recovery. Since 2009, it has been applied as a rescue treatment for patients with severe adult respiratory distress syndrome (ARDS) mainly due to viral causes. In December 2019, several patients presented with a constellation of symptoms of viral pneumonia in China. A new strain of the corona virus family, called COVID-19, has been discovered to be the cause of this severe mysterious illness that was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This new virus continued to spread across the globe leading to the World Health Organization announcing it as a pandemic in the early 2020. By the end of March 2021, the number of COVID-19 cases worldwide exceeded 126 million cases. In Saudi Arabia, the first confirmed case of COVID-19 was reported in the 2nd March 2020. By the end of March 2021, the total number of confirmed COVID-19 cases in Saudi Arabia is just above 360,000. In anticipation of the need of ECMO for the treatment of patients with SARS-CoV-2 based on the previous Middle East respiratory syndrome coronavirus pandemic experience, the Saudi Extra-Corporeal Life Support (ECLS) chapter that is under the umbrella of the Saudi Critical Care Society (SCCS) convened a working group of ECMO experts. The mission of this group was to formulate a guidance for the use of ECMO as a last resort for patients with severe ARDS, especially with COVID-19 based on available evidence. The ECLS-SCCS chapter wanted to generate a document that can be used to simple guide, with a focus on safety, to provide ECMO service for patients with severe ARDS with a special focus on SARS-CoV-2. T he Saudi Extracorporeal Life Support chapter, under the Saudi Critical Care Society (SCCS), was established in April 2018. The SCCS-ECLS is an umbrella body for extracorporeal membrane oxygenation (ECMO) experts and providers from different specialties, including but not limited to intensivists, cardiac surgeons, perfusionists, and nurses. The SCCS-ECLS provides high-fidelity simulation training and educational activities to assure competency among health care workers providing ECMO services in Saudi Arabia. This article is the result of a collaborative effort between ECMO experts across Saudi Arabia. The main goal is to discuss, propose, and advocate ECMO-related affairs and matters based on the best medical evidence available in the literature. We hope that this guidance document will help medical teams who are caring for patients with severe acute respiratory distress syndrome (ARDS) requiring ECMO. We will describe the most common issues the medical team might encounter while the patient is on veno-venous (VV) ECMO for acute respiratory distress syndrome. # I. introduction. Extracorporeal membrane oxygenation is a highly complex, labor-intensive standard of care since 1990 in pediatrics and 2009 in adults; [bib_ref] CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory..., Peek [/bib_ref] it is a lung or heart rescue therapy when all conservative management fails to provide life support to the patient.The last decade has shown increasing demand for this kind of service worldwide, particularly during pandemics such as influenza A (H1N1), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and currently, Coronavirus Disease 2019 . [bib_ref] Preparing for the sickest patients with 2009 influenza A (H1N1), White [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome, Australia [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: a..., Pham [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus, Alshahrani [/bib_ref] Extracorporeal membrane oxygenation is a form of medical life support that comes under the umbrella of extracorporeal life support (ECLS), which encompasses several entities used for the temporary support of patients with respiratory and/or cardiac failure. [bib_ref] The Extracorporeal Life Support Organization Maastricht Treaty for nomenclature in extracorporeal life..., Conrad [/bib_ref] Extracorporeal life support is more comprehensive nomenclature that includes the basic mode VV and veno-arterial (VA) ECMO, and the other modes of support that have evolved during last 2 decades, such as extracorporeal cardiopulmonary resuscitation (ECPR) and extracorporeal carbon dioxide removal (ECCO 2 R) [fig_ref] Figure 1 -: The extracorporeal strategies that can be used for supporting patients with ARDS [/fig_ref] shows the extracorporeal strategies that can be used for supporting patients with ARDS). Extracorporeal life support is usually provided by multispecialty units, including cardiothoracic surgery, pediatric surgery, adult intensive care, anesthesiology, cardiology, pulmonary medicine, intensive care, pediatric intensive care, neonatology, and emergency medicine. [bib_ref] Extracorporeal membrane oxygenation: indications, technique and contemporary outcomes, Ali [/bib_ref] The provision of ECMO varies between the countries that provide this service; it was introduced in Saudi Arabia during the H1N1 pandemic and was significantly utilized during the MERS-CoV outbreaks in 2014 by the Ministry of Health (MOH), with favorable outcomes. [bib_ref] Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus, Alshahrani [/bib_ref] A. Important definitions. The Extracorporeal Life Support Organization (ELSO) is an international consortium of health care institutions dedicated to the development and evaluation of novel therapies for supporting failing organ systems. 10 Extracorporeal Life Support Organization retains an international ECMO registry of affiliated centers. The registry data are mainly used for clinical research, and the development of guidelines. Educational programs are also provide. Extracorporeal life support is defined as the use of mechanical devices to temporarily (days to months) support heart or lung function in case of cardiac or pulmonary failure, with the goal of allowing time for heart or lung recovery or as a bridge to transplant.The ECMO is an external artificial circuit that drains venous blood from the patient, passing it through a membrane, where gas exchange takes place (oxygenation and removal of Co2) outside the body, then the blood will be returned back to the venous system to provide respiratory support or to the arterial system to provide circulatory support [fig_ref] Figure 2 -: General demonstration of the standard components of an extracorporeal membrane oxygenation [/fig_ref] summarized the general demonstration of the standard components of an ECMO circuit). # Disclosure. This document is mainly intended to be a general guide for the safe application of extracorporeal life support (ECLS) in critically ill patients with Acute Respiratory Distress Syndrome (ARDS) and was written by experts in the field. A guidance document should not be considered by no means a standard of care. It will be revised at regular intervals as new evidence emerges. The main goal of this guidance document is to serve as an educational tool to be used as a building block for physicians and other health professionals managing patients with the ARDS who will require extracorporeal membrane oxygenation. This guidance document should not be a substitute of clinical judgment. In no event will ECLS-SCCS be liable for any decision made or action taken in reliance upon the information provided through this guidance document. ## B. types of ecmo. Extracorporeal membrane oxygenation types refers to the form of ECMO that describes a specific site from which a cannula draws blood (access) and returns blood from the ECMO machine to patient (return). - Veno-venous ECMO. Provides respiratory support where blood is drawn from and returned to the venous system of the circulation after being oxygenated and decarboxylated. - Veno-arterial ECMO. Provides circulatory support in which blood is drawn from the venous system and returned to the arterial system of the circulation after being oxygenated and decarboxylated. Venoarterial ECMO types can also be divided according to the cannula insertion approach, that is, either the central or peripheral blood vessels. - Central ECMO. The access and return cannulas are inserted directly in the great vessels of the heart or atrium through sternotomy incision. - Peripheral ECMO. The access and return cannulas are inserted in medium-sized vessels in the groin or neck to access the great vessels of the heart or atrium through a percutaneous, semi-percutaneous, or cut-down approach. ## Ii. patient selection criteria A. Veno-venous ECMO for adult patients with severe ARDS. The 2012 Berlin definition for ARDS is "a type of acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, lung weight, and loss of aerated lung tissue. Patient typically present with hypoxia and bilateral infiltrates in chest images, accompanied a significant increase in lung resistance. At a microscopic level, there is diffuse alveolar edema and inflammation or even hemorrhage". 14 Even with maximal conventional therapies for ARDS, some patients continue to deteriorate. Extracorporeal membrane oxygenation is recognized as a supportive treatment that has been shown to improve survival in patients with severe ARDS after exhausting conventional therapies. [bib_ref] Acute respiratory distress syndrome: The Berlin definition, Ards Definition Task Force [/bib_ref] To date, the best available evidence showing benefit in patient selection criteria for VV ECMO are the 2017 ELSO guidelines 4 and the ECMO to rescue acute lung injury in severe ARDS criteria. [bib_ref] Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome, Combes [/bib_ref] The Murray score [bib_ref] Definition of ALI/ARDS, Raghavendran [/bib_ref] and respiratory ECMO survival prediction score [bib_ref] Predicting survival after extracorporeal membrane oxygenation for severe acute respiratory failure. The..., Schmidt [/bib_ref] ## Iii. important considerations for ecmo cannulation. Early referral for ECMO according to patient selection criteria is important for appropriate timing for deploying ECMO. Cannulation can be performed in any location in the hospital according to the patient's current condition, hospital setting, and staffing. The most common location is bedside in the intensive care unit (ICU). However, some centers prefer performing the procedure under fluoroscopy guidance (such, in the vascular or cardiac catheterization laboratory, or the operating room). This should be carried out only if the patient condition allows safe mobilization and transfer to these areas. Careful layout of the procedure by the cannulating physician with team members is paramount considering the following: A. Equipment availability. iii) Pump flow target and patient weight and body surface area, and patient vascular anatomy and vessel size. B. Consideration required before implementing ECMO. The treating team should obtain ECMO consent from the next of kin [fig_ref] Figure 2 -: General demonstration of the standard components of an extracorporeal membrane oxygenation [/fig_ref]. Cross-matched blood products (at least 2 packed red blood cells) to be ready bedside. Correction of any coagulopathy by transfusion of platelets and fresh frozen plasma according to the patient's condition. Ultrasound (US) machine and cardiac echocardiogram probe must be available for ensuring safety. Medication for sedation and muscle relaxation. Heparin (50-100 U/kg), not to exceed 5000 U bolus (this dose includes the priming solution of circuit and machine if present). If the patient's central line is in the right IJ vein, it should be removed after securing a new central line in the counter left side or elsewhere away from the cannulation site (this should be carried out before cannulation to minimize the risk of bleeding or vascular injury while the patient is on therapeutic heparinization). Lastly, a checklist for ECMO insertion. C. Staff and personnel. No consensus or evidence exists to mandate a specific structure. However, the team must fulfill the skills required to perform patient care safely and effectively. The optimum team number should include but is not limited to: i) cannulating physician, ii) intensivist/anesthetist, iii) ICU Nurse, perfusionist, iv) respiratory therapist, v) floater/ ## Contraindications for vv ecmo for respiratory failure: The following are some of the contraindications for ECMO in patients with severe Acute Respiratory Distress Syndrome that should be considered before referral: Absolute Circulatory collapse requiring cardiopulmonary resuscitation for >15 min (no extracorporeal cardiopulmonary resuscitation). Contradictions for anticoagulation (active bleeding or recent major surgery). Poor baseline functional status (Eastern Cooperative Oncology Group score 0-2). 1 (Appendix A) Significant comorbidities associated with poor outcomes: Neurological (such as, stroke within the last 6 months, seizure disorder, dementia). Respiratory (such as, severe chronic obstructive pulmonary disease [COPD], pulmonary fibrosis, cystic fibrosis). Cardiac (such as, severe heart failure with left ventricular election fraction <30% from any cause, history of major cardiac intervention). Gastrointestinal (such as, severe short gut syndrome, Crohn's disease, ulcerative colitis). Hepatological (such as, liver cirrhosis with child-pugh B or C). Advanced solid organ malignancy (such as, advanced-stage colon cancer). Severe peripheral vascular disease. Severe liver failure with elevated International Normalized Ratio and derangement of liver enzymes. Poor neurological status (due to intracranial bleeding, cerebrovascular accident, or others). ## Relative Prolonged high setting mechanical ventilation (>7 days runner (such as, nurse). The following are important considerations for cannulation: a) full aseptic technique, b) for optimal patient safety and outcome, cannulation must be US-guided, unless the cut-down technique is used, as in a limited number of cases. 17 D. Cannulation technique types. i. Percutaneous. The most commonly used approach in adults with less incidence of infection and more patient safety; [bib_ref] Definition of ALI/ARDS, Raghavendran [/bib_ref] [bib_ref] Percutaneous cannulation for extracorporeal life support, Ganslmeier [/bib_ref] involves vessel puncture, guide wire placement, and serial dilation (Seldinger technique). [bib_ref] Cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: Techniques, limitations,..., Jayaraman [/bib_ref] ii. Semi-percutaneous. Used in some cases with difficult vessel identification by palpation or US such as extracorporeal cardiopulmonary resuscitation (ECPR), through a skin cut and gentle subcutaneous dissection to identify the vessels, followed by vessel puncture, guidewire placement, and serial dilation (Seldinger technique). [bib_ref] Percutaneous cannulation for extracorporeal life support, Ganslmeier [/bib_ref] [bib_ref] Cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: Techniques, limitations,..., Jayaraman [/bib_ref] [bib_ref] Choosing the appropriate configuration and cannulation strategies for extracorporeal membrane oxygenation: the..., Sorokin [/bib_ref] iii. Cut-down. Better avoided or restricted to cases after failure of the previous 2 techniques. It should be performed by a surgeon to identify the vessels and cut in the vessel wall, followed by direct cannula insertion. [bib_ref] Percutaneous cannulation for extracorporeal life support, Ganslmeier [/bib_ref] [bib_ref] Cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: Techniques, limitations,..., Jayaraman [/bib_ref] [bib_ref] Choosing the appropriate configuration and cannulation strategies for extracorporeal membrane oxygenation: the..., Sorokin [/bib_ref] E. Veno-venous ECMO configurations. Venovenous ECMO requires deoxygenated venous blood to be removed from the patient by means of a pump, passing it through a membrane lung oxygenator where gas exchange takes place, and then returning the oxygenated and decarboxylated blood to the venous system [fig_ref] Figure 3 -: Common venvenous [/fig_ref]. i. Femoral-IJ VV ECMO. This is the most common cannulation approach. However, we strongly discourage the use of the left IJ vein as a cannulation site. The 2 cannulas are inserted as follows: 1) A drainage (venous) cannula is inserted in the femoral vein. The tip should be in the inferior cavo-atrial junction or just below. 2) A return cannula (arterial) is inserted in the right IJ vein. The tip should be in the superior cavo-atrial junction. [bib_ref] Cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: Techniques, limitations,..., Jayaraman [/bib_ref] ii. Femoral-fem VV ECMO. This is the safest and easier approach. However, it has a higher incidence of recirculation. It can be used in the presence of a contraindication to right IJ vein insertion (such as, thrombosis, clot, or infection). In this technique, 25 cannulas are inserted in the following fashion: 1) A drainage cannula is inserted in the femoral vein. The tip should be in the inferior vena cava (IVC) below the hepatic veins. 2) A return cannula is inserted in contralateral femoral vein. The tip should be at the cavo-atrial junction or in the RA. 3) The tips of both cannulas should be at least 5-10 cm apart to avoid recirculation. ## Iii. double-lumen single venous cannulation. This cannula consists of a wire-enforced double-lumen single cannula with 2 ports: the drainage port drains deoxygenated blood from both IVC and superior vena cava (SVC) through 2 openings; the other port returns oxygenated blood through another separate opening [fig_ref] Figure 2 -: General demonstration of the standard components of an extracorporeal membrane oxygenation [/fig_ref]. [bib_ref] Cannulation strategies in adult veno-arterial and veno-venous extracorporeal membrane oxygenation: Techniques, limitations,..., Jayaraman [/bib_ref] When using this cannula, it should be placed percutaneously under fluoroscopy guidance, trans-esophageal echocardiography (TEE), or transthoracic echocardiography (providing a good bicaval view can be safely obtained). The proper position of the cannula should be confirmed before removing the drape using different modalities (improvement of patient saturation, TEE demonstrating appropriate flow through the return port in the direction of the tricuspid valve, tip of the drainage cannula in the IVC, chest x-ray . This type of cannulation is discouraged for cases that require retrieval from other centers unless it is carried out by a well-trained cannulating ECMO team and only in special situations (such as, pregnant patients). [bib_ref] Choosing the appropriate configuration and cannulation strategies for extracorporeal membrane oxygenation: the..., Sorokin [/bib_ref] F. Determinants of appropriate flow for VV ECMO. i) Determinants of gas exchange. Oxygenation (fraction of inspired oxygen [FiO2]) is dependent on the blood flow through the membrane and the ratio to the native cardiac output. Therefore, the VV ECMO blood flow rates required for supporting systemic oxygenation in adults are estimated to be 60-80 mL/kg/min. Carbon dioxide clearance through ECMO is determined by the rate of "sweep gas" flow, which relies on the properties of the membrane oxygenator. [bib_ref] Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in..., Schmidt [/bib_ref] ii) Determinants of cannula selection. Generally, cannula size selection depends on the estimated required flow; a rough calculation for the cannula diameter could be used [Fr = D (mm) × 3], where Fr is the French gauge system and D is the diameter of the selected blood vessels to be cannulated. [bib_ref] Blood oxygenation and decarboxylation determinants during venovenous ECMO for respiratory failure in..., Schmidt [/bib_ref] Utilizing the flow size chart provided by the manufacturer for each cannula also aids the best cannula selection. iii) Initial ECMO blood flow settings. Patient body surface area and the patient's general clinical condition (such as, high cardiac output status such as sepsis) plays an important role in the decision of optimal cannula size and target flows. Please note that this depends on the physiological target but can be used as general starting points. It should be adjusted based on physiological responses and parameters: - ECMO for cardiac failure: start with 50-60 mL/kg/ min. Take into consideration that there are several factors that can affect the ECMO flow (such as, site used for vascular access, cannula length and size, and cardiac function). - ECMO for respiratory failure: start with 60-80 mL/kg/min. The ECMO oxygenator is always more efficient in CO 2 extraction compared to O 2 delivery, which is noticeable in the blood gases. Several factors can affect the gas exchange during the ECMO run (such as, flow, membrane type, sweep, and patient condition). - ECCO 2 R (for hypercapnic respiratory failure): 25% of cardiac output. [bib_ref] Cannulation techniques for extracorporeal life support, Pavlushkov [/bib_ref] [bib_ref] Cannulation strategies for percutaneous extracorporeal membrane oxygenation in adults, Napp [/bib_ref] IV. ECMO management. A. General management. The attending ICU consultant is the primary intensivist. While the patient is on ECMO support, an ECMO consultant (intensivist or cardiac surgeon) should always be available as a resource. The ECMO consultant and perfusionist on-call contact information should be kept by the patient's bedside. The ECMO consultant role is to manage the ECMO parameters and help in optimizing the patient condition while on ECMO, working closely with the primary intensivist to come up with a daily plan aiming for weaning the patient off ECMO in a reasonable time when the patient recovers. The perfusionist role is to review the patient with the medical team each morning and again before leaving for the evening. The primary intensivist will review the patient daily and set the ECMO plan, involving colleagues experienced in ECMO as required. B. Anticoagulation on ECMO. Heparin is the most common anticoagulant drug used for preventing clot formation inside the cannula, circuit, and membrane lung targeting an activated clotting time (ACT) goal or activated partial thrombin time (aPTT) adjustment. Systemic anticoagulation is usually used to prevent thrombotic complications (in the machine and the patient). However, this should be carefully monitored and adjusted to prevent bleeding complications, which are unfortunately are still high. [bib_ref] Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO, Chlebowski [/bib_ref] [bib_ref] Pediatric extracorporeal life support organization registry international report 2016, Barbaro [/bib_ref] If ACT is used, a range of 180-200 seconds (sec) has been suggested for VV-ECMO. However, different ACT platforms and their relationship to the measured heparin levels and aPTT are inconsistent, especially in the lower ACT target ranges for ECMO. [bib_ref] Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO, Chlebowski [/bib_ref] There are >300 laboratory methods for monitoring aPTT, with different results obtained depending on the method utilized. As a result of this wide variation, the PTT target (1.5 times the normal value) range used at one ECMO center should not be translated to other centers without confirming the type of assay used for aPTT. [bib_ref] Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO, Chlebowski [/bib_ref] The evidence for low-dose heparin during an ECMO run is evolving; however, all expert opinion ensures its safety. A VV ECMO run can be maintained off heparin for days in individual cases, complicating moderate to severe bleeding providing adequate pump flow to avoid blood clotting; in this case, we advise a backup primed machine to be always available. [bib_ref] Low-dose versus therapeutic anticoagulation in patients on extracorporeal membrane oxygenation: a pilot..., Aubron [/bib_ref] Bleeding and thrombotic complications during ECMO are common and have a significant impact on patient outcomes [bib_ref] Pediatric extracorporeal life support organization registry international report 2016, Barbaro [/bib_ref] [fig_ref] Figure 3 -: Common venvenous [/fig_ref] The perfusionist/ECMO specialist should evaluate and examine membrane lung function daily, with pre-and post-membrane gas analysis. The circuit and ECMO machine should be adjusted, under a controlled environment, at the bedside, and protected against kinking or cannula dislodgment. D. Respiratory management on VV ECMO. The challenge in respiratory management on ECMO is to provide balance between allowing good oxygenation with the excessive pump flow required, good volume status and the conservative fluid management required for recovery of wet lung. ## Management of ventilator setting. Ventilator management after ECMO initiation should not be performed unless the appropriate targeted ECMO pump flow is achieved, and the patient's oxygen saturation has improved; ventilator settings should be adjusted to allow lung rest. [bib_ref] CESAR: conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory..., Peek [/bib_ref] Optimum ventilatory goals should be based on ultra-protective lung ventilation [fig_ref] Figure 5 -: Management of veno-venous ECMO and the ventilator PEEP [/fig_ref] ; however, the best evidence available shows that low tidal volume and driving pressure <15 mmHg are associated with good outcome. Thus, any ventilator setting that achieves these goals is accepted [fig_ref] Figure 5 -: Management of veno-venous ECMO and the ventilator PEEP [/fig_ref]. In patients on VV ECMO, reverse oxygen diffusion may occur if the oxygen tension in the pulmonary artery (due to ECMO and native blood flow) exceeds the alveolar PaO 2 . As a rule of thumb, maintaining an FiO 2 of 0.3-0.6 while the patient is on VV ECMO should avoid this problem. ## Management of hypoxia on ecmo. Permissive hypoxemia is accepted cases to maintain an arterial partial pressure of oxygen (PaO 2 ) of 50-55 mm Hg or 80-85% oxygen saturation, providing partial pressure of carbon dioxide (pCO 2 )is normal, to avoid the late complications of cognitive dysfunction post-ECMO. This could help avoid excessive pump flow and thus decrease hemolysis and other possible complications of high pump flow, and allow also better tolerance of conservative fluid management. [bib_ref] Bedside troubleshooting during venovenous extracorporeal membrane oxygenation (ECMO), Patel [/bib_ref] Management of hypoxia on ECMO should be treated cautiously and systematically to reach the definite cause and treat it accordingly. [bib_ref] Troubleshooting adult ECMO, Sidebotham [/bib_ref] The most common causes of hypoxia on ECMO are [fig_ref] Figure 6 -: Low O 2 saturation on ECMO [/fig_ref] : A) Recirculation, a phenomenon exclusive to VV ECMO, in which reinfused oxygenated blood is withdrawn through the drainage cannula without passing through the systemic circulation. 29 B) Drainage insufficiency. C) Other possible causes are listed in [fig_ref] Table 4 -: Possible causes and management of low O 2 saturation on extracorporeal membrane... [/fig_ref]. ## Blood gases management on ecmo i) Change in patient arterial pO 2 a. Increased arterial pO 2 b. Decreased arterial pO 2 (refer to hypoxia algorithm, [fig_ref] Figure 6 -: Low O 2 saturation on ECMO [/fig_ref] ; ii). Change in patient arterial pCO 2 a. Increased patient arterial pCO 2 ( [bib_ref] Timing and Strategy for weaning from venoarterial ECMO are complex issues, Pappalardo [/bib_ref] If that is the case, the cannula position needs to be adjusted accordingly. [fig_ref] Table 6 -: The frequency distribution of the causes of burns in patients [/fig_ref] summarize the causes and how to respond to them. Avoid aerosol-generating procedures such as bronchoscopy and tracheal suction without an in-line suction system in place unless necessary and clinically ## E. hemodynamic management on vv ecmo. It is important to know that VV ECMO has no direct effect on preload or afterload, and cardiac output is entirely dependent on native cardiac function. The inotropic support requirement pre-ECMO is multifactorial; in most cases, post-ECMO inotropic requirement is reduced due to better organ perfusion and correction of blood gases. A strong relation can also be observed with reducing ventilator settings, which may be due to decreased pulmonary cytokine release. In case of sub-optimal flow, a fluid challenge can be administrated. Although, fluid overload should be prevented. If an arterial saturation of 80-85% could not be achieved, the team should consider the insertion of a second access line to improve saturation > 88%. F. Sedation. Deep sedation sufficient for inhibiting respiratory movement is required after initiation of ECMO up to the first 48 h to achieve stability. The use of infusions complemented by intermittent boluses as needed is highly recommended. Sedation management should be treated during the first 48 h, with early cessation of muscle relaxant if present, preferably not to exceed 48 h. The treating team plan for sedation should by discussed with the ECMO consultant during the entire ECMO run, with daily Richmond agitation sedation scale (RASS) goal or equivalent score and daily assessment of consciousness. Once the patient is stable on VV ECMO, less sedation should be used. This should not be on the expense of making the patient less comfortable. The medical team should aim for the lowest sedation dose possible that will maintain satisfactory oxygen delivery yet at the same time does not compromise patient comfort. It may be possible to extubate the patient while on ECMO. However, this is not common practice, and evidence in outcome is limited to expert opinion and is still evolving. Early physiotherapy and mobilization are highly encouraged, which has been found to be safe with restricted protocols in expert centers. ## I. other medical management on vv ecmo i. investigations required for patients on ecmo - Daily CXR and as indicated. - Daily blood work: complete blood count (CBC), urea, creatinine, electrolytes; magnesium, PO 4 ; liver function tests (LFT) including lactate dehydrogenase (LDH), activated partial thromboplastin time (aPTT), international normalized ratio (INR), fibrinogen, D-dimer, and free plasma hemoglobin or haptoglobin if available. - The ACT is usually used to titrate heparin in the first 24 h and is measured every 2 h over the first day. - After the first 24 ours, aPTT should be performed in the hematology lab every 4-6 hours and used as a guide heparin therapy. Factor XI assay can be used to guide heparin therapy; however, the protocol is complex and not commonly used. - Minimize performing blood collection unless it is necessary (such as, collecting blood cultures). ii. Antibiotics - Should be prescribed as indicated by physiological parameters or laboratory investigations or cultures. ## Iii. feeding - Patient should be fed as per the unit practice. - When possible, a nasogastric tube (NGT) should be inserted. - Prevention gastric stress ulcer: the use of intravenous (IV) proton pump inhibitor is usually recommended. iv. Renal - Pharmacological or mechanical diuresis can be used safely for patients on ECMO. - Fluid status is very important on ECMO and can be very dynamic. The medical team should use the patient's parameters and ECMO flow as a guide. - CRRT please write the meaning in full can be provided as per unit policy from a separate dialysis line or through the ECMO circuit. - CRRT from the ECMO circuit requires the perfusionist to place the connection and has a higher risk of entraining air into the ECMO circuit. v. General nursing care - Logrolling of patient on ECMO (for back care or cleaning) can be carried out but should be minimized. - Needs adequate staffing and experienced team are required for moving patients on ECMO. - Extra caution should be practiced when moving patient on ECMO. - Some expert centers have found that mobilizing the patient or even walking on ECMO is safe; it requires a well-trained ECMO physician and perfusionist/ECMO specialist to manage possible troubleshooting. G. Liberation from VV ECMO. This would require clinical assessment of readiness for weaning off ECMO [fig_ref] Figure 7 -: Assessment of patient readiness for weaning off veno-venous ECMO PEEP [/fig_ref]. If the patient is considered ready to liberate from VV ECMO, then please refer to the "VV ECMO Liberation Process." - Veno-venous ECMO liberation process [fig_ref] Figure 8 -: Process of liberation from veno-venous ECMO [/fig_ref]. Extracorporeal membrane oxygenation discontinuation should pass through 4 defined stages: Stage I: Signs of improvement, stage II: ECMO weaning, Stage III: Trial off, and finally Stage IV: Decannulation. [bib_ref] How to wean a patient from veno-arterial extracorporeal membrane oxygenation, Aissaoui [/bib_ref] Reduction of ECMO support in terms of sweep gas reduction and FiO 2 requirement. [bib_ref] How to wean a patient from veno-arterial extracorporeal membrane oxygenation, Aissaoui [/bib_ref] 2. Stage II: ECMO weaning. Stage II is defined as the process of gradually decreasing total ECMO support to remove mechanical heart/lung support from the patient. Weaning trials off ECMO should take place on moderate ventilator settings to allow escalation in case of deterioration after decannulation of ECMO. In stage II, advancement from lung rest to a lung protective strategy to provide safe mechanical ventilator settings on ECMO support is better to be defined as: i) FiO 2 <50%, ii) Positive end-expiratory pressure ≤10, iii) Vt 6-8 mL/kg for ideal body weight (IBW) to keep peak inspiratory pressure <30 and plateau <25, iv) RR (respiratory rate) <28 bpm to obtain mechanical ventilation ~100 mL/kg, v) Acceptable arterial blood gases (ABG) on decremental ECMO support: pH >7.3, PaO 2 >60 mm Hg, PaCO 2 ≤60 mmHg (providing pH >7.3). vi) Compliance is stable or improving preferably > 0.5 mL/kg IBW. Adjust sedation to allow spontaneous breathing. [bib_ref] Timing and Strategy for weaning from venoarterial ECMO are complex issues, Pappalardo [/bib_ref] If the above parameters are satisfied, the sweep gas flow is reduced in steps to 1-2 L/min sweep, while FiO 2 is maintained at 50%. The pCO 2 should be ≤60 mmHg with normal pH . Please note that for respiratory VV ECMO, the ECMO circuit blood flow does not need to be decreased or adjusted while attempting weaning from VV ECMO. ## Stage i: signs of improvement. this stage starts after improvement of lung function and 3. Stage III (Trial off). Defined as temporary cessation of ECMO support (sweep turned off: 0 L/min on VV ECMO) as a test for native lung recovery prior to decannulation. Turn off oxygenator sweep gas flow; maintain ECMO blood flow. Over 6 h, if gas exchange, respiratory mechanics, and hemodynamic parameters are acceptable, stop heparin infusion, then proceed for decannulation and discontinuing ECMO. In this stage, sweep gas flow is reduced in steps to 1-2 L/min; sweep FiO 2 is maintained at 100%. The pCO 2 should be ≤60 mmHg with normal pH . Extracorporeal membrane oxygenation circuit blood flow does not need to be adjusted or changed while attempting weaning from VV ECMO. [bib_ref] A Weaning protocol for venovenous extracorporeal membrane oxygenation with a review of..., Grant [/bib_ref] 4. Stage IV (Decannulation). Defined as removing the access and drainage cannulas and stopping ECMO support. Follow-up 24 h for possible bleeding from cannula sites. It is highly recommended to rule out any possible deep venous thrombosis (DVT) 48 hours post-decannulation. Some centers prefer to resume therapeutic anticoagulants after decannulation for 48 hours to avoid the development of DVT at the cannulation sites and to avoid pulmonary embolism (PE). Formal assessment of the status of the cannulated vessels (VV ECMO, veins; VA ECMO, vein and artery) using Doppler US should be carried out within 48-72 hours after decannulation. Decannulation is usually performed in the ICU at the bedside unless there is a need for vascular access repair or difficulty of removal that requires surgical intervention. [bib_ref] Manual of extracorporeal membrane oxygenation (CMO) in the ICU, Brogan [/bib_ref] In a special situation: Forced premature ECMO liberation on safe high ventilator settings may be required when the patient develops complications that require urgent ECMO discontinuation (such as, massive bleeding). This should be performed in consultation with the ECMO consultant, and a second opinion is always advised (such as, another ECMO consultant or the command center lead). ## V. troubleshooting. Several common scenarios can be encountered during the patient run on ECMO. Some of them are related to the patient and some of them are related to the machine. The medical team must be prepared to deal with these issues (Appendix A). ## Vi. Eextracorporeal membrane oxygenation during the COVID-19 pandemic and special considerations. Since the start of the COVID-19 pandemic in Wuhan, China, in early 2020, the SCCS has been actively monitoring and evaluating the situation across the globe since the World Health Organization (WHO) announced the emergence of the novel coronavirus. On March 2, 2020, the MOH announced the first confirmed case of COVID-19 in Saudi Arabia.Since then, the SCCS has been actively involved in developing several scientific statements and customized guidelines by local experts based on up-to-date information to aid health care practitioners. [bib_ref] The Saudi critical care society clinical practice guidelines on the management of..., Alhazzani [/bib_ref] Early in the pandemic, Ramanathan et al 37 encouraged that health care systems should make appropriate plans in the anticipation of the need for ECMO in patients with COVID-19 SARS-CoV. As ELSO is the scientific body and world leading group in managing patients with ECMO, they have released a consciences with the title "A Consensus Document from an International Group of Interdisciplinary Extracorporeal Membrane Oxygenation Providers" that have been published the American Society for Artificial Internal Organs (ASAIO) journal. [bib_ref] Extracorporeal Life Support Organization Coronavirus disease 2019 interim guidelines: a consensus document..., Shekar [/bib_ref] The main message is that the delivery of ECMO should be based on the healthcare system ability to maintain this finite and resource intensive modality without compromising other resources. The consciences paper working group have strongly discouraged the initiation of a new ECMO center during the COVID-19 pandemic for the treatment of patients with SARS-CoV. In a study by [bib_ref] Extracorporeal membrane oxygenation support in COVID-19: an international cohort study of the..., Barbaro [/bib_ref] 1035 patients from 213 hospitals across the globe who received ECMO for COVID-19 ARDS. Ninety days mortality for this cohort was approximately 37%. A study conducted in Paris-Sorbonne University Hospital Network, France in a health network with an expert ECMO group had similar results. [bib_ref] Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome associated with COVID-19:..., Schmidt [/bib_ref] On April 9, 2020, the Saudi ECLS chapter, which is under the SCCS, released a statement paper for managing patients with ARDS due to COVID-19 (Appendix, [fig_ref] Figure 6 -: Low O 2 saturation on ECMO [/fig_ref]. This statement was quite conservative because, at that time, there was insufficient scientific evidence on the support of patients with ARDS secondary to COVID-19, yet the chapter members felt that some groups of patients might benefit from ECMO, and at the same time it would allow evaluation of the available but limited ECMO resources in the country (including: the number of centers, machines, supply, cannulas, and trained medical personal). With better understanding of the pathophysiology of ARDS in patients with COVID-19, especially patients who would require ECMO, the Saudi ECLS chapter released a second version of the statement with more liberal patient selection criteria (Appendix, [fig_ref] Figure 7 -: Assessment of patient readiness for weaning off veno-venous ECMO PEEP [/fig_ref]. An ECMO hotline has been created under the umbrella of the MOH command and control center. The main objective of the ECMO hotline is to connect critical care providers to local ECMO experts and to facilitate the management of patients who could benefit from ECMO support. To date, more than 180 patients have been supported with several forms of ECMO (with >95% supported with VV ECMO) (Source: MOH ECMO Supervisor, Dr. M H Azzam). ## Eastern cooperative oncology group (ecog) performance status Grade ECOG 0 Fully active, able to carry out all pre-disease performance without restriction 1 Physically strenuous activity is restricted, but is ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about for >50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair for >50% of waking hours 4 Completely disabled. Cannot carry out any selfcare. Totally confined to bed or chair 5 Dead [fig_ref] Table 1 -: General indications for veno-venous [/fig_ref]. ii. Pump failure [fig_ref] Figure 2 -: General demonstration of the standard components of an extracorporeal membrane oxygenation [/fig_ref] If the pump suddenly stops, the medical team should call for help. Then start by clamping the ECMO lines and transfer the circuit to the replacement emergency pump driver; plug into battery power. Focus on resuscitating the patient by increasing mechanical ventilator parameters (FiO2 of 100%, increase respiratory rate, manual ventilation, so on). When the circuit is connected to the functional pump, increase the RPMs to previous setting. iii. Oxygenator failureSeveral predictors and indicators can highlight an impending oxygenator failure: ↑ pCO2, ↓pO2, ↓patient O 2 % saturation, Increase in transmembrane pressure and the presence of plasma or blood leakage from gas outlet. This can be confirmed by doing a pre-and post-oxygenator blood gases. If the PO2 is not increasing appropriately based on the FiO2 supply, then oxygenator failure should be suspected. In case of an oxygenator failure, the management should focus on increase sweep and FiO2 then call perfusionist. Ventilate the patient and maintain cardiac output. If no improvement or patient is deteriorating, then an Urgent ECLS team callout should be carried out and the membrane should be changed. Check pre-and post-oxygenator blood gases ↑ FiO2 d) ↓ pCO2 Check pre-and post-oxygenator blood gases ↑ Sweep iv. Circuit rupture [fig_ref] Figure 3 -: Common venvenous [/fig_ref] In the scenario of a circuit rupture, the ECMO lines should be Clamp the lines before and after the breach. Manage the patient as per advanced cardiac life support (ACLS). And an urgent ECLS team call-out should be carried out. [fig] Figure 1 -: The extracorporeal strategies that can be used for supporting patients with ARDS. ECMO: extracorporeal membrane oxygenation (ECMO). ECCO 2 R: extracorporeal CO 2 removal [/fig] [fig] Figure 2 -: General demonstration of the standard components of an extracorporeal membrane oxygenation (ECMO) circuit. Saudi Med J 2021; Vol. 42 (6) https://smj.org.sa [/fig] [fig] Figure 3 -: Common venvenous(VV) extracorporeal membrane oxygenation (ECMO) configurations. A) Conventional VV ECMO, fem-IJ configuration. B) Fem-fem VV ECMO. C) Single cannula with dual ports, one for drainage and another for return that directs oxygenated blood toward the tricuspid valve. [/fig] [fig] Figure 4 -: Anticoagulation on veno-venous extracorporeal membrane oxygenation. INR: International Normalized Ratio, aPTT: activated partial thromboplastin time, ACT: activated clotting time, CBC: complete blood count pressure should be forwarded to the ECMO consultant. [/fig] [fig] Figure 5 -: Management of veno-venous ECMO and the ventilator PEEP: peek end expiratory pressure, Pplat: plateau pressure, ECMO: extracorporeal membrane oxygenation, ARDS: acute respiratory distress syndrome, FiO2: oxygenation, IBM: ideal body mass, IBW: ideal body weight, H 2 0: water, RR: respiratory rate, PaO2: partial pressure of oxygen [/fig] [fig] Figure 6 -: Low O 2 saturation on ECMO. LDH: lactate dehydrogenase, ECMO: extracorporeal membrane oxygenation, PEEP: peek end expiratory pressure, IV: FiO 2 : fraction of inspired oxygen, Hb: hemoglobin, PO2: partial pressure of oxygen, DIC: disseminated intravascular coagulation, SVC: superior vena cava, IV: intravenous [/fig] [fig] Figure 7 -: Assessment of patient readiness for weaning off veno-venous ECMO PEEP: peek end expiratory pressure, Pplat: plateau pressure, ECMO: extracorporeal membrane oxygenation, ARDS: Acute Respiratory Distress Syndrome, FiO2: oxygenation, ABG: arterial blood gasses reversal of the primary disease. This is usually assessed by: i) Improvement of CXR (not mandatory), ii) Improvement of lung compliance and gas exchange while on ECMO, evident by: a) Improvement of tidal volume (Vt) on fixed pressure control settings and b) [/fig] [fig] Figure 8 -: Process of liberation from veno-venous ECMO. peek end expiratory, Pplat: plateau pressure, ECMO: extracorporeal membrane oxygenation, ARDS: Acute Respiratory Distress Syndrome, FiO2: oxygenation, IBW: ideal body weight, RSC; respiratory system compliance, H: hours, ABG: arterial blood gasses, CXR: chest x-ray, PEEP: peek end expiratory pressure Saudi Med J 2021; Vol. 42 (6) https://smj.org.sa [/fig] [fig] Figure A1 -: Variable flow on veno-venous extracorporeal membrane oxygenation (ECMO). Saudi Med J 2021; Vol. 42 (6) https://smj.org.sa 2) Venous insufficiency • Low flow, venous negative pressure alarm, or fluctuation of pump flow are possible signs of venous insufficiency. Patient SpO2 may decrease [/fig] [fig] Figure A2 -: Pump failure. VV: veno-venous, VA: veno-arterial, ECMO: extracorporeal membrane oxygenation, ICU: intensive care unit, ACLS: advanced cardiac life support [/fig] [fig] Figure A3 -: Circuit rupture. VV: veno-venous, VA: veno-arterial, ECMO: extracorporeal membrane oxygenation, ICU: intensive care unit, ACLS: advanced cardiac life support Saudi Med J 2021; Vol. 42 (6) https://smj.org.sa v. Accidental decannulation (Figure A4) In case of an accidental decannulation, the ECMO lines should be clamped and the site of cannula on the patient should be compressed. Manage the patient as per ACLS. An Urgent ECLS team callout. [/fig] [fig] Figure A4 -: Accidental decannulation VV: veno-venous, VA: veno-arterial, ECMO: extracorporeal membrane oxygenation, ICU: intensive care unit, ACLS: advanced cardiac life support vi. Air embolism (Figure A5) In the scenario of an air embolism, the ECMO lines should be clamped and Switch off the ECMO. The patient should be managed as per ACLS. An urgent ECLS team callout. [/fig] [fig] Figure A5 -: Accidental decannulation VV: veno-venous, VA: veno-arterial, ECMO: extracorporeal membrane oxygenation, ICU: intensive care unit, ACLS: advanced cardiac life support [/fig] [table] Table 1 -: General indications for veno-venous (VV) ECMO. for VV ECMO for respiratory failure:Consider referring a patient with severe acute respiratory distress syndrome (ARDS) after optimization of all other conventional modalities if the patient has: [/table] [table] Table 3 -: Possible causes and management of bleeding on extracorporeal membrane oxygenation (ECMO). [/table] [table] Table 5: b. Decreased patient arterial pCO 2 . If adequate oxygenation cannot be maintained (persistently low O 2 saturation) at a low or normal central venous pressure Saudi Med J 2021; Vol. 42 (6) https://smj.org.sa [/table] [table] Table 4 -: Possible causes and management of low O 2 saturation on extracorporeal membrane oxygenation (ECMO). [/table] [table] Table 6 -: The frequency distribution of the causes of burns in patients [/table] [table] Table A1 -: Venous insufficiency. Change in venous cannula position Reduce pump speed (rpm) temporarily and optimize ventilator settings This will improve venous drainage until the cause is addressed and there is definitive management Hypovolemia If patient is hypovolemic due to high urine output: Aggressive diuresis, bleeding, etc. Volume assessment Give volume/transfuse Other causes of increased intrathoracic or abdominal pressure (pneumothorax, cardiac tamponade, intrabdominal bleeding, and so on) Venous line obstruction by clot or kink or twist Change the patient position and/or venous cannula position Tip migration Check by x-ray Check tubing and pump head for fibrin or clot Consider changing the cannula or circuit Consider FAST (focused assessment with sonography for trauma) exam and manage accordingly May require surgical intervention [/table] [table] Table A2 -: Possible causes of oxygenator failure. [/table] [bib_ref] Extracorporeal membrane oxygenation for 2009 influenza A(H1N1) acute respiratory distress syndrome, Australia [/bib_ref]	None	https://smj.org.sa/content/smj/42/6/589.full.pdf	Extracorporeal membrane oxygenation (ECMO) is considered as a supportive treatment that provides circulatory and ventilatory support and can be thought off as a bridge to organ recovery. Since 2009, it has been applied as a rescue treatment for patients with severe adult respiratory distress syndrome (ARDS) mainly due to viral causes. In December 2019, several patients presented with a constellation of symptoms of viral pneumonia in China. A new strain of the corona virus family, called COVID-19, has been discovered to be the cause of this severe mysterious illness that was named severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2). This new virus continued to spread across the globe leading to the World Health Organization announcing it as a pandemic in the early 2020. By the end of March 2021, the number of COVID-19 cases worldwide exceeded 126 million cases. In Saudi Arabia, the first confirmed case of COVID-19 was reported in the 2nd March 2020. By the end of March 2021, the total number of confirmed COVID-19 cases in Saudi Arabia is just above 360,000. In anticipation of the need of ECMO for the treatment of patients with SARS‑CoV‑2 based on the previous Middle East respiratory syndrome coronavirus pandemic experience, the Saudi Extra-Corporeal Life Support (ECLS) chapter that is under the umbrella of the Saudi Critical Care Society (SCCS) convened a working group of ECMO experts. The mission of this group was to formulate a guidance for the use of ECMO as a last resort for patients with severe ARDS, especially with COVID-19 based on available evidence. The ECLS-SCCS chapter wanted to generate a document that can be used to simple guide, with a focus on safety, to provide ECMO service for patients with severe ARDS with a special focus on SARS‑CoV‑2.
ef821ecd8097d484f2ed0d61ea18e1c93afa9077	pubmed	Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease	Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease The European Network for Infectious Diseases (EUNID) is a network of clinicians, public health epidemiologists, microbiologists, infection control, and critical-care doctors from the European member states, who are experienced in the management of patients with highly infectious diseases. We aim to develop a consensus recommendation for infection control during clinical management and invasive procedures in such patients. After an extensive literature review, draft recommendations were amended jointly by 27 partners from 15 European countries.Recommendations include repetitive training of staff to ascertain infection control, systematic use of cough and respiratory etiquette at admission to the emergency department, fl uid sampling in the isolation room, and analyses in biosafety level 3/4 laboratories, and preference for point-of-care bedside laboratory tests. Children should be cared for by paediatricians and intensive-care patients should be cared for by critical-care doctors in high-level isolation units (HLIU).Invasive procedures should be avoided if unnecessary or done in the HLIU, as should chest radiography, ultrasonography, and renal dialysis. Procedures that require transport of patients out of the HLIU should be done during designated sessions or hours in secure transport. Picture archiving and communication systems should be used. Post-mortem examination should be avoided; biopsy or blood collection is preferred. # Introduction Over the past two decades, many new and re-emerging diseases have posed threats to public health and have provided new challenges for infectious disease researchers worldwide. Expansion of human populations has caused both a greater proximity to wildlife habitats, resulting in the emergence of new zoonoses, and a massive urbanisation process, which facilitates the rapid spread of communicable diseases in human beings. Travel across the world has become increasingly frequent, resulting in the ever-increasing risk of worldwide contagion spread. These emerging problems were highlighted during the severe acute respiratory syndrome (SARS) epidemic. 1 Imported highly infectious diseases (HID), such as Lassa fever and viral haemorrhagic fever, have been reported many times in the literature but have seldom been at the origin of an outbreak. 2,3 Terrorist attacks with biological agents pose a substantial threat to the safety, health, and security of the citizens of every country. As defi ned in the 2007 issue of the Biosafety in Microbiological and Biomedical Laboratories manual, 4 "group 3 agents are pathogens that usually cause serious human or animal disease but do not ordinarily spread from one infected individual to another and eff ective treatment and preventive measures are available," whereas "group 4 are pathogens that usually cause serious human or animal disease and that can be readily transmitted from one individual to another, directly or indirectly. Eff ective treatment and preventive measures are not usually available." Several laboratoryassociated infections with group 3 and 4 pathogenic agents have already been reported. [bib_ref] Laboratory-acquired infections with Hantaan virus, the etiologic agent of Korean hemorrhagic fever, Lee [/bib_ref] [bib_ref] Laboratory acquired tick-borne meningoencephalitis: characterisation of virus strains, Avsic-Zupanc [/bib_ref] [bib_ref] Brief report: treatment of a laboratory-acquired Sabia virus infection, Barry [/bib_ref] [bib_ref] Laboratory-acquired Sabia virus infection, Ryder [/bib_ref] [bib_ref] Laboratory-acquired vaccinia infection, Loeb [/bib_ref] Although laboratories that handle group 3 and 4 agents should comply with biosafety regulations, laboratory leakage can happen at any time, for example, when working with a known agent or when attempting to isolate an unknown infectious agent, such as occurred with mimivirus. [bib_ref] Laboratory infection of a technician by mimivirus, Raoult [/bib_ref] Experience shows that the recognition and isolation of a new infectious agent is often followed by a reported laboratory-acquired infection caused by the new isolate, as was reported for SARS. [bib_ref] Biological safety cabinetry, Kruse [/bib_ref] [bib_ref] Laboratory-acquired severe acute respiratory syndrome, Lim [/bib_ref] The infection of a single laboratory worker with a highly infectious agent could be the origin of an outbreak, particularly if the agent has the capability of human-to-human transmission (ie, SARS-associated coronavirus). [bib_ref] Laboratory-acquired severe acute respiratory syndrome, Lim [/bib_ref] In some situations, such as a cough in so-called "superspreader" patients with extremely drug-resistant tuberculosis, smallpox, or SARS-associated coronavirus, or exposure to infected blood of a patient with late-phase haemorrhagic fever, the inoculums to which health-care workers are exposed are likely to be equivalent to those received by a laboratory worker during specimen handling. The care of such patients should consequently be administered in a way to ensure the same level of protection and safety to health-care workers as to laboratory workers exposed to the same agent. # Methods The European Network for Infectious Diseases (EUNID) comprises 30 national representatives and experts from [bib_ref] Laboratory acquired tick-borne meningoencephalitis: characterisation of virus strains, Avsic-Zupanc [/bib_ref] European member states and is funded by the European commission, within its Public Health and Risk Assessment Programme.It was created to exchange information, share best practices, develop training, and improve the connection between national and regional Review infectious disease experts. This network of clinicians, public health epidemiologists, microbiologists, infectioncontrol and critical-care clinicians, who are experienced in the management of HID, represent national or regional infectious diseases units designated to care for patients with HID. One of EUNID's agreed tasks was to develop a consensus statement on the design and operation of high-level isolation units (HLIU) in Europe. [bib_ref] Framework for the design and operation of high-level isolation units: consensus of..., Bannister [/bib_ref] An HID is transmissible from person to person, causes life-threatening illness, presents a serious hazard in health-care settings and the community, and therefore requires specifi c control measures. [bib_ref] Framework for the design and operation of high-level isolation units: consensus of..., Bannister [/bib_ref] An HLIU is defi ned as a health-care facility that is specifi cally designed to provide safe, secure, high-quality and appropriate care, with optimum infection containment, infection prevention, and control procedures for a single patient or a small number of patients who have, or who may have, an HID. These units have also been described as biocontainment units by US experts. [bib_ref] Designing a biocontainment unit to care for patients with serious communicable diseases:..., Smith [/bib_ref] We defi ne an isolation room as a single-bed room with negative pressure. Our task was to develop a consensus statement for infection control during clinical management and invasive procedures in HID patients admitted to an HLIU. To assess this task, an expert (PB) was co-opted and charged by EUNID to do an extensive review and draft recommendations on infection control in the situations mentioned above. The draft recommendations were amended by the coordination team, and further refi ned jointly by the 27 partners from 15 European member states and the coordination team. The fi nal consensus was reached and validated during two consecutive meetings in Rome in May and October, 2007. The draft manuscript was then shared within the network by e-mail and revised to incorporate comments and additional evidence provided by participants until a fi nal version was reached. # Results ## Situations in which a patient would need to be admitted in an hliu Among the several possible scenarios that may be considered, epidemics outside Europe of a yet unknown contagious agent or a known group 3 or 4 agent, such as SARS-associated coronavirus or viral haemorrhagic fever, are the most likely to occur. Alternatively, a laboratory worker may become sick after being exposed to a known agent in a registered biosafety level 3 or 4 laboratory while doing his or her duty, such as in the last SARS outbreak in China and Singapore. [bib_ref] Laboratory-acquired severe acute respiratory syndrome, Lim [/bib_ref] [bib_ref] Recent Singapore SARS case a laboratory accident, Senior [/bib_ref] A third possible situation is intentional release of a bioterrorism agent. If an outbreak of a human-to-human transmissible disease begins in one country, the fi rst case it likely to be missed. Thus, other implementations, such as routine respiratory and hand hygiene in health-care settings, healthcare personnel surveillance, and prompt reporting of such patients to national public-health authorities are mandatory. [bib_ref] Severe acute respiratory syndrome: preparedness, management, and impact, Loeb [/bib_ref] The decision to care for patients in an HLIU is based on the capability of the agent to have human-to-human transmission, its transmission rate, and the availability of primary or secondary prophylaxis, such as vaccines or eff ective antimicrobial therapy. Although the role of ## Giant viruses ## Mimivirus Hospital-acquired pneumonia [bib_ref] Laboratory infection of a technician by mimivirus, Raoult [/bib_ref] ## § unknown standard droplet HLIU=High-level isolation unit. SARS=severe acute respiratory syndrome. As defi ned by the Centers for Disease Control and Prevention, WHO, and the European Community Directive.†Note that most of the guidelines are based on a very small number of clinical cases and that level of evidence and grading are not necessarily accurate. ‡In vaccinated personnel. §Not an offi cial classifi cation, but we recommend this level because laboratory-acquired pneumonia has previously occurred. ## Admission of patients with hid to emergency departments Emergency departments of general hospitals are the primary units where interaction with an unknown HID is most likely, and because many such units were not prepared for this kind of medical situation, they paid a heavy price during the SARS outbreak. [bib_ref] SARS exposure and emergency department workers, Chang [/bib_ref] [bib_ref] SARS outbreak in the Greater Toronto Area: the emergency department experience, Borgundvaag [/bib_ref] [bib_ref] Responding to the severe acute respiratory syndrome (SARS) outbreak: lessons learned in..., Farquharson [/bib_ref] Even now, most of our hospitals are still not prepared to face these kinds of situations. [bib_ref] Emergency departments (EDs) in the United Kingdom (UK) are not prepared for..., Anathallee [/bib_ref] Until a suitable network of care for such patients, with communication between health-care workers prior to referral, becomes eff ective in each country, patients suspected of being infected with a highly contagious agent are more likely to be referred to the emergency department of a general hospital by their general practitioner. As a consequence, the emergency department of any hospital should be prepared for such events, and both training and structural features should be implemented. [bib_ref] Severe acute respiratory syndrome: preparedness, management, and impact, Loeb [/bib_ref] Based on studies of SARS transmission, measures designed to control respiratory droplets and secretions, along with hand hygiene, would seem to off er signifi cant protection to other patients and health-care workers who have close contact with source patients. [bib_ref] Eff ectiveness of precautions against droplets and contact in prevention of nosocomial..., Seto [/bib_ref] Given the challenge of recognising early HID cases, and considering the potential for the spread of respiratory infections in health-care settings, the US Centers for Diseases Control and Prevention (CDC) recommended a broader strategy to prevent health-care-associated transmission of respiratory illnesses in response to SARS.In addition to standard precautions, the CDC suggest that an effi cient measure to reduce the risk of infection transmission needs to be systematically implemented by health-care workers. The CDC described the new standard approach to manage patients with febrile respiratory illness as "respiratory hygiene" or "cough etiquette".Patients with cough and fever should be encouraged to report symptoms at admission and should be encouraged or asked to wear a surgical mask and wash their hands after contact with respiratory secretions. These patients should be separated from other patients in the waiting area, and should be examined and assessed as soon as possible by the emergency staff in a single room.Signs should be displayed in the waiting areas to promote these measures and to educate patients and health-care workers, and emergency staff should comply with droplet precautions. However, because the modes of infectious agent transmission are often underestimated, as was recently reported for infl uenza and SARS, [bib_ref] Transmission of infl uenza: implications for control in health care settings, Bridges [/bib_ref] and because tuberculosis cannot be identifi ed without biological testing, EUNID recommends that droplet precaution should be upgraded to airborne precaution each time Situations in which a patient would need to be admitted to an HLIU - Patients with an unknown human-to-human transmittable or a potentially transmittable epidemic febrile illness that is native or imported from abroad - Patients with a known infectious disease caused by a group 3 or 4 agent At admission of patients with HID to an emergency department - Systematically apply standard precautions and cough and respiratory etiquette - Set up at least one single room with a dedicated route and direct access, or an isolation room as recommended by EUNID for a referral hospital, † if HLIU cannot be used for ruling out HID diagnoses - Off er special training to the emergency department team - Retain close relationships with the HLIU team of the referral hospital ## Admission and management of paediatric patients with hid in an hliu - For infection-control reasons, all children suspected to be infected with an HID should be admitted to an HLIU - Family participation should be minimised - The HLIU responsible manager should make all eff orts to be prepared and be able to provide nursing care compatible with children's requirements ## Intensive-care practice in patients with hid - If possible, perform intensive-care therapy in the HLIU in collaboration with the infectious disease team; the HLIU should be pre-equipped for critical care - If a patient with HID is cared for in the intensive-care unit, the unit should be subjected to negative pressure - Manual ventilation duration during resuscitation procedures should be reduced to a minimum - Use NPPV instead of facial mask aerosol therapy when possible and intubation/ mechanical ventilation instead of NPPV when safely achievable with maximum precautions - Endotracheal intubation should be done with rapid sequence induction by the most skilled person available, who should wear personal protective equipment - Meticulous infection-control measures must be followed in case of ventilated patients with HID, particularly during suctioning, tracheotomy, and bronchoscopy with or without bronchoalveolar lavage HLIU=High-level isolation unit; NPPV=non-invasive positive pressure ventilation. *As summarised in tables 1 and 2. †A hospital to which the patients with HID are usually referred to either by national authority directives or by their own expertise and reference. ‡This remains a matter of debate in our group. that involvement of one of these agents is suspected. Consequently, chest radiography should be done separately from other patients, a systematic examination of sputum for acid-fast bacteria should be prescribed when pneumonia is diagnosed (to rule out tuberculosis), and the patient should remain in isolation until the threat of tuberculosis is eliminated. [bib_ref] Foundations of the severe acute respiratory syndrome preparedness and response plan for..., Srinivasan [/bib_ref] Patients with suspected HID should be placed directly in an emergency department isolation room (EDIR), if available. During admission, such patients should avoid any contact with other patients and unprotected healthcare workers, and therefore direct access to the EDIR from outside the unit is required. [bib_ref] Hospital preparedness for severe acute respiratory syndrome in the United States: views..., Srinivasan [/bib_ref] EDIRs should comply as much as possible with the design and operational management recommendations made by EUNID for HLIU. [bib_ref] Framework for the design and operation of high-level isolation units: consensus of..., Bannister [/bib_ref] Whereas general respiratory hygiene rules and cough etiquette should apply to every emergency department of every general hospital, isolation rooms could be available in referral hospitals only. A patient with a possible or confi rmed HID, if not admitted directly to an HLIU, should be transferred from the EDIR to the HLIU in a secure manner, by use of a safe isolation transportation system, 58 or at least by staff wearing personal protective equipment and using a clear and secure route. Although these general recommendations may be diffi cult to apply in the usual understaff ed, overworked, and busy environments, implementation of these measures is important. These recommendations would also help prevent the transmission of many other important pathogens that are spread by the droplet route, such as infl uenza and Mycoplasma pneumoniae. 53 ## Sampling hid patients for laboratory analysis Clinicians should remember that the most likely cause of fever in a tropical traveller is malaria, which is far more common than a new or emerging HID. Consequently, EUNID fi rst advocates that everything possible should be done to rule out the most frequent diff erential diagnoses without delay. To reduce the risk of transmission to health-care workers, samples from patients should be taken in the EDIR or HLIU, depending on availability. Severely ill patients may necessitate frequent blood sampling and intravenous line placement for reliable antimicrobial or antiviral drug administration. To reduce exposure due to accidental needle-stick incidents, we recommend the use of a routinely secured arterial line and central venous line access by an HID-trained physician, thus allowing safe serial blood sampling and drug administration without further needle-based procedures. If possible, all routine diagnostic tests should be processed in a biosafety level 3 or 4 laboratory that is located close to the HLIU or on the same campus to avoid unnecessary transportation of contaminated samples. 4, [bib_ref] Framework for the design and operation of high-level isolation units: consensus of..., Bannister [/bib_ref] Once inactivated, the sample can be processed in a routine clinical laboratory with PCR or blood fi lm analysis. Under certain handling precautions, the use of a certifi ed autoanalyser in routine tests has been suggested as being safe. However, some experts believe that samples that are likely to be highly contagious, such as blood contaminated by Ebola virus, cannot be handled safely in a routine laboratory. The development of a pointof-care test, such as for arterial blood gas, blood electrolyte, or haemoglobin content, and more recently for microbiology (ie, malaria), or for early diagnosis of lower respiratory-tract infections, off ers an alternative to routine tests because they can be done at patients' bedsides. 60 ## Caring for paediatric patients with hid in an hliu Hospital-acquired infections can cause major problems in paediatric wards, and compliance with isolation procedures needs to be ensured. [bib_ref] Preventing nosocomial infection in paediatric wards, Purssell [/bib_ref] [bib_ref] Pediatric nosocomial infections: children are not little adults, Harris [/bib_ref] During the SARS epidemic, infection-control measures overshadowed family-centred nursing practices in the management of paediatric patients, [bib_ref] Balancing infection control practices and family-centred care in a cohort of paediatric..., Chan [/bib_ref] and created inevitable confl ict. [bib_ref] Bowlby and Robertson revisited: the impact of isolation on hospitalized children during..., Koller [/bib_ref] To eff ectively control infection, family participation should be minimised, and all children with suspected HID should be admitted to the HLIU. Consequently, everything should be organised in the HLIU to provide nursing care that respects the privacy of the parents and children. ## Intensive care units and patients with hid The risk of being infected with SARS-associated coronavirus was reported to be about 13-times higher among physicians and nurses who performed or assisted in endotracheal intubations in intensive care units (ICUs) than in those who did not. [bib_ref] Transmission of severe acute respiratory syndrome in critical care: do we need..., Hugonnet [/bib_ref] Nurses who became ill were often exposed to SARS-associated coronavirus within 48 h of a patient's admission, during which time the patient usually deteriorated with symptoms, increasing the spread of droplets or aerosols (eg, dyspnoea, cough, etc). [bib_ref] Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation, Fowler [/bib_ref] [bib_ref] Illness in intensive care staff after brief exposure to severe acute respiratory..., Scales [/bib_ref] Patients admitted to the ICU are usually severely ill, and are likely to have a high viral load and to be at a point of maximum infectiousness. [bib_ref] Clinical progression and viral load in a community outbreak of coronavirus-associated SARS..., Peiris [/bib_ref] Non-invasive positive pressure ventilation (NPPV) is a mode of ventilation assistance used in early acute respiratory failure and acute respiratory distress syndrome. NPPV reduces the intubation rate and is eff ective in the treatment of SARS-related acute respiratory failure without posing infection risks to health-care workers. [bib_ref] Development of a standard treatment protocol for severe acute respiratory syndrome, So [/bib_ref] [bib_ref] Description and clinical treatment of an early outbreak of severe acute respiratory..., Zhao [/bib_ref] [bib_ref] A hospital outbreak of severe acute respiratory syndrome in Guangzhou, China, Wu [/bib_ref] In this setting, intubation has been avoided in up to two-thirds of cases in some studies. [bib_ref] A retrospective study of 78 patients with severe acute respiratory syndrome, Xiao [/bib_ref] [bib_ref] Non-invasive versus invasive mechanical ventilation for respiratory failure in severe acute respiratory..., Yam [/bib_ref] If aerosolisation and airborne transmission are discounted, respiratory secretions or fl uids, or both, are the main route of SARS transmission, ultimately leading to an overwhelming risk of infection via intubation. However, this mode of transmission does not occur with other airborne pathogens, most notably avian infl uenza, which can aerosolise or disperse up to 0·5 m around a patient undergoing NPPV. [bib_ref] Noninvasive positive-pressure ventilation: an experimental model to assess air and particle dispersion, Hui [/bib_ref] The main problem with dispersion through NPPV is not the exhalation portion of the respiratory circuit but the inevitable mask Review leaks. Consequently, intubation or mechanical ventilation should be preferred to NPPV if safely achievable to control droplet aerosolisation and dispersion. Consequently, endotracheal intubation should be done by the most skilled person available. In addition, that person should wear personal protective equipment, including eye protection, and use rapid sequence induction.ICU rooms should be subjected to negative pressure and a minimum of 15 air changes per hour. [bib_ref] ICU management of severe acute respiratory syndrome, Lapinsky [/bib_ref] Some researchers advocate the use of a powered air-purifying respirator, particularly during high-risk manipulations such as endotracheal intubation, because it off ers supplementary protection with a better fi t to the healthcare worker's face. [bib_ref] SARS: ventilatory and intensive care, Yam [/bib_ref] However, its use is a matter of debate because the risk of dysfunction seems important, which may increase the risk of exposure. Problems in cleaning, disinfection, and storage of the respirator may also increase the risk of exposure. Endotracheal intubation is not the only high-risk procedure in ICU patients; cardiopulmonary resuscitation was also reported to be a very high-risk procedure during the SARS epidemic. [bib_ref] Possible SARS coronavirus transmission during cardiopulmonary resuscitation, Christian [/bib_ref] Patients with other HIDs, such as viral haemorrhagic fever, should also be treated in an ICU. Although the main route of transmission of viral haemorrhagic fever is contact with body fl uids, airborne transmission has been suggested with the Reston and Zaire strains of Ebola virus in monkeys. [bib_ref] Kass handbook of infectious diseases: exotic viral infections, Mccormick [/bib_ref] In an outbreak of Ebola in a Johannesburg hospital, no subsequent cases of the disease occurred despite the staff being involved in numerous hazardous procedures. [bib_ref] Unexpected Ebola virus in a tertiary setting: clinical and epidemiologic aspects, Richards [/bib_ref] Despite the fact that this hospital opted for high-level barrier nursing, which entailed the isolation of the patient in a cubicle and the use of protective clothing plus high-effi ciency particulate air-fi ltered respirators to minimise exposure to aerosols, universal blood and body-fl uid precautions may have been suffi cient for protection. 82 ## Special procedures The management of invasive diagnostic or therapeutic procedures in a patient with HID is a challenge. However, there were few reports on hospital-acquired HIDs during invasive procedures before the SARS era. In fact, until now, HID outbreaks had only occurred in countries or at times when such techniques were not available, and the recent SARS epidemic has revealed the risks in such situations. [bib_ref] The epidemiology of the outbreak of severe acute respiratory syndrome (SARS) in..., Yu [/bib_ref] Of note, available evidence on risk factors is weak and somewhat indirect, according to the commonly accepted hierarchy of evidence. Much work needs to be done to separate the essential risk factors from the superfl uous ones. High-risk aerosolgenerating procedures were well summarised in the last WHO interim guidelines.Panel 2 shows the EUNID recommendations for infection control in the management of patients with HID during these special procedures. ## Bronchoscopy Although diagnostic bronchoscopy or fl exible lung endoscopy is not necessary in some scenarios (ie, an ongoing outbreak of a known disease), some situations need such invasive procedures to rule out diff erential diagnoses or to collect samples for laboratory - The examination should be kept as short as possible to answer the clinical questions - For HLIU-admitted patients, bedside radiography should be provided to avoid transport of patients; radiographic equipment should then be kept in the HLIU - Radiographs should be interpreted only by a designated radiologist who is aware of infection-control procedures, and by use of a picture-archiving and communication system, if available 84 - For ultrasound scanning, a sonographic scanner should be designated as a portable radiograph to be used only for HID patients - For CT or MRI, we strongly recommend that the department appoints a staff member to monitor and ensure that all department staff fully comply with the infection-control measures according to the guidelines - Designated sessions or hours, either out of offi ce hours or at the end of a session, should be assigned for such patients ## Renal dialysis - Treat HID patients who require dialysis at their bedside with either peritoneal dialysis or haemodialysis - Designate dedicated haemodialysis machines - Decontaminate dialysate as infectious waste Post-mortem examination - Risks and benefi ts must be carefully considered - Limited autopsy or post-mortem collection of blood and percutaneous biopsy are preferred - The biosafety precautions recommended for clinicians and laboratory staff working with infected patients and specimens must also be followed during post-mortem examination - Perform the autopsy only if necessary and in a biosafety level 3/4 isolation room, which can serve as the HLIU HLIU=High-level isolation unit. ## Review investigation. SARS transmission has been reported or suggested after the intubation of patients,and use of a nebuliser by health-care workers in patients with SARS resulted in a major outbreak of the disease. [bib_ref] SARS: experience at Prince of Wales Hospital, Hong Kong, Tomlinson [/bib_ref] In a retrospective study among critical-care nurses in Toronto, [bib_ref] SARS among critical care nurses, Loeb [/bib_ref] the probability of a SARS infection was 6% in nurses who assisted during intubation, suctioning, and manipulating the oxygen mask. In the same study, wearing a mask, especially an N95 mask, was deemed protective. [bib_ref] SARS among critical care nurses, Loeb [/bib_ref] A high-fl ow-rate oxygen mask may also result in health-care worker infection, [bib_ref] The epidemiology of the outbreak of severe acute respiratory syndrome (SARS) in..., Yu [/bib_ref] and we have thus suggested that NPPV is preferred to facial mask aerosol therapy if available. Bronchoscopy has also been suggested to increase SARS-associated coronavirus transmission in health-care workers. [bib_ref] Description and clinical treatment of an early outbreak of severe acute respiratory..., Zhao [/bib_ref] The aerosolisation of lung pathogens during fl exible endoscopy and hospital-acquired infections during these procedures are both well documented and have led to standard guidelines for fl exible endoscopy. [bib_ref] American College of Chest Physicians and American Association for Bronchology [corrected] consensus..., Mehta [/bib_ref] Similar transmissions would probably occur with other respiratory agents, such as avian infl uenza and hantavirus pulmonary syndrome. Bronchoscopy, airway suctioning, and other procedure that may induce coughing and expose health-care workers to potentially infected aerosolised respiratory droplets pose an increased risk of transmission of those agents. In most hospitals, rooms dedicated for bronchoscopy are under negative pressure, but these rooms are not necessarily air fi ltered. ## Gastrointestinal endoscopy In addition to airborne transmission, SARS-associated coronavirus may also be transmitted by direct contact with infected respiratory secretions and other body fl uids, similar to viral haemorrhagic fever viruses. [bib_ref] Responding to the severe acute respiratory syndrome (SARS) outbreak: lessons learned in..., Farquharson [/bib_ref] [bib_ref] SARS transmission, risk factors, and prevention in Hong Kong, Lau [/bib_ref] [bib_ref] SARS: epidemiology, clinical presentation, management, and infection control measures, Sampathkumar [/bib_ref] [bib_ref] Listening to SARS: lessons for infection control, Wenzel [/bib_ref] Contact with contaminated environmental surfaces and inanimate objects is suspected to have resulted in the transmission of SARS, as suggested by reports that some health-care workers became infected even though they had no direct contact with SARS-infected patients. [bib_ref] SARS transmission, risk factors, and prevention in Hong Kong, Lau [/bib_ref] [bib_ref] An outbreak of severe acute respiratory syndrome among hospital workers in a..., Ho [/bib_ref] [bib_ref] Managing SARS amidst uncertainty, Wenzel [/bib_ref] [bib_ref] Management of hospital-acquired severe acute respiratory syndrome with diff erent disease spectrum, Chiang [/bib_ref] Data also suggest that SARS-associated coronavirus and orthopoxvirus can survive on hard surfaces such as plastic and stainless steel for several hours, if not days. [bib_ref] Bichat guidelines for the clinical management of haemorrhagic fever viruses and bioterrorismrelated..., Bossi [/bib_ref] [bib_ref] Management of hospital-acquired severe acute respiratory syndrome with diff erent disease spectrum, Chiang [/bib_ref] Moreover, many group 3 and 4 viruses, including SARS-associated coronavirus, have been identifi ed in human faeces. [bib_ref] SARS: epidemiology, clinical presentation, management, and infection control measures, Sampathkumar [/bib_ref] [bib_ref] Managing SARS amidst uncertainty, Wenzel [/bib_ref] [bib_ref] Management of hospital-acquired severe acute respiratory syndrome with diff erent disease spectrum, Chiang [/bib_ref] Although there is no published report of transmission of SARS to health-care workers and other patients during gastrointestinal endoscopy, the potential for such transmission exists. 95 ## Radioimaging: ct and mri, chest radiography, and ultrasonography Most of our knowledge on managing infection control in radiology departments comes from experience of tuberculosis and SARS. Radiology technicians have a relative risk for a positive tuberculin skin test of 1·7 compared with other health-care workers, and those working for less than 1 year have a lower risk of infection, indicating that radiology technicians are more exposed to tuberculosis during their practice. [bib_ref] Risk of tuberculous infection among healthcare workers in a tertiary-care hospital in..., Keskiner [/bib_ref] At the Prince of Wales Hospital in Hong Kong in March, 2003, at least 50 health-care workers, including radiographers, were infected by SARS. [bib_ref] Eye of the storm: the roles of a radiology department in the..., Ho [/bib_ref] Because imaging plays an important part in the diagnosis and management of HID, the role of the radiology department is to provide an immediate and effi cient radiological service for patients with suspected or confi rmed HIDs. Chest radiography is mandatory in such a situation. To minimise the risk of cross-infection, transportation of patients with HID should be as limited as possible. For ambulatory patients with suspected HIDs, a satellite radiography centre should be set up with portable radiography equipment in the vicinity of the EDIR dedicated to HID patients in order to confi rm or to reject the diagnosis. [bib_ref] Severe acute respiratory syndrome: avoiding the spread of infection in a radiology..., King [/bib_ref] For patients in the HLIU, bedside radiography should be provided to avoid transportation of patients. [bib_ref] Eye of the storm: the roles of a radiology department in the..., Ho [/bib_ref] [bib_ref] Rapid creation of a temporary isolation ward for patients with severe acute..., Fung [/bib_ref] To avoid transmission of fomites, the radiograph fi lm should be handled with care and should only be interpreted by a designated radiologist who is aware of infection control. The fi lm-processing area, where cassettes are brought back to the department after bedside radiography in the HLIU, should be considered as high risk, unless the cassettes were processed in the HLIU by following a protocol of double bag sealing, and should be disinfected. [bib_ref] Severe acute respiratory syndrome: avoiding the spread of infection in a radiology..., King [/bib_ref] [bib_ref] Rapid creation of a temporary isolation ward for patients with severe acute..., Fung [/bib_ref] Images should be interpreted through a picture-archiving and communication system, if available. [bib_ref] Eye of the storm: the roles of a radiology department in the..., Ho [/bib_ref] [bib_ref] Severe acute respiratory syndrome: management and reconfi guration of a radiology department..., Tsou [/bib_ref] For ultrasound scanning, a sonographic scanner should be designated as a portable radiograph that is only used for HID patients. One machine should be dedicated for a specifi c area such as the HLIU. The examination should be kept as short as possible to answer the clinical questions. The transducer should be covered with disposable covers that are discarded between patients. The value of a CT scan in assessing the diagnosis of HIDs, such as SARS, has been established, and a CT scan is sometimes mandatory for a patient's assessment. [bib_ref] Value of CT in assessing probable severe acute respiratory syndrome, Rao [/bib_ref] Because this examination can be done only in the radiology department, stringent infection-control measures need to be followed, and the examination should be done only if absolutely necessary for the patient's recovery. We strongly recommend that the radiology department appoint a staff member to monitor and ensure that all staff fully comply with the infection-control measures according to the guidelines. Designated sessions or hours, either outside offi ce hours or at the end of a session, should be assigned for such patients. Patients should be transported in a special isolation carrier or in a defi ned way to avoid any contact with other patients or unprotected personnel. [bib_ref] Hospital preparedness to bioterrorism and other infectious disease emergencies, Ippolito [/bib_ref] [bib_ref] Severe acute respiratory syndrome: management and reconfi guration of a radiology department..., Tsou [/bib_ref] The department should be divided into low-risk and high-risk areas. After a CT scan, the gantry table and fl oor should be cleaned, and any bed linen should be changed. Film cassettes should be decontaminated properly before fi lm processing. In all Review cases, radiology technicians, radiologists, and other radiology personnel should comply with universal precautions, including the wearing of a mask, cap, gown, and gloves during direct contact with patients. ## Renal dialysis The main reported dialysis-associated infection is viral hepatitis. As a consequence, guidelines have been edited to prevent nosocomial transmission of this agent to personnel and patients.When the guidelines were followed in a European study, 103 no reported hospitalacquired cases of hantavirus haemorrhagic fever with renal syndrome were reported, despite 30-50% of patients being in need of haemodialysis. Most of our knowledge in the management of HID with renal failure has been acquired from SARS outbreaks. By comparison with other patients, the care of patients undergoing renal dialysis poses several additional infection-control issues in the disposal of spent dialysate (both haemodialysis and peritoneal dialysis) and in the prevention of cross-contamination within the dialysis unit. [bib_ref] Severe acute respiratory syndrome in dialysis patients, Kwan [/bib_ref] During the SARS episode, patients receiving dialysis were kept in the SARS isolation ward with the other patients with SARS. All patients with peritoneal dialysis were treated with intermittent peritoneal dialysis during their hospital stay. The dialysis exchange was done by the ward staff , who wore full protective gear, as recommended by WHO, including waterproof disposable gowns, caps, gloves, face shields, and N95 face masks. [bib_ref] Severe acute respiratory syndrome in dialysis patients, Kwan [/bib_ref] The spent peritoneal dialysis effl uent was decontaminated with a 2% sodium hypochlorite solution. Haemodialysis was also done by the ward staff , who wore full protective gear, in a room especially equipped for SARS patients in the isolation ward. [bib_ref] Severe acute respiratory syndrome in dialysis patients, Kwan [/bib_ref] Dedicated haemodialysis machines were used with an ordinary tap water supply that passed through a fi lter without reverse osmosis or any other water treatment. Spent dialysate was decontaminated as described above, and all of the blood tubing was discarded as infectious waste. Because they were potentially contaminated, unspent dialysate concentrate and the sodium bicarbonate cartridge were also discarded as infectious waste. The dialysis machine was disinfected after each haemodialysis session with a sodium hypochlorite solution according to the manufacturer's instructions. Particular attention should be paid to the infection control of dialysate effl uents and decontamination of the machines. ## Post-mortem examination Although autopsies have been done safely on patients with HID in some circumstances, without prior knowledge of diagnoses such as Ebola haemorrhagic fever, HID agents are transmissible at autopsy, which raises concerns about the protection of pathologists and autopsy personnel. [bib_ref] The modern autopsy: what to do if infection is suspected, Mazuchowski [/bib_ref] Tuberculosis was the fi rst autopsytransmitted disease to be reported in the literature, [bib_ref] Tuberculosis acquired in laboratories and necropsy rooms, Collins [/bib_ref] and transmission is also thought possible with multidrugresistant or extremely drug-resistant tuberculosis. Aerosol production during autopsy, particularly from ruptured organs, had been recognised early in this situation and has led to some precautions. [bib_ref] Aerosols in the mortuary, Newsom [/bib_ref] During the fi rst reported episode of hantavirus pulmonary syndrome, the fi rst fi ve suspected patients were autopsied with standard precautions only, even though the agent was isolated and classifi ed as a group 3 agent. [bib_ref] Hantaviral biosafety issues in the autopsy room and laboratory: concerns and recommendations, Nolte [/bib_ref] Fortunately, no transmission to autopsy personnel occurred. During the SARS episode, many autopsies were done, and although there was no case of transmission, several investigators have raised concerns over biosafety in autopsy rooms. [bib_ref] The modern autopsy: what to do if infection is suspected, Mazuchowski [/bib_ref] [bib_ref] Hantaviral biosafety issues in the autopsy room and laboratory: concerns and recommendations, Nolte [/bib_ref] [bib_ref] Biosafety level 3 laboratory for autopsies of patients with severe acute respiratory..., Li [/bib_ref] Recent guidelines have been published to prevent infection during autopsy. [bib_ref] Health and safety at necropsy, Burton [/bib_ref] Before an autopsy is done on a patient suspected to have died from an HID, the possible risks and benefi ts must be carefully considered. [bib_ref] Hospital preparedness to bioterrorism and other infectious disease emergencies, Ippolito [/bib_ref] Limited autopsy or post-mortem collection of blood and percutaneous liver biopsy material may be appropriate. Several pathologists suggest that safety measures applied to laboratory workers should also be applied during and after autopsy. Furthermore, patients who have died from an unknown HID or from a known group 3 or 4 agent should be autopsied only if necessary and in a biosafety level 3 or 4 isolation room. [bib_ref] Hospital preparedness to bioterrorism and other infectious disease emergencies, Ippolito [/bib_ref] [bib_ref] Hantaviral biosafety issues in the autopsy room and laboratory: concerns and recommendations, Nolte [/bib_ref] [bib_ref] Biosafety level 3 laboratory for autopsies of patients with severe acute respiratory..., Li [/bib_ref] # Conclusions The literature on HIDs, particularly SARS, indicates that there is a need for hospitals to be prepared for these events and that HLIUs urgently need to be built in European member state hospitals. Research and development of universal, bedside, reproducible, and transferable diagnostic tools are mandatory. Prompt reporting to the authorities is needed so that a rapid response can be organised. These measures should be accompanied by harmonised recommendations for the ## Search strategy and selection criteria The literature review was done by use of Medline and the Web of Science with the following key words: "SARS [all]", "laboratory-acquired infection", "laboratory-associated infection", "imported [each agent's name]", and "[each group 3 and 4 agent's name]". More than 1400 references were obtained. Selection criteria within the topics were the impact factor and half-life of the journal, followed by journal availability. The topics selected were as follows: patient's criteria for admission to the HLIU, admission to the emergency department, safe sampling for laboratory investigation, isolation of suspected HID patient in HLIU, intensive-care management of HID patients, HID in paediatric patients, practice of invasive procedures such as bronchoscopy and gastroscopy, radio imaging, renal dialysis, and post-mortem examination of HID patients. Only English-language articles were reviewed. Websites such as WHO, CDC, and other scientifi c and international research society's guidelines were also used. Review safe care of these unusual patients. The recommendations reported here by our group will hopefully help establish consensual protocols. Networking for the standardisation of procedures and the management of these patients is mandatory. ## Confl icts of interest We declare that we have no confl icts of interest. [fig] Panel 1: European Network for Infectious Disease (EUNID) 25 recommendations for infection control while managing patients with a highly infectious disease (HID) [/fig] [fig] Panel 2: European Network for Infectious Disease (EUNID) 25 recommendations for infection control during special procedures in patients with a highly infectious disease (HID) Bronchoscopy • Avoid all unnecessary procedures • Comply with established guidelines for prevention of respiratory infection during such procedures • Perform the bronchoscopy in the HLIU at the bedside, avoiding moving the patient unnecessarily; if not possible, perform these procedures in an air-controlled environment Gastrointestinal endoscopy • Avoid in HID patients, unless absolutely necessary • Adherence to current guidelines for the reprocessing of endoscopes is recommended to prevent transmission of group 3/4 agents via both potentially contaminated gastrointestinal endoscopes and bronchoscopes • Perform endoscopy in the HLIU at the bedside, avoiding unnecessary moving of the patient; if not possible, perform these procedures in an air-controlled environment Imaging (chest radiography, ultrasonography, CT, and MRI) [/fig] [table] Table 1: European Network of Infectious Disease (EUNID) recommendations for care of patients with known bacterial and fungal infections [/table] [table] Table 2: European Network of Infectious Disease (EUNID) recommendations for care of patients with known viral infections [/table]	None	http://www.thelancet.com/article/S1473309909700702/pdf	None
eaed31fbe871af9796f084594bce3b0a017e226c	pubmed	Radiation therapy for gynecologic malignancies during the COVID-19 pandemic: International expert consensus recommendations	Radiation therapy for gynecologic malignancies during the COVID-19 pandemic: International expert consensus recommendations An international panel of gynecologic radiation oncologists offer recommendations for RT during the COVID-19 pandemic.- Recommendations for cervical cancer, uterine cancer, vulvar cancer, vaginal cancer and ovarian cancer have been provided.- Recommendations for RT timing, fractionation, and dose have been provided for external beam radiation and brachytherapy.- The panel emphasizes strategies to reduce risk of transmission of the novel SARS-CoV-2 to patients and healthcare workers.- These recommendations may be used any time an event occurs which limits healthcare resources, including natural disasters.a b s t r a c tObjective. To develop expert consensus recommendations regarding radiation therapy for gynecologic malignancies during the COVID-19 pandemic.Methods. An international committee of ten experts in gynecologic radiation oncology convened to provide consensus recommendations for patients with gynecologic malignancies referred for radiation therapy. Treatment priority groups were established. A review of the relevant literature was performed and different clinical scenarios were categorized into three priority groups. For each stage and clinical scenario in cervical, endometrial, vulvar, vaginal and ovarian cancer, specific recommendations regarding dose, technique, and timing were provided by the panel.Results. Expert review and discussion generated consensus recommendations to guide radiation oncologists treating gynecologic malignancies during the COVID-19 pandemic. Priority scales for cervical, endometrial, vulvar, vaginal, and ovarian cancers are presented. Both radical and palliative treatments are discussed. Management of COVID-19 positive patients is considered. Hypofractionated radiation therapy should be used when feasible and recommendations regarding radiation dose, timing, and technique have been provided for external beam and brachytherapy treatments. Concurrent chemotherapy may be limited in some countries, and consideration of radiation alone is recommended.Conclusions. The expert consensus recommendations provide guidance for delivering radiation therapy during the COVID-19 pandemic. Specific recommendations have been provided for common clinical scenarios encountered in gynecologic radiation oncology with a focus on strategies to reduce patient and staff exposure to COVID-19. # Introduction On , the World Health Organization (WHO) declared the 2019 coronavirus disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a pandemic [bib_ref] An ounce of prevention: coronavirus (COVID-19) and mass gatherings, Escher [/bib_ref]. Currently, there is neither a vaccine nor confirmed effective medical treatments against SARS-CoV-2. Public health officials from the U.S. Centers for Disease Control and Prevention (CDC) and WHO have issued recommendations for increased hygiene vigilance, use of masks to reduce spread of respiratory droplets, and social distancing for all persons, as well as screening, testing, and contact tracing to be organized by governments. Around the world, local and federal governments have enacted mandatory quarantines, banned mass gatherings, closed nonessential businesses and schools, and significantly reduced or eliminated travel across regional and international borders in an effort to slow the spread of the virus and avoid overwhelming the capacity of the healthcare system [bib_ref] An ounce of prevention: coronavirus (COVID-19) and mass gatherings, Escher [/bib_ref] [bib_ref] The effect of travel restrictions on the spread of the 2019 novel..., Chinazzi [/bib_ref] [bib_ref] Managing Cancer care during the COVID-19 pandemic: agility and collaboration toward a..., Ueda [/bib_ref]. Many hospitals have implemented strategies to prevent the spread of the virus among patients and staff including converting in-person appointments to telemedicine visits, reducing or rescheduling routine follow up appointments, limiting hospital visitors, restricting or eliminating medical student and resident interactions with patients, and postponing elective procedures and surgeries [bib_ref] Radiation therapy in King County, Washington during the COVID-19 pandemic: balancing patient..., Dinh [/bib_ref] [bib_ref] Cancer care delivery challenges amidst coronavirus disease -19 (COVID-19) outbreak: specific precautions..., Shankar [/bib_ref] [bib_ref] Cancer guidelines during the COVID-19 pandemic, Burki [/bib_ref]. However, the treatment of patients with cancer is time-sensitive and delayed treatment has been associated with inferior local control and survival [bib_ref] Effect of radiotherapy delay in overall treatment time on local control and..., Ferreira [/bib_ref] [bib_ref] The impact of overall radiotherapy treatment time and delay in initiation of..., Soyfer [/bib_ref] [bib_ref] Does delay in starting treatment affect the outcomes of radiotherapy? A systematic..., Huang [/bib_ref] [bib_ref] The effect of treatment time in locally advanced cervical cancer in the..., Song [/bib_ref] [bib_ref] The prognostic impact of overall treatment time on disease outcome in uterine..., Lin [/bib_ref] [bib_ref] Carcinoma of the uterine cervix. I. Impact of prolongation of overall treatment..., Perez [/bib_ref] [bib_ref] Prolongation of overall treatment time as a cause of treatment failure in..., Haviland [/bib_ref] [bib_ref] Association of Treatment Delays with Survival for patients with head and neck..., Graboyes [/bib_ref] [bib_ref] A Delay from Diagnosis to Treatment Is Associated with a Decreased Overall..., Dolly [/bib_ref] [bib_ref] Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia..., Chen [/bib_ref]. As such, several radiation oncology departments around the world have come up with contingency plans for the treatment of cancer patients during the COVID-19 pandemic. Radiation oncology department-specific [bib_ref] Radiation therapy in King County, Washington during the COVID-19 pandemic: balancing patient..., Dinh [/bib_ref] [bib_ref] Efforts to reduce the impacts of COVID-19 outbreak on radiation oncology in..., Chen [/bib_ref] [bib_ref] Radiotherapy care during a major outbreak of COVID-19 in Wuhan, Wu [/bib_ref] , disease site-specific [bib_ref] Adapting radiotherapy treatments for breast Cancer patients during the COVID-19 pandemic: hypo-fractionation..., Al-Rashdan [/bib_ref] [bib_ref] How we treat patients with lung cancer during the SARS-CoV-2 pandemic: primum..., Banna [/bib_ref] [bib_ref] Breast radiotherapy under COVID-19 pandemic resource constraints -approaches to defer or shorten..., Braunstein [/bib_ref] [bib_ref] The impact of coronavirus (COVID-19) on head and neck cancer patients' care, De Felice [/bib_ref] [bib_ref] Practice recommendations for lung cancer radiotherapy during the COVID-19 pandemic: an ESTRO-ASTRO..., Guckenberger [/bib_ref] [bib_ref] Treatment approach in locally advanced rectal cancer during Coronavirus (COVID-19) pandemic: long..., De Felice [/bib_ref] , and patient population-specific guidelines [bib_ref] Clinical strategies for treating pediatric cancer during the outbreak of 2019 novel..., Yang [/bib_ref] have been published in an effort to reduce patient visits to the clinic, prioritize patient treatments, consider testing for asymptomatic patients and provide guidance on how to best protect patients and staff when treating patients with confirmed or suspected infection with SARS-CoV-2. For patients with gynecologic malignancies, radiation therapy (RT) is often an integral component of multi-modality management and can be delivered in the definitive, adjuvant, and palliative setting. However, RT requires repeated visits to radiation oncology clinics and may place patients at increased risk of exposure to SARS-CoV-2. Additionally, cancer patients may have an increased risk of contracting the virus or difficulty clearing the virus once infected due to their immunocompromised state. Two independent studies have reported a greater risk of severe events (ICU admission, mechanical ventilation, and death) secondary to COVID-19 in cancer patients compared to patients without cancer in China [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] [bib_ref] Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three..., Zhang [/bib_ref]. Radiation oncologists must carefully consider the risks and benefits of RT against the risk of contracting SARS-CoV-2 for each individual patient. Furthermore, the risks to healthcare staff and the use of limited healthcare resources, such as personal protective equipment (PPE) and ventilators, must be considered as well. An international panel of experts of gynecologic radiation oncology convened to review relevant literature and discuss recommendations regarding the timing and delivery of RT for patients with gynecologic malignancies. This report is meant to provide a framework for clinical decision making. However, when evaluating a patient for consideration for RT during the COVID-19 pandemic, the radiation oncologist should take into consideration the following: the anticipated peak and length of the pandemic in a certain geographic area, the capacity of the healthcare system (including the availability of PPE and highly-trained staff), the age and medical comorbidities of each patient, the magnitude of benefit derived from delivery of RT, and the potential risk of delay, modification, or omission of RT. The impact of the pandemic on radiology, surgical oncology, and medical oncology may influence RT recommendations. In some locations, cancer screening examinations such as mammography and colonoscopy are not being offered which may result in more advanced disease presentations. In many countries, elective surgical procedures have been delayed in order to limit patients from entering the health care system, provide adequate intensive care facilities for COVID positive patients, and to preserve crucial supplies of PPE. Though most cancer operations are not considered elective, the lack of available ventilators, recovery spaces, and PPE may result in delays for surgical procedures. Finally, use of chemotherapy may be limited or unavailable in some countries due to manufacturing and supply chain disruptions or deferred to avoid risks of patients becoming immunocompromised. # Methods An international panel of ten gynecologic radiation oncologists convened to develop consensus guidelines regarding the timing and delivery of RT for patients with gynecologic malignancies. Based on different clinical scenarios, the panel was asked to place patients in three priority risk groups (A, B, or C) adapted from the Pandemic Planning Clinical Guideline for Patients with Cancer published by Cancer Care Ontario. For the purposes of our panel recommendations, priority A patients are defined as patients who are deemed critical and may require treatment during the pandemic, even if the patient has known or suspected infection with COVID-19. Priority A also includes patients with rapidly progressive tumors that are potentially curable with prompt initiation of treatment. Priority B patients are those who require treatment but whose situation is non-critical. If staff or PPE shortages occur to the extent that clinics are only able to provide care for priority A patients, priority B patients could be delayed up to 8-12 weeks without significant risk of harm. Priority C patients include patients with non-life-threatening conditions whose treatment may be delayed without anticipated change in outcome for an indeterminate period of time. In this group, we have also included patients for whom observation or alternative therapies could be considered instead of RT with minimal or no detriment in outcome. [fig_ref] Table 1: Working definitions of priority groups used by the consensus panel [/fig_ref] summarizes the working definitions of the priority groups. For patients with metastatic disease, we have compiled recommendations on treatment of symptomatic abdominopelvic disease. However, recommendations for palliative RT to other distant metastatic sites (e.g. brain metastases, spine metastases, etc.) from gynecologic primary sites have not been considered for the purpose of this paper. Recommendations regarding palliative RT during the COVID-19 pandemic have been previously published. Consensus on treatment recommendations was reached through extensive discussion via videoconference call. All authors had access to a shared electronic document and they were able to provide recommendations for treatment management as well as references to published literature to support their recommendations. Recommendations were compiled by author C.E. and forwarded to all members of the expert consensus panel. Any disagreements among members of the panel were discussed by e-mail until a consensus was reached. All authors have reviewed and given support to the final recommendations. # Results ## Cervical cancer The recommendations from the consensus panel for patients with cervical cancer are provided in [fig_ref] Table 2: Consensus panel recommendations for patients with cervical cancer [/fig_ref]. [bib_ref] Lessons learned from hurricane Maria in Puerto Rico: practical measures to mitigate..., Gay [/bib_ref]. - For patients requiring brachytherapy, inpatient treatment with one insertion rather than outpatient treatment with multiple insertions is preferable to reduce aerosolizing procedures that may occur during anesthesia and to minimize close contact with the patient required for procedures. An attempt should be made to maximize the number of fractions of RT delivered for each applicator insertion. - The number of delivered RT fractions should be reduced to the fewest number when possible while respecting tolerance doses of nearby OARs. For instance, HDR brachytherapy delivered as 24 Gy in three fractions or 28 Gy in four fractions should be prioritized over longer fractionation schedules. For external beam RT, any boosts should be performed using a simultaneous integrated boost (SIB) technique rather than a sequential cone-down boost to reduce the number of RT fractions [bib_ref] Management of Nodal Disease in advanced cervical Cancer, Jürgenliemk-Schulz [/bib_ref] [bib_ref] Simultaneously integrated boost (SIB) spares OAR and reduces treatment time in locally..., Feng [/bib_ref] [bib_ref] Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated..., Boyle [/bib_ref]. CRT to 45-50 Gy [bib_ref] Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone..., Peters [/bib_ref] Can be delayed up to 8 weeks [bib_ref] Radiation duration in women with cervical Cancer treated with primary Chemoradiation: a..., Tergas [/bib_ref] if necessary based on consensus panel opinion e Patients with metastatic disease with discomfort controlled with oral pain medications or minimal bleeding who require palliative RT 10 Gy × 1 f. (can be repeated monthly up to 2 more times) [bib_ref] 10-Gy single-fraction pelvic irradiation for palliation and life prolongation in patients with..., Onsrud [/bib_ref] [bib_ref] Whole pelvis megavoltage irradiation with single doses of 1000 rad to palliate..., Boulware [/bib_ref] [bib_ref] Once-monthly radiotherapy for the palliation of pelvic gynecological malignancy, Hodson [/bib_ref] [bib_ref] 1000 CGY single dose palliation for advanced carcinoma of the cervix or..., Halle [/bib_ref] "Quad Shot" of 3.7 Gy BID x 4 f. (can be repeated monthly up to 2 more times) [bib_ref] Phase II study of multiple daily fractionations in the palliation of advanced..., Spanos [/bib_ref] [bib_ref] Effect of rest interval on tumor and normal tissue response-a report of..., Spanos [/bib_ref] 4 Gy × 5 f. [bib_ref] Short-course palliative radiotherapy for uterine cervical cancer, Kim [/bib_ref] [bib_ref] Short-course palliative radiation therapy leads to excellent bleeding control: a single Centre..., Sapienza [/bib_ref] BID: twice daily; BT: brachytherapy; CRT: chemoradiotherapy; EBRT: external beam radiation therapy; EF: extended field; Fx: fraction; GOG: Gynecologic Oncology Group; Gy: Gray; IC: intracavitary; IS: interstitial; HDR: high-dose rate; LDR: low-dose rate; PA: paraaortic; PDR: pulsed-dose rate, RT: radiation therapy; SIB: simultaneous integrated boost; WP: whole pelvis. a Boost clinically positive nodes with SIB technique to reduce total number of fractions. b HDR, PDR, or LDR brachytherapy may be used based on resource availability. c Combined intracavitary/interstitial applicators. d To reduce risk of exposure to COVID-19, a single application with the delivery of multiple fx is preferred. e The decision to delay therapy and the interval of delay should be determined based on (1) individual risk of the patient to have an adverse outcome due to COVID-19 based on age and medical comorbidity, (2) individual risk of disease progression given treatment delay, and (3) epidemiologic data based on the projected peak of the pandemic in a specific geographic area. - For patients who cannot receive systemic therapy and require external beam RT, the panel recommends a dose of 50 Gy in 25 fractions to the pelvis when possible. In addition, accelerated radiation therapy delivered six days per week may also be used [bib_ref] Can pure accelerated radiotherapy given as six fractions weekly be an option..., Sharma [/bib_ref]. - All treatment should be completed within 8 weeks when feasible, and delays are not recommended given the potential impact on survival. Post-operative patients - Patients receiving post-operative RT may be delayed up to 8-12 weeks if necessary depending on the clinical scenario. ## Endometrial cancer The recommendations from the consensus panel for patients with endometrial cancer are provided in [fig_ref] Table 3: Consensus panel recommendations for patients with endometrial cancer [/fig_ref]. A summary of recommendations from the consensus panel includes: General - For external beam RT, any boosts should be performed using a simultaneous integrated boost (SIB) technique rather than a sequential cone-down boost to reduce the number of RT fractions [bib_ref] Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated..., Boyle [/bib_ref] [bib_ref] Simultaneous integrated boost volumetric modulated arc therapy in the postoperative treatment of..., Macchia [/bib_ref] [bib_ref] Adjuvant volumetric-modulated arc therapy with simultaneous integrated boost in endometrial cancer. Planning..., Macchia [/bib_ref]. ## Patients with inoperable disease - Patients with symptomatic, inoperable disease receiving radiation therapy with or without chemotherapy should be treated expeditiously. - For patients with endometrioid histology, hormonal therapy may be used to delay RT start. - SBRT delivered to a dose of 20-30 Gy in 4-5 fractions may be used as a boost in patients who cannot tolerate or refuse brachytherapy [bib_ref] Use of image-guided stereotactic body radiation therapy in lieu of intracavitary brachytherapy..., Kemmerer [/bib_ref] [bib_ref] A phase II trial of stereotactic ablative radiation therapy as a boost..., Albuquerque [/bib_ref]. However, the consensus panel recommends that brachytherapy boosts remain the standard of care and should always be preferred over SBRT boosts. The potential risks of increased toxicity and inferior local control associated with SBRT boosts should be discussed with the patient prior to treatment [bib_ref] A phase II trial of stereotactic ablative radiation therapy as a boost..., Albuquerque [/bib_ref]. ## Post-operative patients - Many patients receiving adjuvant radiation therapy may safely be delayed between 6 and 8 weeks after surgery depending on the clinical scenario. - Brachytherapy fractionation regimens with fewer total fractions should be preferentially used, while respecting tolerance doses to nearby OARs. For instance, patients receiving post-operative vaginal cuff brachytherapy may be treated with a shorter fractionation regimen such as 21 Gy in 3 fractions instead of longer fractionation regimens such as 24 Gy in 6 fractions. - The panel recommends patients with stage IA grade 3, Stage IB grade 1-2, and patients with low-risk stage II disease [bib_ref] Multi-institutional analysis of vaginal brachytherapy alone for women with stage II endometrial..., Harkenrider [/bib_ref] may be preferentially treated with adjuvant vaginal cuff brachytherapy instead of external beam radiation therapy to minimize the number of treatment visits required. ## Vulvar cancer The recommendations from the consensus panel for patients with vulvar cancer are provided in [fig_ref] Table 4: Consensus panel recommendation for patients with vulvar cancer [/fig_ref]. A summary of recommendations from the consensus panel includes: General - Patients with intact de novo or recurrent disease receiving definitive radiation therapy with or without chemotherapy should be treated expeditiously. - For external beam RT, any boosts should be performed using a simultaneous integrated boost (SIB) technique rather than a sequential cone-down boost to reduce the number of RT fractions [bib_ref] Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated..., Boyle [/bib_ref] [bib_ref] A dosimetric evaluation of dose escalation for the radical treatment of locally..., Bloemers [/bib_ref]. ## Post-operative patients - Patients receiving adjuvant radiation therapy may be safely delayed between 6 and 8 weeks after surgery depending on the clinical scenario. - Post-operative patients found to have positive nodes at the time of surgery should have RT promptly initiated. ## Vaginal cancer The recommendations from the consensus panel for patients with vaginal cancer are provided in [fig_ref] Table 5: Consensus panel recommendation for patients with vaginal cancer [/fig_ref]. A summary of recommendations from the consensus panel includes: General - There were no clinical scenarios reviewed that were categorized as priority C. - Patients with intact disease receiving definitive radiation therapy with or without chemotherapy should be treated expeditiously. - For external beam RT, any boosts should be performed using a simultaneous integrated boost (SIB) technique rather than a sequential cone-down boost to reduce the number of RT fractions [bib_ref] Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated..., Boyle [/bib_ref]. ## Post-operative patients - Post-operative patients with close or positive margins or pathologically involved nodes with no gross residual disease, may be delayed up to 6-8 weeks from the time of surgery depending on the clinical scenario. ## Ovarian cancer The recommendations from the consensus panel for patients with ovarian cancer are provided in [fig_ref] Table 6: Consensus panel recommendation for patients with ovarian cancer [/fig_ref]. A summary of recommendations from the consensus panel includes: General - There were no clinical scenarios reviewed that were categorized as priority C. - Patients previously treated with surgery and chemotherapy with an isolated locoregional relapse may be treated with involved-field radiation therapy. ## All disease sites Across disease sites, the panel has recommendations regarding external beam and brachytherapy fractionation, treatment breaks, and systemic therapy. ## External beam radiation therapy When different fractionation regimens are available for external beam radiation therapy, the panel recommends the total number of fractions be minimized while respecting the tolerance doses of organs at risk. For instance, when possible, the use of a simultaneous integrated boost (SIB) should be used instead of a sequential cone-down boost to limit the number of fractions [bib_ref] Management of Nodal Disease in advanced cervical Cancer, Jürgenliemk-Schulz [/bib_ref] [bib_ref] Methods, safety, and early clinical outcomes of dose escalation using simultaneous integrated..., Boyle [/bib_ref]. This will help to minimize patient visits to the clinic as well as risks of infection to patients and healthcare personnel. Finally, if a patient contracts the SARS-CoV-2 virus or is a person under investigation (PUI), a treatment break may be required. For patients requiring a treatment break, consider adding additional radiation dose to account for tumor repopulation during the treatment break. The potential benefits of additional radiation dose must be carefully weighed against the potential risks of additional dose to organs at risk. Gay et al. have outlined specific guidelines regarding treatment breaks for patients with cervical cancer [bib_ref] Lessons learned from hurricane Maria in Puerto Rico: practical measures to mitigate..., Gay [/bib_ref]. For patients who cannot be safely put on a break throughout the duration of infection with [bib_ref] Interval between hysterectomy and start of radiation treatment is predictive of recurrence..., Cattaneo 2nd [/bib_ref] ; if already started on treatment and the patient becomes COVID-19 positive or a person under investigation (PUI), then up to 14 days between fractions is acceptable. b VCBT can be completed after the completion of chemotherapy instead of prior to chemotherapy or between chemotherapy cycles. c EBRT can be delayed but should start no later than 8 weeks post chemotherapy; consider if BT alone is a reasonable substitute for these patients after weighing risks and benefit. d Patients with bulky disease (N0.5 cm thick) should be considered for IS brachytherapy. e EBRT should be started within 6-8 weeks post-operatively. SARS-CoV-2, we recommend these patients be treated at the end of the day to minimize risks of infection to other patients. ## Brachytherapy When planning brachytherapy, consider the use of locoregional anesthesia or conscious sedation over the use of general anesthesia to minimize aerosolizing procedures such as general endotracheal intubation or use of laryngeal mask airways (LMA). There is an increased risk of aerosol generation associated with these procedures that may lead to airborne transmission of the virus to healthcare personnel [bib_ref] Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus..., Wax [/bib_ref]. Intubation has a high risk of aerosol production during the procedure; but once the tube is in place, the cuff provides a seal within the airway preventing further aerosolization [bib_ref] The role of the endotracheal tube cuff in microaspiration, Hamilton [/bib_ref]. While empirical data is currently lacking, expert opinion suggests that LMA use may carry greater risk than endotracheal intubation, particularly with the use of higher positive pressures that may result in air leak and continuous aerosolization throughout the procedure. If general anesthesia is necessary for a case, published protocols and guidelines regarding airway management during the COVID-19 pandemic should be reviewed with anesthesia providers and, if indicated, used to limit risks of viral transmission to healthcare personnel [bib_ref] Consensus statement: safe airway society principles of airway management and tracheal intubation..., Brewster [/bib_ref] [bib_ref] Consensus guidelines for managing the airway in patients with COVID-19: guidelines from..., Cook [/bib_ref] [bib_ref] Extubation of patients with COVID-19, Silva [/bib_ref]. Precautions should be taken to limit the number of individuals in the room to anesthesia personnel only during intubations and extubations and all individuals present must have airborne PPE. To further mitigate risk, some institutions have initiated universal COVID-19 testing for all patients undergoing procedures, particularly those requiring endotracheal intubation. When available, testing for COVID-19 prior to the procedure will help determine if a patient is COVID-19 positive and will inform providers of appropriate PPE requirements. This information may also be used to decide if a patient should be delayed or treated with an alternative method such as SBRT. At a minimum, for all patients with negative COVID-19 testing or 10 Gy × 1 f. (can be repeated monthly up to 2 more times) [bib_ref] 10-Gy single-fraction pelvic irradiation for palliation and life prolongation in patients with..., Onsrud [/bib_ref] [bib_ref] Whole pelvis megavoltage irradiation with single doses of 1000 rad to palliate..., Boulware [/bib_ref] [bib_ref] Once-monthly radiotherapy for the palliation of pelvic gynecological malignancy, Hodson [/bib_ref] [bib_ref] 1000 CGY single dose palliation for advanced carcinoma of the cervix or..., Halle [/bib_ref] "Quad Shot" of 3.7 Gy BID x 4 f. (can be repeated monthly up to 2 more times) [bib_ref] Phase II study of multiple daily fractionations in the palliation of advanced..., Spanos [/bib_ref] [bib_ref] Effect of rest interval on tumor and normal tissue response-a report of..., Spanos [/bib_ref] 4 Gy × 5 f. [bib_ref] Short-course palliative radiotherapy for uterine cervical cancer, Kim [/bib_ref] [bib_ref] Short-course palliative radiation therapy leads to excellent bleeding control: a single Centre..., Sapienza [/bib_ref] Post-operative patients with close/positive margins or pathologically involved nodes with no gross residual disease. Close/positive margins a,b : IC/IS BT +/− EBRT [bib_ref] American brachytherapy society consensus guidelines for interstitial brachytherapy for vaginal cancer, Beriwal [/bib_ref] [bib_ref] Outcomes with image-based interstitial brachytherapy for vaginal cancer, Manuel [/bib_ref] or CRT [bib_ref] Concurrent chemoradiation for vaginal cancer, Miyamoto [/bib_ref] Pathologically involved nodes: CRT to 10 Gy × 1 f. (can be repeated monthly up to 2 more times) [bib_ref] 10-Gy single-fraction pelvic irradiation for palliation and life prolongation in patients with..., Onsrud [/bib_ref] [bib_ref] Whole pelvis megavoltage irradiation with single doses of 1000 rad to palliate..., Boulware [/bib_ref] [bib_ref] Once-monthly radiotherapy for the palliation of pelvic gynecological malignancy, Hodson [/bib_ref] [bib_ref] 1000 CGY single dose palliation for advanced carcinoma of the cervix or..., Halle [/bib_ref] "Quad Shot" of 3.7 Gy BID x 4 f. (can be repeated monthly up to 2 more times) [bib_ref] Phase II study of multiple daily fractionations in the palliation of advanced..., Spanos [/bib_ref] [bib_ref] Effect of rest interval on tumor and normal tissue response-a report of..., Spanos [/bib_ref] 4 Gy × 5 f. [bib_ref] Short-course palliative radiotherapy for uterine cervical cancer, Kim [/bib_ref] [bib_ref] Short-course palliative radiation therapy leads to excellent bleeding control: a single Centre..., Sapienza [/bib_ref] Isolated locoregional relapse in patients with prior surgery and chemotherapy Definitive IFRT to BID: twice per day; Fx: fraction; Gy: Gray; IFRT: involved-field radiation therapy; RT: radiation therapy. those presumed to be negative when pre-operative testing is not available, the panel recommends the use of a surgical mask and eye protection. In addition, appropriate PPE should be used even with procedures being performed with conscious sedation as there is a risk of coughing associated with sedative agents [bib_ref] Procedural sedation in the acute care setting, Brown [/bib_ref] and some patients may ultimately require intubation during the course of the procedure if complications arise. The number of fractions delivered for each applicator insertion should be monitored and brachytherapy fractionation regimens that minimize the total number of fractions delivered should be considered, when normal tissue tolerance permits, to reduce the number of required procedures and treatments during an RT course. For inpatient tandem and ovoid or interstitial procedures, this includes the use of twice daily treatments delivered a minimum of 6 h apart with immobilization and imaging, if available, each day to ensure accurate treatment of the target and avoidance of organs at risk. ## Chemotherapy The decision to proceed with concurrent, sensitizing chemotherapy should be made after a careful assessment of patient risk factors, expected magnitude of benefit from systemic therapy, and resource availability. If chemotherapy is omitted in patients with cervical cancer, dose escalation with external beam RT or brachytherapy may be used but tolerance doses to nearby organs at risk should be respected. Alternatively, accelerated RT delivered in six daily fractions per week may be used to compensate for omission of chemotherapy in patients who cannot or refuse to receive chemotherapy [bib_ref] Can pure accelerated radiotherapy given as six fractions weekly be an option..., Sharma [/bib_ref]. These decisions should be made using a shared decision making approach with patient and caregiver knowledge and involvement. # Discussion An international expert consensus panel comprised of ten experts in gynecologic radiation oncology have reviewed the relevant literature and developed clinical practice recommendations to assist radiation oncologists treating gynecologic malignancies during the COVID-19 pandemic. Dissenting opinions were discussed openly and completely. Consensus was reached via the communications methods described above. Simliar to other disease sites, a priority scale was developed to triage patients with gynecologic malignancies [bib_ref] An integrated program in a pandemic: Johns Hopkins radiation oncology department, Wright [/bib_ref]. Priority A patients should be treated expeditiously due to the severity of patient symptoms or because these patients have potentially curative, rapidly growing tumors and the opportunity for cure may be lost if treatment is delayed. While resources are not constrained, many priority B patients should be treated expeditiously, but radiation oncologists should consider if a potential delay in therapy may allow patient treatment after the regional peak of COVID-19 cases. If the capacity of the healthcare system is overwhelmed and resources are limited, priority B patients may be safely delayed in order to conserve resources for priority A patients. Priority C patients may delay RT for a longer interval or omit radiation in favor of observation or other therapeutic options. In the event that the pandemic continues for an extended period of time, patients who were initially placed into priority B may ultimately choose to omit RT. These patients should be closely monitored and should receive early salvage therapy at the time of recurrence. This approach is supported from prospective phase II data by Chopra et al. that established 5-year local control, disease free, and overall survival rates of 84%, 73%, and 74.5%, respectively, with the use of RT as early salvage therapy for vaginal recurrences of cervical cancer [bib_ref] MRI-and PET-Guided Interstitial Brachytherapy for Postsurgical Vaginal Recurrences of Cervical Cancer: Results..., Chopra [/bib_ref]. These guidelines are meant to help clinicians prioritize treatments but are not meant to serve as a replacement for clinician judgement. For each patient, the radiation oncologist must carefully consider the patient's risk of contracting SARS-CoV-2 (based on age, comorbidities, immunocompetence), the risks of modifying, delaying or omitting radiation therapy, epidemiologic characteristics of the geographic region (anticipated peak, anticipated duration of peak), and availability of healthcare resources (highly-trained personnel, PPE). For patients with a diagnosis of COVID-19, there must be a careful balancing of the risks of immunosuppression from RT and chemotherapy with the risks of cancer progression that may arise from delay or omission of therapy. Additionally, the risks of exposure to SARS-CoV-2 among other patients and healthcare workers should be considered. Clinicians may use these guidelines, along with their clinical judgement, when determining if or how RT should be modified during the COVID-19 pandemic. All decisions regarding modification, delay, or omission of RT should be clearly communicated to the patient along with the rationale, risks, benefits, and alternatives. If a decision to delay RT is made, the clinician and patient should have a thorough understanding of a follow up plan to minimize the risk of patients being lost to follow-up. Patients who choose to omit radiation therapy should be provided with a plan for cancer surveillance. These recommendations are not intended to be static and they will continue to evolve based on local epidemiology of the SARS-CoV-2 virus, resource availability, and the development of effective medical therapies or a vaccine for SARS-CoV-2. However, these recommendations are meant to provide clinicians with a framework for triaging patients with gynecologic malignancies when there is any kind of resource limitation. As such, in the future, these guidelines may also be used for patient triage in the aftermath of other resource-limiting events such as natural disasters. ## Declaration of competing interest Christen Elledge, Supriya Chopra, Beth Erikson, David Gaffney, Anuja Jhingran, Ann Klopp, and Catherine Yashar have nothing to disclose. Akila Viswanathan is the principal investigator of NIH R01 CA237005. Sushil Beriwal is a consultant for Varian and Medical Director of Via Oncology, outside the submitted work. Cyrus Chargari receives grant funding from Roche, personal fees from Merck Sharp & Dohme Corp., Elekta, and GlaxoSmithKline, as well as non-financial support from TherAguiX and GlaxoSmithKline, all outside the submitted work. William Small is the co-chair of the NRG Gyn Committee, has served on an advisory board for Merck, and has received honoraria for invited talks from Carl Zeiss Meditech, outside the submitted work. [table] Table 1: Working definitions of priority groups used by the consensus panel. [/table] [table] Table 2: Consensus panel recommendations for patients with cervical cancer. [/table] [table] Table 3: Consensus panel recommendations for patients with endometrial cancer. [/table] [table] Table 4: Consensus panel recommendation for patients with vulvar cancer. [/table] [table] Table 5: Consensus panel recommendation for patients with vaginal cancer. [/table] [table] Table 6: Consensus panel recommendation for patients with ovarian cancer. [/table]	None	http://www.gynecologiconcology-online.net/article/S0090825820323015/pdf	None
2ac68733c29b7b0d9cb3f6bc3fcf420b0e6cc5ce	pubmed	Summary version of the standards, options and recommendations for nonmetastatic breast cancer (updated January 2001)	Summary version of the standards, options and recommendations for nonmetastatic breast cancer (updated January 2001) [bib_ref] ) Standards, options and recommendations for non metastatic breast cancer patients, Mauriac [/bib_ref] ## Clinical diagnosis (figures 1 and 2) Diagnostic work-up of an abnormality in the breast Clinical examination In patients with locally and regionally advanced disease, clinical examination is likely to be of greater diagnostic value than in patients with less advanced disease (standard). Tumours with the following characteristics are unlikely to be operable, and are associated with a poor short-term prognosis: inflammatory change, deep extension, lymphadenopathy, breast oedema and/or lymphoedema in the upper limbs. These factors also indicate an increased risk of locoregional and metastatic recurrence (standard). Thus, nonoperability is not always due to difficulties associated with the surgery itself. Surgery may still be appropriate, however, to achieve local control, despite a poor prognosis. Imaging can be used to confirm findings from clinical examination. In some cases, clinical examination will be normal, so that the diagnosis will only be possible following imaging (standard). ## Diagnostic imaging A standard bilateral mammogram with two views (front and external oblique), can be complemented by other views and by ultrasonography (standard). The equipment used for mammography should undergo regular quality control (standard). To confirm the diagnosis, additional views and enlargements may be necessary (option). Specific imaging is not indicated in the examination of lymphadenopathy. Standard reporting of mammograms should Procedures or treatments which are considered to be of benefit, inappropriate or harmful by unanimous decision based on the best available evidence Options Procedures or treatments which are considered to be of benefit, inappropriate or harmful by a majority, based on the best available evidence Recommendations Additional information to enable the available options to be ranked using expect criteria (e.g. survival, toxicity) with an indication of the level of evidence Definition of level of evidence Level A There exists a high standard meta-analysis or several high-standard randomised clinical trials which give consistent results ## Level b There exists good quality evidence from randomised trials (B1) or prospective or retrospective studies (B2). The results are consistent when considered together Level C The methodology of the available studies is weak or their results are not consistent when considered together Level D Either the scientific data does not exist or there is only a series of cases ## Expert agreement The data does not exist for the method concerned but the experts are unanimous in their judgement be used in which the stated diagnosis is based on the mammographic features suspicious of malignancy using the American College of Radiology classification (recommendation). The diagnostic findings should be discussed by a multidisciplinary team. When the level of suspicion from imaging justifies histological verification, this should be done using interventional breast diagnostic techniques in an outpatient setting under a local anaesthetic. ## Pretreatment diagnosis The diagnosis of malignancy can be obtained from cytology (fineneedle aspiration) or tissue sample (core biopsy), whereas the diagnosis of an invasive carcinoma can only be made from a biopsy sample (standard). The histological diagnosis of impalpable lesions should be compared with the diagnostic hypotheses generated from diagnostic imaging (recommendation). The diagnosis of ductal carcinoma in situ, lobular carcinoma in situ and atypical hyperplasia from a needle biopsy sample should always be reconfirmed using a sample obtained by surgical excision (recommendation, level of evidence: B1). Regular assessment of the diagnostic performance of image-guided biopsy systems is recommended (recommendation, expert agreement). ## Pathological examination and classification frozen sections Examination of frozen sections is not indicated for isolated clusters of microcalcification or for a tumour measuring less than 10 mm (standard). It is indicated in other cases where it is likely to modify the surgical plan (standard). This examination should not jeopardise the quality of the excised sample and therefore the reliability of the final histological diagnosis (standard). ## Surgical margins The standard histological report should mention the findings from the diagnostic work-up and all factors necessary for establishing the prognosis: the size of the malignant lesion(s) (in mm); the histological type; the histological grade (specifying the grading system used); the percentage of any ductal carcinoma in situ (DCIS); the presence of peritumoral vascular invasion; the status of the surgical margins, including that of all additional excised samples. For an invasive tumour, the measurement of the infiltrating component should be given, including data from macroscopic and microscopic examinations (recommendation). The overall size of the lesions (including the invasive component and any associated intraductal component) can be documented (option, expert agreement). If there is intraductal carcinoma only, the size of the lesions should be assessed by combining the findings from the radiological and histopathological examinations (recommendation). If this assessment is difficult (multiple foci, etc.), the number of 'positive' sections out of the total number of sections examined should be stated (recommendation, expert agreement). The quality of the excised sample is defined by two criteria (recommendation): the distance (in mm) between all malignant foci and the nearest excision margin (identified using surgical guide marks); the nature of the tumour lesion (invasive or intraductal) nearest to the surgical margin. In cases where the surgical margin is invaded by tumour, the extent of this should be specified (recommendation, expert agreement). ## Mastectomy The standard histological report for a mastectomy sample should state the details of the diagnostic work-up and those factors required to establish the prognosis: the sites and number of malignant lesions; the size of the malignant lesions (in mm); the histological type of the tumour; the histological grade (specifying the grading system used); the percentage of DCIS, if present; the presence of peritumoral vascular invasion; the presence of extension into the nipple (specifying position and type: intraductal, infiltrating, Paget's disease); the presence if any of cutaneous or pectoralis major fasciomuscular involvement. For an invasive tumour, the extent of the invasive component should be given, integrating data from macroscopic and microscopic examinations (recommendation). The overall extent of the lesions (including the invasive component and any associated intraductal component) can be documented (option, expert agreement). If there is intraductal carcinoma only, the size of the lesions should be assessed by integrating the data from radiological and microscopic examinations (recommendation). If this assessment is difficult (multiple foci, etc.), the number of 'positive' sections out of the total number of sections examined should be given (recommendation, expert agreement). ## Axillary dissection All lymph nodes removed by axillary dissection should undergo full histological examination using a series of macroscopic sections (standard). The standard histological report for the samples from axillary dissection should specify: the number of lymph nodes examined; the number of metastatic lymph nodes, including the presence of micrometastases and if a sentinel node biopsy was performed before axillary dissection (standard); the number of metastatic lymph nodes with capsular rupture. Optimal quality for axillary examination requires sampling from at least 10 lymph nodes (standard, level of evidence: B1). This is usually achieved by a level I/II axillary dissection (standard, level of evidence: B1). Surgical guide marks should be made to orientate the sample, at least at one end (standard). The technique of sentinel node biopsy may avoid axillary dissection in 85 -90% of patients without lymph node involvement (level of evidence: B1), but cannot be recommended until the results of ongoing studies are available (recommendation, expert agreement). This technique requires input from a multidisciplinary team experienced in the area (recommendation, level of evidence: B1). ## Histological classification of breast cancer The standard histological classification of breast cancer is that developed by the World Health Organisation (WHO) (standard). The standard for histo-prognostic grading is that developed by Elston and Ellis (standard). This is applicable to all invasive cancers with the exception of medullary carcinomas and in situ carcinomas (standard). The coding of lesions can be performed using the CIMO/SNOMED system (WHO classification) and/or the ADICAP system (French classification) (option). ## Investigations for the detection of metastatic disease There is no indication to undertake a metastatic screening before the confirmation of a diagnosis of an invasive carcinoma (standard). This is also true for in situ carcinomas (standard). If a mastectomy is planned, a metastatic screening should be performed prior to surgery to avoid unnecessary surgery in women who already have metastatic disease, even if the probability is low (recommendation). In the absence of symptoms, a metastatic screening should only be performed after evaluation of the metastatic risk factors (see section on Prognostic factors) (recommendation). Assays of CA 15.3 and other tumour markers should not be done during the initial work-up because of their low sensitivity (standard, level of evidence: B2). At a more advanced stage of disease, they are often elevated but have no diagnostic value. Tumour markers can sometimes be used as a reference when poor prognostic factors are present (option). No study has shown an independent prognostic value for tumour markers. Nonspecific markers, such as CA 125, CA19-9 and TPA, should not be assayed (standard). ## Prognostic factors predictive factors for lymph node involvement It is essential to perform a clinical examination of the axillary region even though it is imprecise (standard, level of evidence: B1). Lymph node involvement generally progresses towards the apex of the axilla (standard, level of evidence: B1). Tumour size is the principal risk factor for lymph node involvement (standard, level of evidence: B1). Histologically confirmed axillary involvement, tumour size and young age are the main predictive factors for internal mammary node involvement (standard, level of evidence: B2). The influence of the tumour site is controversial. ## Predictive factors for local breast recurrence The most important clinical factors are young age (under 35 or 40 years old) and premenopausal status. The most important histological factors are: positive excision margins and the presence of an extensive ductal in situ component associated with the invasive component, high-grade tumour, the presence of peritumoral vascular invasion and inappropriate treatment. ## Predictive factors for metastatic disease The most important clinical factors are young age (under 35 or 40 years old), tumour size and axillary node involvement. The histological factors with the strongest prognostic value are tumour size, histologically confirmed node involvement, the number of axillary nodes involved (X4), a high-grade tumour and positive excision margins. The presence of peritumoral vascular invasion is also a predictive factor for metastatic disease. ## Predictive factors for therapeutic response Hormone receptor status should be determined in all cases of invasive disease (standard), using either a biochemical or immunohistochemical method (standard). The analysis for overexpression of c-erbB-2 should not be performed on a routine basis (standard). The predictive factors for response to chemotherapy, including c-erbB-2, are in the process of being evaluated. Cellular proliferation should be assessed in all infiltrating tumours, using either the mitotic index, S phase fraction measurement or Ki67 immunohistochemical assay (recommendation, expert agreement). Quality control is mandatory in all laboratories irrespective of the prognostic test performed (standard). ## Treatment modalities surgery Irrespective of the surgical technique used, tumour excision should be complete with negative margins and should be adapted to the tumour size and the breast volume (standard). The optimal size of excision to ensure negative margins has not been defined (standard). When breast-conserving surgery is to be undertaken, the aesthetic result should be acceptable to the patient (standard). Central tumours can be treated in a conservative manner if excision is complete (sometimes requiring excision of the nippleareolar complex) (option). Modified radical mastectomy is equivalent to radical mastectomy in terms of local control and survival (standard). Breastconserving treatments with lumpectomy followed by radiotherapy are equivalent to mastectomy in terms of local recurrence and survival (standard, level of evidence: A). Subcutaneous mastectomy should not be considered for invasive or noninvasive breast cancer (recommendation, expert agreement). ## Complications after axillary node dissection There appears to be no technique available to assess the risk of sequelae (particularly lymphoedema) following surgery to this anatomically complex and strategic area where several different lymphatic regions converge (back, legs, anterior thoracic wall and breast). Early physiotherapy for the shoulder and the thoracic wall is by far the most significant preventative treatment. Informing patients of the best means of prevention remains the best means of preventing lymphoedema. Lymphatic drainage is not indicated as a preventative measure (recommendation). ## Radiotherapy Radiotherapy reduces the risk of mortality due to breast cancer (standard, level of evidence: A). However, it may increase the risk of long-term cardiovascular mortality if an inappropriate technique is used. Breast, chest wall or lymph node irradiation should be performed with caution, with the aim of limiting the irradiation of healthy tissue, while satisfying quality assurance criteria (standard). The dose prescription is standardised (the International Commission on Radiation Units (ICRU)) (standard, level of evidence: A). After breast-conserving surgery, breast radiotherapy should always be performed, using a minimum dose of 50 Gy in 25 fractions (standard, level of evidence: A). Breast irradiation after breast-conserving surgery significantly reduces the risk of local recurrence irrespective of the initial disease stage (standard, level of evidence: A). In women under 50 years old, a boost should be administered routinely to the tumour bed even when the margins are clear (standard, level of evidence: B). Guidelines from an expert committee of the French Society of Oncological Radiotherapy (SFRO, 1991) cover the choice of target volume for irradiation following breast-conserving surgery. After mastectomy, the benefit from chest wall radiotherapy is greater in patients with the highest number of risk factors (standard, level of evidence: A). Irradiation of the internal mammary lymph nodes is indicated in all cases of axillary lymph node involvement (standard, level of evidence: B1) and when the tumour is medial or central (standard, expert agreement). Irradiation of the infra-and supraclavicular lymph nodes is indicated in the presence of axillary lymph node involvement (standard, level of evidence: B1). The omission of lymph node irradiation, as defined above, is only justified in the setting of a randomised clinical trial (standard, expert agreement). The choice of immediate breast reconstruction should not jeopardise the optimal use of locoregional radiotherapy and systemic treatment (recommendation). After axillary dissection, radiotherapy to the axilla should be avoided as much as possible because of the increased risk of locoregional complications (standard, level of evidence: C). ## Chemotherapy Anthracycline-containing polychemotherapy is currently the most commonly used regimen in France and is more efficacious than the CMF regimen: cyclophosphamide, methotrexate and fluorouracil (5-FU) (standard, level of evidence: A). This is supported by the conclusions from the NIH consensus conference . Adjuvant chemotherapy improves progression-free survival and overall survival in patients with node-positive breast cancer and in certain patients without node involvement. Premenopausal women seem to benefit more than menopausal women. Doxorubicin, epirubicin, 5-FU, cyclophosphamide and methotrexate used in combination every 3 -4 weeks, with a maximum of six cycles, is the reference treatment. The optimal number of cycles (four to six cycles) is unknown. Chemotherapy should be started promptly. The efficacy of perioperative chemotherapy has not been clearly proved, and should only be undertaken in the setting of a randomised clinical trial. High-dose chemotherapy, with or without stem cell infusion, is under evaluation and cannot be considered as a therapeutic standard. The optimal dose for epirubicin remains to be determined. have not yet been shown to offer any benefit as adjuvant or neoadjuvant treatment. Induction or neoadjuvant chemotherapy is an option in operable breast cancer where first-line breast-conserving surgery is not possible, in the absence of multifocal lesions, and where the patient would prefer breast conservation (option). Compared with adjuvant therapy, induction or neoadjuvant therapy has no effect on survival but has been shown to avoid mastectomy in more than 50% of women. The risk of local recurrence is higher than with a primary mastectomy and the possibility of breast-conserving surgery is reduced. After neoadjuvant chemotherapy, locoregional treatment should be performed in the same manner as that used for first-line locoregional treatment (standard). In premenopausal women, the combination of hormone therapy with adjuvant chemotherapy does not lead to a significant improvement in global survival or progression-free survival. This may be due to the low number of young women treated with tamoxifen and/or the lack of stratification for hormone receptor status in previous studies (standard, level of evidence: A). However, the practice was recommended in November 2000 by the NIH consensus conference . ## Hormone therapy Treatment with adjuvant tamoxifen is beneficial, despite its side effects, irrespective of the patients' age, if the tumour expresses oestrogen receptors (standard, level of evidence: A). Tamoxifen should not be prescribed to women with tumours that do not express oestrogen receptors (standard, level of evidence: A). The optimal duration for adjuvant hormone therapy with tamoxifen is 5 years at a dose of 20 mg day À1 (standard, level of evidence: A). Patients treated with tamoxifen should have regular gynaecological clinical examinations (recommendation, expert agreement). Additional examinations are not necessary in the absence of symptoms. Neoadjuvant treatment with antioestrogens can be used in elderly women with slowly evolving hormone-sensitive tumours (option, level of evidence: B1). This should be followed when possible by optimal locoregional treatment (option, expert agreement). At present, antioestrogens cannot be considered as standard neoadjuvant treatment for initially operable tumours. Hormone therapy can be administered for different reasons, depending on the patients' age: suppression of ovarian function in women with ovarian activity and/or as an antioestrogen, antioestrogenic therapy in postmenopausal women. In postmenopausal women, the combination of chemotherapy with an antioestrogen significantly improves progression-free survival and overall survival (standard, level of evidence: A). The ratio of efficacy (overall or recurrence-free survival) and risk (toxicity) should be considered when taking the decision to prescribe this combination. The efficacy/risk ratio favours treatment in women with major metastatic risk factors (recommendation, expert agreement). Other hormone therapy (progestogens, aromatase inhibitors) should not be considered as adjuvant treatments except in the setting of a randomised clinical trial (standard). ## Breast reconstruction and additional treatments When mastectomy is necessary to obtain local control and the patient would prefer immediate breast reconstruction, multidisciplinary consultation is essential to assess the need for locoregional (irradiation) or systemic (chemotherapy or hormone therapy) treatment. Breast reconstruction is not a cancer treatment but is an integral component of breast cancer care (standard). It can be performed immediately or be delayed, but should never interfere with the administration of other treatments (chemotherapy and/or radiotherapy) (standard). Poor prognosis is not a contraindication for breast reconstruction (standard). However, the patient's performance status and/or a high risk of recurrence of the disease can be relative contraindications (standard). The patient should participate in the final decision (standard). There are three main techniques for reconstruction: submuscular inplant, latissimus dorsi flap or TRAM (transverse rectus abdominis myocutaneous) pedicle flaps and microanastomosed free flaps (option). If the patient requires radiotherapy but wants immediate breast reconstruction, autologous tissue techniques should be used. A prosthesis can be irradiated but the patient should be informed about the potential risks, particularly that of substantial contraction as seen in about 50% of patients. ## Treatment strategy The patient should participate in her treatment decisions at every stage. ## Treatment evaluation Treatment evaluation involves both functional and aesthetic evaluation, consideration of possible side effects and the patients' quality of life (standard). Painful scarring (leading to limited mobility of the arm/shoulder) and lymphoedema are the most frequently observed complications after surgery. The aesthetic result depends on the quality of the surgery and radiotherapy technique (standard). Aesthetic problems do not occur following chemotherapy alone, but are observed when chemotherapy is used concomitantly with radiotherapy (standard). Visual analogue scales of well being are useful for assessing quality of life. Fatigue has a significant impact on quality of life and can be related to treatment and/or a depressive reaction. This should always be taken into consideration by the physician and its importance should not be underrated. Questionnaires exist for assessing fatigue and quality of life (standard). ## Locoregional treatment Surgery and/or radiotherapy are used for the locoregional control of the disease. ## Management of impalpable tumours The therapeutic strategy for ductal carcinomas in situ is not covered in this document. The therapeutic management of impalpable tumours is often a stepwise process guided by the histological results of the previous intervention. The patient should be informed right from the start about the risks associated with repeated interventions. First decisional step [fig_ref] Figure 3: Impalpable operable tumour -locoregional treatment [/fig_ref] : This first step is diagnostic and potentially therapeutic and consists of a radiologically proven complete excision and histological analysis of the lesion (standard). In the absence of a palpable macroscopic lesion, a frozen section and primary axillary dissection should not be performed (recommendation, expert agreement). If microcalcifications are present, a mammogram should be performed 2 months after surgery (recommendation, expert agreement). Second decisional step: This step depends on the status of the surgical margins and the extent of the microcalcification before and/or after surgery. * Microinvasive cancer (infiltrating component p2 mm): There is no specific data concerning the risk of progression of microinvasive cancers. The recommendations are the same as those proposed for invasive cancers . -Extensive microcalcifications at diagnosis (breast-conserving surgery inappropriate): Modified radical mastectomy followed by immediate breast reconstruction should be offered (standard). -Clear margins and no residual microcalcifications: The breast should be irradiated (standard). Modified radical mastectomy can be considered if the patient refuses conservative treatment (option). Axillary dissection or axillary radiotherapy may also be performed (option). In the absence of known risk factors for metastatic recurrence, adjuvant systemic treatment should not be given (recommendation, level of evidence: B). -Involved margins and/or residual microcalcifications: Mastectomy is the standard treatment (standard). Reexcision and breast radiotherapy, or axillary dissection and radiotherapy can be performed (option). If reexcision does not provide clear margins, mastectomy should be performed (standard). * Invasive cancer : -Extensive micro-calcifications at diagnosis: Modified radical mastectomy is indicated (standard). In the event of lymph node invasion, radiotherapy to the chest wall and lymph nodes (internal mammary chain, infra-and supraclavicular) should be performed (standard). -Clear margins and/or absence of residual microcalcifications: The standard procedure is axillary dissection and breast radiotherapy (standard). If the patient presents with lymph node involvement, this should be followed by lymph node irradiation (internal mammary chain, infraand supraclavicular) (standard). It is also possible to irradiate the lymph nodes without axillary surgery (option). -Invaded margins and/or presence of residual microcalcifications: Modified radical mastectomy should be performed (standard). In the event of lymph node involvement, this should be followed by the chest wall and lymph nodes (internal mammary chain, infra-and supraclavicular) irradiation (standard). Re-excision combined with axillary dissection, followed by breast radiotherapy can be undertaken. Breast radiotherapy with a boost to the tumour bed can also be considered (option). Invasive carcinoma 2nd decision step Microinvasive cancer 2nd decision step * Preoperative diagnosis of an invasive lesion by core biopsy will allow immediate investigation for axillary node involvement (see [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] : 3rd decision step) If microcalcifications present * Carcinomas in situ have not been included here and will be treated in a specific document Management of a single, palpable, Localised tumour treatable by breast-conserving surgery A single palpable localised tumour can be completely excised with a wide margin [fig_ref] Figure 6: Operable palpable tumour -locoregional treatment [/fig_ref]. This is dependent on the probability of achieving an excision with clear margins and a satisfactory aesthetic result. First decision step [fig_ref] Figure 7: Operable palpable tumour -locoregional treatment [/fig_ref] : Lumpectomy (7frozen section), axillary dissection and breast radiotherapy is the standard. The breast should always be irradiated; this has been shown to reduce considerably the rate of local recurrence (recommendation, level of evidence. A). Axillary dissection should only be undertaken after the diagnosis of an invasive carcinoma has been confirmed (recommendation, expert agreement). It is essential to examine all tissue margins (recommendation). Central tumours can be managed with conservative treatment (recommendation, expert agreement). If the patient refuses conservative treatment, a modified radical mastectomy can be considered (option). If microcalcifications are present, a postoperative mammogram is essential to verify the presence or absence of residual lesions after conservative treatment (standard, expert agreement). . This association can be given to patients over 50 years old who have other risk factors for recurrence (option). * Positive excision margins . -When re-excision is possible (histologically clear margins possible and a satisfactory aesthetic result). The standard procedure is to undertake re-excision and breast radiotherapy (standard). This should be followed by a boost to the tumour bed if the patient is under 50 years old (standard) or has other risk factors (option). If a boost to the tumour bed and/or re-excision is performed, the aesthetic result should be satisfactory (recommendation, expert agreement). If the patient refuses re-excision, breast radiotherapy with a boost to the tumour bed can be considered (option). Modified radical mastectomy can also be considered (option). [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Indication for adjuvant treatment [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Indication for nodal radiotherapy 3rd decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] * To obtain clear margins Operable impalpable tumour -locoregional treatment. -When re-excision is impossible (the margins will be involved after re-excision, and/or the aesthetic result will not be satisfactory). Modified radical mastectomy should be performed (standard). Immediate breast reconstruction can be considered if there are no other risk factors for locoregional recurrence and/or this does not prejudice the administration of additional treatment (option). If the patient refuses mastectomy and there is a high risk of metastatic recurrence or if there is minimal invasion of the excised tissue margins, breast radiotherapy and a boost to the tumour bed can be proposed (option, level of evidence: D). Third decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] : This depends on the extent of axillary node involvement. * Absence of axillary node involvement: The decision depends on the tumour localisation. -Lateral tumour The nodal areas should not be irradiated (standard). -Central and/or medial tumour The internal mammary chain should be irradiated (standard). Infra-and supraclavicular radiotherapy can also be considered (option). Nodal irradiation for low-risk tumours is not recommended, and is currently under evaluation. Irrespective of the tumour localisation, axillary radiotherapy should not be performed in the absence of Indications for nodal radiotherapy 3rd decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Indications for nodal radiotherapy 3rd decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Standards: Operable impalpable tumour -locoregional treatment. [formula] - [/formula] ## Operable palpable breast tumour Single localised tumour that can be completely excised ( histologically proven nodal involvement (recommendation, level of evidence: A). * Presence of axillary node involvement: Screen for distant metastases (standard) and irradiate infra-and supraclavicular plus internal mammary nodes (standard). If extensive nodal involvement is present, the whole of the axillary region can be irradiated (option). Radiotherapy should only be omitted in the setting of a randomised clinical trial (option). Palpable tumour, primary breast-conserving surgery not possible First decision step: A metastatic screen should be undertaken (standard) [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref]. A modified radical mastectomy should be performed in the absence of metastases (standard). Nonsurgical treatment (medical or radiotherapy) can be considered (option). Nonsurgical treatment is not indicated for multifoci lesions where the local treatment should be mastectomy (recommendation, expert agreement). If primary radiotherapy or medical treatment is performed, locoregional control must be obtained (recommendation, level of evidence: A) [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref].A preliminary biopsy can be performed to assess the prognostic factors that are necessary to guide locoregional and adjuvant treatment (recommendation, expert agreement). When immediate reconstruction is offered, it should not jeopardise the administration of locoregional and/or systemic treatment (recommendation). Second decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] : This step occurs after mastectomy and axillary dissection and is dependent on the presence or absence of risk factors for local recurrence. * Absence of risk factors for local recurrence: Chest wall radiotherapy is not indicated (standard). * Presence of risk factors for local recurrence: Chest wall radiotherapy is indicated (standard). Third decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] : This step is dependent on the extent of axillary node involvement (see section on 'Management of a single palpable localised tumour treatable by breast-conserving surgery, third decision step'). Adjuvant therapy [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] The aim of adjuvant therapy is to reduce the risk of metastatic recurrence and thus improve survival. Risk factors for metastatic recurrence should be assessed during the initial examination and Risk factors: age<50 years old; lymph node involvement; vascular invasion; grade III tumour; high mitotic index; negative hormone receptors Clear margins? yes no Breast cancer after primary breast-conserving surgery 2nd decision step yes no Risk factors for local recurrence? Breast cancer after primary breast-conserving surgery 2nd decision step positive margins Indication for nodal radiotherapy 3rd decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Breast cancer after primary breast-conserving surgery 2nd decision step clear margin(s) and other risk factor(s) for local recurrence Standards: - breast radiotherapy - boost if patient<50 years Options: - boost if patient>50 years and other risk factors present - mastectomy if other risk factors present Operable palpable tumour -locoregional treatment. Breast cancer after primary breast-conserving surgery 2nd decision step positive margins* Breast cancer after primary breast-conserving surgery 2nd decision step Indications for nodal radiotherapy 3rd decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Standard: modified radical mastectomy Options: - immediate breast reconstruction if no other risk factor(s) for locoregional recurrence and/or this will not jeopardise the administration of additional treatments - breast radiotherapy and boost to tumour bed if mastectomy refused or when the risk of local recurrence is accompanied with the risk of metastatic recurrence or minimally positive excision margins Re-excision possible?** Clear margins? Operable palpable tumour -locoregional treatment. Central and/or medial tumour Indication for adjuvant treatment [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Indication for adjuvant treatment [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Indication for adjuvant treatment [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Standards: - perform metastatic assessment - radiotherapy (infra/supraclavicular and internal mammary chain) Options: - irradiation of the whole of the axilla if major node involvement - no irradiation of lymph nodes except in the setting of a prospective clinical trial Standards: radiotherapy to the internal mammary chain Options: - infra/supraclavicular radiotherapy - no node radiotherapy for lesions thought to be low risk (under evaluation) ## Lateral tumour Standard: no radiotherapy to nodes [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Operable tumour -indication for nodal radiotherapy. Adjuvant therapy after first-line chemotherapy or hormone therapy There is no standard treatment. Hormone therapy with tamoxifen can be given if the tumour is positive (or unknown) for oestrogen receptors (option) [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref]. Adjuvant therapy after first-line radiotherapy The size of the initial lesion may justify the use of adjuvant medical therapy (recommendation) [fig_ref] Figure 2: Diagnosis [/fig_ref]. ## Follow-up Follow-up should focus on the evaluation of the treatment results, screening for relapse, treatment of side effects and psychosocial and professional rehabilitation [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref]. This requires a multidisciplinary approach. ## Follow-up of the conserved breast Clinical examination should be performed 4 months after treatment to assess treatment toxicity (standard). Clinical followup should then be repeated every 6 months for 5 years and then yearly for 10 years (standard). Routine follow-up should be continued after 10 years, but the timing can be adjusted depending on the risk of local recurrence (option). An annual mammogram should be performed starting 6 months after treatment (standard). Breast cancer after modified radical mastectomy 2nd decision step yes no Presence of risk factors for local recurrence? Indication for nodal radiotherapy 3rd decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Indication for nodal radiotherapy 3rd decision step [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Standard: chest wall radiotherapy Standard: no chest wall radiotherapy [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Palpable tumour, breast-conserving surgery not possible: modified radical mastectomy. ## Follow-up of the chest and lymph node areas Routine clinical examination forms the basis of follow-up for the thoracic wall and the lymph node areas after treatment for breast cancer. ## Follow-up of the contralateral breast Clinical examination and a mammogram should be performed at the same frequency as above for the follow-up of the conserved breast (standard, expert agreement). ## General follow-up after treatment of patients in complete remission History taking and clinical examination form the basis of followup (standard). In the absence of symptoms or signs, a routine screen for metastases is not indicated (standard, level of evidence: A). If a metastasis is found, the patient should undergo a full workup (recommendation, expert agreement). The frequency of general clinical follow-up is the same as that for locoregional follow-up (recommendation, expert agreement). ## Rehabilitation after treatment for breast cancer Rehabilitation should start before treatment with clear specific information about possible post-treatment complications and how they can be prevented and/or managed (standard). Functional problems of arm or shoulder movement require early physiotherapy (standard). Lymphoedema can be treated with physical methods and systemic therapy (recommendation). Coumarin is no longer indicated because of its toxicity and lack of efficacy (standard). To avoid weight gain, dietary advice should be provided routinely (recommendation). Sexual problems should be evaluated and treated (recommendation). The need for contraception and family planning advice should be discussed individually taking into consideration each patient's preference (recommendation). Hormone replacement treatment for postmenopausal symptoms should not be prescribed after treatment for breast cancer, except in specific cases. The prescription of hormone replacement treatment after breast cancer is being evaluated prospectively. Nonhormonal treatments exist for the various symptoms (recommendation). Standard follow-up [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] ER+ve, presence of oestrogen receptors. ## Standard: chemotherapy and tamoxifen Options: - chemotherapy and ovarian suppression ± tamoxifen - ovarian ablation ± tamoxifen (without chemotherapy) [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Operable tumour -adjuvant medical treatment (N þ ve, premenopausal woman or p50 years old). Standard follow-up [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] ER+ve , presence of oestrogen receptors. ## Standard: tamoxifen Option: tamoxifen + chemotherapy [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Operable tumour -adjuvant treatment (N þ ve, postmenopausal woman or 450 years old). Psychological support may well be required at some stage during the management process (option). Social support, to strengthen the psychological support, should be provided routinely to help patients and their families (option). Patient rehabilitation groups can contribute to the psychosocial support of patients (option). ## Management of patients with recurrent disease Management of local recurrence after breast-conserving treatment for breast cancer Local recurrence should be treated with surgery. Radiotherapy should not be considered except in specific cases (standard). The standard treatment is a simple total mastectomy (standard). Immediate reconstruction can be considered (option). If oestrogen receptors are present, additional hormone therapy is recommended (recommendation). Breast-conserving surgery can only be considered if the patient refuses mastectomy or if mastectomy is technically impossible. In this case, the patient should be informed of the high risk of recurrent disease (recommendation). As the efficacy of additional chemotherapy is unknown, this should only be considered in the Standard follow-up [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Standard follow-up [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Standard follow-up [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] ER+ve, presence of oestrogen receptors. ER+ve, presence of oestrogen receptors. [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Palpable tumour, breast-conserving surgery not possiblelocal treatment after neoadjuvant treatment. Standard follow-up [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Standard follow-up [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] Standard follow-up [fig_ref] Figure 1: Diagnosis -clinically detectable breast abnormality [/fig_ref] ER+ve, presence of oestrogen receptors. [fig] : Results from cytology may be sufficient if primary surgery is planned. [/fig] [fig] Figure 1: Diagnosis -clinically detectable breast abnormality. [/fig] [fig] Figure 2: Diagnosis [/fig] [fig] Figure 3: Impalpable operable tumour -locoregional treatment. [/fig] [fig] Figure 6: Operable palpable tumour -locoregional treatment. [/fig] [fig] Figure 7: Operable palpable tumour -locoregional treatment. [/fig] [table] Table 1: Definition of 'Standards, Options and Recommendations' [/table] [table] Table 3: Management of patients with breast cancer with lymph node involvement (N+ve) Premenopaual woman or p50 years old (Figure 16) Post menopausal woman or 450 years old (Figure 17)ER+ve ¼ presence of oestrogen receptors; ERÀve ¼ absence of oestrogen receptors. [/table] [table] Table 4: Management of patients with breast cancer without lymph node involvement (NÀve) Premenopausl woman or p50 years old (Figure 18) Postmenopausal woman or 450 years old (Figure 19)Risk of metastatic recurrence aPresence of one or more risk factors for metastatic recurrence. ER+ve ¼ presence of oestrogen receptors; ERÀve ¼ absence of oestrogen receptors. [/table]	None	https://www.nature.com/articles/6601081.pdf	None
e447d9d48523915117a67e97daef58c7e2f05956	pubmed	Amalgam (Part 2): Safe Use and Phase Down of Dental Amalgam	Amalgam (Part 2): Safe Use and Phase Down of Dental Amalgam ## Scope In 2013, the Minamata Convention on Mercury supported a gradual phase down of dental amalgam usage in restorative dental treatment. It was adopted in 2017 making it necessary to plan and act strategically to reduce the need for dental amalgam for restorative treatments. The Convention also emphasized the need to strengthen dental curricula towards disease prevention and health promotion as well as teaching alternative restorative materials and techniques, including the minimum intervention approach as appropriate. ## Definitions Minamata Convention on Mercury: an international treaty developed by the United Nations Environment Programme, governing the mining, trade in and use of mercury. Dental amalgam: filling material for teeth prepared by mixing mercury with dental amalgam alloy.Dental amalgam alloy: powder or compressed powder pellets of an alloy consisting mainly of silver, tin and copper which, when mixed with mercury, produces a dental amalgam.PRINCIPLES FDI supports the World Health Organization for the phase down of dental amalgam usage, through decreasing demand for its need. Decreasing demand may be accomplished through increased emphasis on disease prevention and health promotion, and research into development and availability of equivalent alternative treatment options. Dental treatment should ensure that dental restorative materials continue to be used in a safe and effective manner for patients and oral healthcare providers, while respecting the environment. international dental journal 7 2 ( 2 0 2 2 ) 1 2 − 1 3 POLICY All treatment decisions should be based on the current scientific evidence, the best interests of patients and the sound clinical judgement by the dental practitioner, while considering the integrity of the environment and the health of the population. Amalgam tattoos cause tissue discoloration but are otherwise benign. No treatment is necessary. Localized oral lichenoid lesions may occur next to amalgam restorations in very rare instances, due to many factors such as an autoimmune reaction or allergic reaction to amalgam components. If such patients are positive to skin allergy patch testing for mercury or other amalgam components, replacement of the restorations may improve their mucosal lesions. FDI supports the following practices in the phase down of dental amalgam: Increased emphasis on disease prevention and health promotion. Enhanced research and development of quality mercuryfree materials for dental restorations, including on their potential health and environmental impacts. Appropriate education in the use of appropriate alternative restorative materials and techniques in universities and continuing education courses. Reduce and if possible avoid the use of dental amalgam in: lesions that are suitable for other restorative materials, especially in first restorative treatment and young patients; individuals with special medical conditions such as severe renal disease, or those with allergic reactions to amalgam or (erosive) lichenoid contact lesions in the oral mucosa; except when deemed necessary by the dental practitioner based on the specific needs of the patient and the clinical situation. This policy may be implemented differently in various countries or regions and where special regulations may apply. ## Disclaimer The information in this Policy Statement was based on the best scientific evidence available at the time. It may be interpreted to reflect prevailing cultural sensitivities and socioeconomic constraints. [fig] CONTEXT: The existing FDI Policy Statements on the safety of dental amalgam (Possible Local Adverse Effects of Amalgam Restorations, 2007; Safety of Dental Amalgam, 2007) and their use in the context of phase down according to the Minamata Convention on Mercury (Dental Amalgam and the Minamata Convention on Mercury, 2014; Dental Amalgam Phase Down, 2018) are updated by and integrated into this Policy Statement. [/fig]	None	None	None
1bf4a8217769c75ed990435646da16650b8cc662	pubmed	Considerations on biologicals for patients with allergic disease in times of the COVID‐19 pandemic: An EAACI statement	Considerations on biologicals for patients with allergic disease in times of the COVID‐19 pandemic: An EAACI statement # Abstract The outbreak of the SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) pandemic re-shaped doctor-patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS-CoV-2 is not known. Severe COVID-19 patients may experience a "cytokine storm" and associated organ damage characterized by an exaggerated release of pro-inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti-inflammatory cytokines and type 2 responses. This expert-based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID-19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self-application. In case of an active SARS-CoV-2 infection, biological treatment needs to be stopped until clinical recovery and SARS-CoV-2 negativity is established and treatment with biologicals should be re-initiated. Maintenance of add-on therapy and a constant assessment of disease control, apart from acute management, are demanded. ## \| introduc ti on The outbreak leading to the pandemic of SARS-CoV-2-induced coronavirus disease 2019 (COVID-19) has pushed healthcare systems to the limits of their capacity across the globe. This infection can cause severe respiratory illness and multi-organ failure with clinical presentations greatly resembling SARS-CoV-1 and MERS-CoV, resulting in intensive care unit (ICU) admission and high mortality. We discuss immunological and clinical considerations for patients on biologic agents (biologicals) targeting the type 2 inflammatory response due to difficult-to-treat allergic diseases in the context of COVID-19. ## \| immunolog ic al fe ature s of sar s -cov-infec ti on in the conte x t of t ype infl ammation Both innate and adaptive immune responses participate in antiviral immunity. The interactions between SARS-CoV-2 and both arms of the immune system have been poorly clarified until now, particularly in the view of asymptomatic individuals, patients with mild disease, and those who fully recover. Natural killer cells are involved in control of the acute phase of the viral infection, whereas CD8 + T cells are the key player in the following steps. 1 Antibodysecreting cells and T follicular helper cells are instrumental in the production of specific antiviral IgA, IgM, and IgG antibodies early on. [bib_ref] Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in..., Channappanavar [/bib_ref] [bib_ref] Breadth of concomitant immune responses prior to patient recovery: a case report..., Thevarajan [/bib_ref] [bib_ref] Profiling Early Humoral Response to Diagnose Novel Coronavirus Disease (COVID-19), Guo [/bib_ref] Antibody-dependent macrophage activation as well as lymphocyte and macrophage pyroptosis (an excessive form of inflammatory cell apoptosis) might occur and contribute to more severe tissue damage, as described in SARS-CoV infection. [bib_ref] Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, Channappanavar [/bib_ref] [bib_ref] Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, Channappanavar [/bib_ref] [bib_ref] Immunological responses against SARS-coronavirus infection in humans, Xu [/bib_ref] and, more recently, COVID-19 patients 9 suggest an overshooting immune response in severe cases with widespread lung damage and disease aggravation around 7-14 days after onset. Those severe COVID-19 patients may also experience a picture of a so-called cytokine storm and associated organ damage, particularly acute respiratory distress syndrome, acute kidney and liver failure, myocarditis, and disseminated vascular coagulation. These manifestations are characterized by an exaggerated release of pro-inflammatory cytokines, such as IL-1β, IL-6, IL-8, and TNF-α . Consequently, these highly increased pro-inflammatory cytokines are believed to be potential targets for biological therapy. These type 1-and type 3-driven inflammatory responses are counteracted by anti-inflammatory cytokines, such as IL-10 and TGF-β, as well as potentially type 2 responses. Moreover, eosinophils have been reported to play a role in virus response. [bib_ref] Eosinophils capture viruses, a capacity that is defective in asthma, Sabogal Pineros [/bib_ref] Lower eosinophil counts were reported in association with severe cases, while an elevated eosinophil count was associated with a better prognosis 9 although no functional relationship has been established so far and this finding may be an epiphenomenon. Thus, probably all shades of cytokine responses (type 1 and type 3, type 2, and regulatory cytokines) are required in the healing of SARS-CoV-2 infection. An appropriate induction and downregulation of individual response batteries is necessary to achieve an efficient viral clearance, an avoidance of excessive inflammatory reaction, and irreversible tissue damage . ## \| sar s -cov-2 infec ti on and allerg i c d is e a s e In line with a paucity of mechanistic data on COVID-19 in the context of type 2 inflammation, knowledge on the disease course in patients treated with biologicals targeting type 2 inflammation due to severe asthma or other atopic diseases, such as CSU, AD, and CRSwNP, is scarce to absent. To our knowledge by April 12, 2020, only 6 studies presented disease characteristics of SARS-CoV-2 infection on patients with allergy or atopic diseases as a comorbidity ; Supplementary Material). While in a study including F I G U R E 1 Cellular networks during SARS-CoV-2 infection. Initially, infection with the SARS-CoV-2 induces both humoral and cellular (innate and adaptive) immune responses. Recruitment of antibody-secreting cells (ASC) and interaction with T follicular helper cells (Tfh) occurs early before the resolution of symptoms and leads to the production of IgA, IgM, and IgG against viral nucleoprotein (NP) and surface spike protein receptor-binding domain (RBD). SARS-CoV-2 binding antibodies may participate in tissue damage by macrophage activation via FcγRI. SARS-CoV-2 infects several types of cells (alveolar lung cells, macrophages, endothelial cells, lymphocytes) stimulating type I IFN production, which is crucial for the protection of uninfected cells and the enhancement of natural killer (NK) cell cytotoxic activity. Virus-cell interactions lead to the release of mediators. The secretion of large amounts of cytokines and chemokines is promoted in infected cells and effector cell populations in response to virus. These mediators, in turn, alert tissue-resident lymphocytes (including also innate lymphoid cells, ILCs) and recruit other leukocytes, predominantly in the lungs.Dendritic cells function as sensor cells and present virus antigens to T cells. This process leads to T-cell activation and differentiation, including the production of cytokines associated with Th1 and Th17 profile, and subsequently activates CD8 + cytotoxic T cells. Both, inflammation and cell damage, induce and result in the release of danger signals and alarmins (IL-33, IL-25, TSLP) that may promote both Th2 cells and ILC2 cells. The immune network during the course of infection includes the involvement of regulatory T (Treg) cells, able to secrete IL-10 and TGF-β 1591 patients infected with SARS-CoV-2 and admitted to ICUs of Lombardy, Italy, asthma was not referred to as a specific comorbidity and grouped under "others." 11 Allergic disease seemed to have no influence on presented symptoms and the course of the disease. [bib_ref] Covid-19 in Critically Ill Patients in the Seattle Region -Case Series, Bhatraju [/bib_ref] [bib_ref] Eleven Faces of Coronavirus Disease, Dong [/bib_ref] [bib_ref] Clinical Features of 69 Cases With Coronavirus Disease, Wang [/bib_ref] [bib_ref] Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, Zhang [/bib_ref] None of these patients were on biologicals to treat their pre-existing allergic disease. In a recent report from the COVID-19-Associated ## \| b i olog i c al ther apie s targ e ting t ype 2 infl ammation: ke y issue s In the past years, new biological therapies for severe asthma, atopic dermatitis (AD), chronic rhinosinusitis with nasal polyps (CRSwNP), F I G U R E 2 Hypothesis of a favorable evolution of SARS-CoV-2 infection in the context of type 2 cytokine and regulatory cytokine responses. The hypothetical evolution of the antiviral immune response during SARS-CoV-2 infection may unfold as following: Lung injury triggered by virus is propagated by innate and adaptive immune system. Adaptive responses are triggered shortly after activation of the innate system. During the infection course, a dynamic balance between pro-inflammatory type 1 and Th17 cells as well as Treg populations and anti-inflammatory type 2 responses is upregulated. Both high levels of certain type 2 (IL-4, IL-13) and regulatory cytokines (IL-10, TGF-β) could protect from worsening of lung tissue damage targeting different aspects of the type 2 immune response. [bib_ref] Precision medicine and phenotypes, endotypes, genotypes, regiotypes, and theratypes of allergic diseases, Agache [/bib_ref] [bib_ref] EAACI IG Biologicals task force paper on the use of biologic agents..., Boyman [/bib_ref] [bib_ref] Future research trends in understanding the mechanisms underlying allergic diseases for improved..., Breiteneder [/bib_ref] [bib_ref] Biologicals in allergic diseases and asthma: Toward personalized medicine and precision health:..., Palomares [/bib_ref] [bib_ref] Biologicals in atopic disease in pregnancy: an EAACI position paper, Pfaller [/bib_ref] [bib_ref] New biological treatments for asthma and skin allergies, Eyerich [/bib_ref] [bib_ref] The EAACI/GA(2)LEN/EDF/ WAO guideline for the definition, classification, diagnosis and management of..., Zuberbier [/bib_ref] [bib_ref] EUFOREA consensus on biologics for CRSwNP with or without asthma, Fokkens [/bib_ref] [bib_ref] Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal..., Jonstam [/bib_ref] Anti-IL-5 monoclonal antibodies (mepolizumab and reslizumab) are approved for severe asthma with peripheral eosinophilia, uncontrolled under high-intensity treatment. Benralizumab, a monoclonal antibody that binds to the α subunit of IL-5 receptor (IL-5Rα), 25 was also recently approved for uncontrolled eosinophilic severe asthma. Dupilumab, a monoclonal antibody directed against the α subunit of the IL-4 receptor (IL-4Rα) acting as a dual antagonist of both IL-4 and IL-13, was approved for uncontrolled severe type 2 asthma, moderate-to-severe AD, and CRSwNP. Omalizumab, a humanized monoclonal anti-IgE antibody, has also been approved for IgEmediated persistent allergic asthma and CSU. ## \| b lo cking t ype 2 infl ammati on and vir al infec tions The low number of reports of patients on biologicals targeting type 2 disease is encouraging since type 2 diseases may predispose patients to viral infections due to compromised barriers. [bib_ref] Targeting Antiviral Pathways for Treatment of Allergic Diseases, Rowe [/bib_ref] There is no evidence, which suggests immune response to COVID-19 will be impaired in asthma patients treated with anti-IL5, anti-IL5Ra, anti-IL4/IL13, or anti-IgE medications. In the absence of any data indicating a potential for harm, it would be reasonable to continue administration of biologic agents during the COVID-19 pandemic in patients for whom such agents are clearly indicated and have been effective. ACAAI www.colle ge.acaai.org April 8, 2020 For patients with severe asthma currently on a biologic therapy, there is no information at this time that these treatments should be stopped. These severe asthma patients are at an increased risk to COVID-19 infection, and optimal control of their chronic condition is of upmost importance. - Unavailable therapy with biologics may lead to many patients requiring treatment with systemic steroids and potentially negative impact on immune responses directed against SARS-CoV-2 - Stopping treatment with biologics may lead to worsening of the underlying disease, which may therefore provide negative influence on the course of acquired COVID-19 disease. According to WHO, patients with chronic lung disease (eg, such as asthma) may be prone to more severe disease. a. viral asthma exacerbations occur less frequently and with lower severity under treatment with biologics b. those immune processes targeted by biologics most probably do not affect virus defense - Based on current knowledge, we therefore recommend to maintain treatment based on a joint agreement between treating physician and patient. ## Aad WAO worldallergy.org April 8, 2020 For patients: "There is currently no evidence that inhaled corticosteroids (nasal or bronchial), antihistamines or biologic medications have any effect on the risk of contracting COVID-19. If you stop or modify your treatment, you run the risk that your allergic disease, particularly your asthma control, could become worse, causing you to need rescue medical treatment or be admitted to the hospital." https://www.world aller gy.org/UserF iles/file/Aller gic_patie nts_during_COVID -19.pdf PAS [bib_ref] Position statement of expert panel of the Polish Allergology Society on the..., Kowalski [/bib_ref] - It is recommended to continue biologic therapy with anti-IgE or anti-IL-5 in patients with severe asthma. - It is acceptable to start and then continue biologic therapy with anti-IgE or anti-IL-5 antibodies in patients with severe bronchial asthma in accordance with the current Biological Treatment Programme of the National Health Fund. - Continuation and, in specific cases, initiation of biologic therapy with anti-IgE antibodies (omalizumab) in patients with severe chronic urticaria are acceptable. (AE) in severe eosinophilic asthma. [bib_ref] Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and..., Agache [/bib_ref] For anti-IgE (omalizumab) and anti-IL-4Rα (dupilumab) treatments, rate ratios were rather small. [bib_ref] Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and..., Agache [/bib_ref] Benralizumab and omalizumab showed an increase in AEs with lowto-moderate certainty in severe allergic asthma. [bib_ref] Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for..., Agache [/bib_ref] There was an increased rate of dupilumab-related AEs (low certainty) in severe asthma. [bib_ref] Efficacy and safety of treatment with dupilumab for severe asthma: A systematic..., Agache [/bib_ref] Data from clinical trials demonstrated good safety profiles of biologicals with regard to viral infections of the upper respiratory tract . 36-38 ## \| pr ac ti c al and clini c al recommendations ## \| recommendations from national societies Time restrictions did not allow for official guidelines to be published so far. However, several societies issued statements on the use of biologicals during the COVID-19 pandemic ( ## \| eaaci statement on the management of allergic disease with type 2 targeting biologicals during covid-19 pandemic The key recommendation for an accurate management of nonin- cations as recommended by current guidelines) should be continued, as described for asthma, AD, CRSwNP, and CSU. [bib_ref] The EAACI/GA(2)LEN/EDF/ WAO guideline for the definition, classification, diagnosis and management of..., Zuberbier [/bib_ref] [bib_ref] EUFOREA consensus on biologics for CRSwNP with or without asthma, Fokkens [/bib_ref] [bib_ref] EAACI Guidelines on Allergen Immunotherapy: House dust mite-driven allergic asthma, Agache [/bib_ref] [bib_ref] EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy, Pajno [/bib_ref] [bib_ref] EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy, Sturm [/bib_ref] [bib_ref] Medical algorithms: Management of chronic rhinosinusitis, Fokkens [/bib_ref] Surgical interventions for CRSwNP should be delayed in any case possible. . Once resolution/recovery of the disease is established (eg, via a negative SARS-CoV-2 test) but no shorter than 2 weeks postonset of the disease/positive testing, the re-administration of the biological should be re-initiated . ## \| con clus ions In conclusion, current evidence does not suggest a higher risk for severe COVID-19 in allergic individuals but data that allow esti- of such data is imperative for future data-informed adaptations of these guidelines. ## Co n fli c t o f i nte r e s t [fig] Hospitalization: Surveillance Network based on data from 14 US states from March 1, 2020, to March 30, 2020, 17% of hospitalized COVID-19 patients had asthma as a comorbidity. The highest percentage was in the 18-to 49-year-old patient group with 27.3% asthmatics. No information on severity of the disease and therapy has been provided. This supports the importance of a prospective assessment of atopic diseases in the context of COVID-19. [/fig]	None	https://europepmc.org/articles/pmc7300800?pdf=render	The outbreak of the SARS‐CoV‐2‐induced coronavirus disease 2019 (COVID‐19) pandemic re‐shaped doctor‐patient interaction and challenged capacities of healthcare systems. It created many issues around the optimal and safest way to treat complex patients with severe allergic disease. A significant number of the patients are on treatment with biologicals, and clinicians face the challenge to provide optimal care during the pandemic. Uncertainty of the potential risks for these patients is related to the fact that the exact sequence of immunological events during SARS‐CoV‐2 is not known. Severe COVID‐19 patients may experience a “cytokine storm” and associated organ damage characterized by an exaggerated release of pro‐inflammatory type 1 and type 3 cytokines. These inflammatory responses are potentially counteracted by anti‐inflammatory cytokines and type 2 responses. This expert‐based EAACI statement aims to provide guidance on the application of biologicals targeting type 2 inflammation in patients with allergic disease. Currently, there is very little evidence for an enhanced risk of patients with allergic diseases to develop severe COVID‐19. Studies focusing on severe allergic phenotypes are lacking. At present, noninfected patients on biologicals for the treatment of asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, or chronic spontaneous urticaria should continue their biologicals targeting type 2 inflammation via self‐application. In case of an active SARS‐CoV‐2 infection, biological treatment needs to be stopped until clinical recovery and SARS‐CoV‐2 negativity is established and treatment with biologicals should be re‐initiated. Maintenance of add‐on therapy and a constant assessment of disease control, apart from acute management, are demanded.
97f3ef6a12bd070c39b1ee6b07d507ad5723827a	pubmed	SASLT Practice Guidelines: Management of Hepatitis C Virus Infection	SASLT Practice Guidelines: Management of Hepatitis C Virus Infection This guideline has been approved by the Saudi Association for the Study of Liver diseases and Transplantation and represents the position of the Association.These practice guidelines have been written to assist physicians and other health care providers to aid in the recognition, diagnosis, and management of chronically infected hepatitis C virus (HCV) patients. They are based on a formal review and analysis of published literature on the topic that impact the management of chronic HCV infection, and the experience of the authors in hepatitis C. In addition, various international practice guidelines and consensus documents on management of chronic hepatitis C were considered in the development of these guidelines. The recommendations contained herein suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care related to the disease.Our understanding of the natural history of HCV infection and the potential for therapy of the resultant disease is continuously improving. However, despite the increasing knowledge, areas of uncertainty still exist and therefore clinicians, patients, and public health authorities must continue to make choices on the basis of the evolving evidence. Therefore, these guidelines are intended to be flexible and may be updated periodically as new information becomes available.MATERIALS AND METHODSThe Saudi Association for the Study of Liver diseases and Transplantation (SASLT) formed a task force to evaluate the current epidemiology, trends in, and management of the hepatitis C virus (HCV) infection in Saudi Arabia. A majority of the members of the committee were hepatologists.The first step was a broad literature search of published literature on every aspect of the epidemiology, natural history, risk factors, diagnosis and management of HCV. All available literature on the topic was examined critically, and the available evidence was then classified according to its importance.The contents of the resulting document, including the recommendations contained in it, have been discussed in detail and agreed upon by members of the SASLT task force. The document was also reviewed by a content expert from another country and valuable additional input was incorporated. Subsequently, and after review by the board of directors, the guidelines were approved and endorsed by SASLT. These practice guidelines have been written to assist physicians and other health care providers to aid in the recognition, diagnosis, and management of chronically infected hepatitis C virus (HCV) patients. They are based on a formal review and analysis of published literature on the topic that impact the management of chronic HCV infection, and the experience of the authors in hepatitis C. In addition, various international practice guidelines and consensus documents on management of chronic hepatitis C were considered in the development of these guidelines. The recommendations contained herein suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care related to the disease. Our understanding of the natural history of HCV infection and the potential for therapy of the resultant disease is continuously improving. However, despite the increasing knowledge, areas of uncertainty still exist and therefore clinicians, patients, and public health authorities must continue to make choices on the basis of the evolving evidence. Therefore, these guidelines are intended to be flexible and may be updated periodically as new information becomes available. # Materials and methods The Saudi Association for the Study of Liver diseases and Transplantation (SASLT) formed a task force to evaluate the current epidemiology, trends in, and management of the hepatitis C virus (HCV) infection in Saudi Arabia. A majority of the members of the committee were hepatologists. The first step was a broad literature search of published literature on every aspect of the epidemiology, natural history, risk factors, diagnosis and management of HCV. All available literature on the topic was examined critically, and the available evidence was then classified according to its importance. The contents of the resulting document, including the recommendations contained in it, have been discussed in detail and agreed upon by members of the SASLT task force. The document was also reviewed by a content expert from another country and valuable additional input was incorporated. Subsequently, and after review by the board of directors, the guidelines were approved and endorsed by SASLT. ## Saslt practice guidelines: management of hepatitis c virus infection ## Goals of these guidelines These are as follows: 1. To provide a concise, evidence-based review of the diagnosis and management of chronic HCV infection in Saudi Arabia. 2. To help initiate plans to prevent HCV infection in the population. 3. To achieve early and accurate diagnosis of patients with HCV infection. 4. To provide an evidence-based approach for the management of HCV-infected patients. 5. To facilitate appropriate and timely referrals between primary, secondary, and tertiary care providers. 6. To identify gaps in the knowledge and understanding of the incidence of HCV in Saudi Arabia that require further research. ## Epidemiology prevalence and incidence HCV infection is a leading cause of cirrhosis, liver failure and liver cancer worldwide, making it a major public health issue. The World Health Organization (WHO) estimates a worldwide prevalence of 3%. Each year, three to four million people are newly diagnosed with HCV, and it remains endemic in many countries of the world. [bib_ref] Hepatitis C virus infection: The new global epidemic, Butt [/bib_ref] [bib_ref] New therapies for hepatitis C virus infection, Soriano [/bib_ref] [bib_ref] Viral hepatitis in HIV infection, Koziel [/bib_ref] According to the WHO, there are at least 21.3 million HCV carriers in Eastern Mediterranean countries, a figure close to the combined number of estimated carriers in the Americas and Europe. A large, cross-community, population-based survey from different regions of Saudi Arabia was performed among children aged 1-10 to estimate the prevalence of HCV in Saudi children. Out of 4,496 children, [bib_ref] Risk of hepatitis C virus infection among household contacts of Saudi patients..., Arif [/bib_ref] (0.90%) tested positive for HCV antibodies. However, the survey was performed using a first generation Enzyme-linked Immunosorbent Assay (ELISA) kit that is known to produce false-positives. [bib_ref] Prevalence of antibody to hepatitis C virus among Saudi Arabian children: A..., Al-Faleh [/bib_ref] As a part of a hepatitis B virus (HBV) vaccination follow-up study, children were also tested for HCV serology using a more reliable third generation ELISA test coupled with a Recombinant Immunoblot Assay (RIBA) for confirmation. [bib_ref] Long-term protection of hepatitis B vaccine 18 years after vaccination, Alfaleh [/bib_ref] This study showed the prevalence of HCV antibodies to be higher in adolescents than in younger children: from 0.04% in 1997 (children aged 1-12 years), to 0.22% for adolescents aged [bib_ref] Changing pattern of hepatitis viral infection in Saudi Arabia in the last..., Fz [/bib_ref] [bib_ref] Hepatitis C in dialysis units: The Saudi experience, Karkar [/bib_ref] [bib_ref] High prevalence of and risk factors for hepatitis C in haemodialysis patients..., Huraib [/bib_ref] [bib_ref] A proposed system for nomenclature of hepatitis C viral genotypes, Simmonds [/bib_ref] [bib_ref] The natural history of chronic hepatitis C infection, Strader [/bib_ref] [bib_ref] National institutes of health consensus development conference: Management of hepatitis C: 2002, Seeff [/bib_ref] [bib_ref] Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and..., Seeff [/bib_ref] [bib_ref] High rate of spontaneous negativity for hepatitis C virus RNA after establishment..., Scott [/bib_ref] [bib_ref] Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in..., Fattovich [/bib_ref] [bib_ref] Chronic hepatitis C virus disease: An evaluation of procedures for diagnosis and..., Stadhouders [/bib_ref] [bib_ref] Serum HCV RNA levels correlate with histological liver damage and concur with..., Adinolfi [/bib_ref] [bib_ref] Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected..., Benhamou [/bib_ref] year olds, and 11.9% in ≥ 55 year olds in a cohort of outpatient's attendees and hospital-admitted patients. [bib_ref] Hepatitis C: Prevalence and common genotypes among ethnic groups in Jeddah, Saudi..., Fakeeh [/bib_ref] However, these seemingly high rates are not generalizable as the patient population was not representative of the country in general. The Saudi Ministry of Health (MOH) report found a much higher proportion of HCV infection in adults when compared to patients younger than 15 years old (998/8,186,369), despite similar mean population sizes. Memish et al, reported an almost 45fold higher annual incidence of seropositivity in those ≥ 15 years vs. children < 15 years of age. [bib_ref] Incidence trends of viral hepatitis A, B, and C seropositivity over eight..., Memish [/bib_ref] The prevalence in the general population is generally considered uncertain, since most studies were conducted more than 10 years ago. [bib_ref] Hepatitis C: Prevalence and common genotypes among ethnic groups in Jeddah, Saudi..., Fakeeh [/bib_ref] [bib_ref] Profile of hepatitis C virus and the possible modes of transmission of..., Al-Faleh [/bib_ref] [bib_ref] Intrafamilial transmission of hepatitis C virus (HCV): A major mode of spread..., Nasser [/bib_ref] [bib_ref] Hepatitis C virus antibodies in high-risk Saudi groups, Bahakim [/bib_ref] HCV has been reported to be on the decline over the past decade, although it remains a major public health concern in the country. While HCV infection has been a reportable disease in Saudi Arabia since 1990, the level of reporting compliance is unknown, hence epidemiologic estimates may be inaccurate. However, blood donors are screened, and pre-marital testing for HCV infection has been mandatory since January 2008. It is estimated that well over one million individuals have already been screened. Nested data, not confirmed by PCRbased testing, reported from the General Directorate for Communicable Diseases, Riyadh region, revealed a HCV sero-prevalence of 0.33%. [bib_ref] Is there a need to include HIV, HBV and HCV viruses in..., Alswaidi [/bib_ref] A large community-based study reporting the actual prevalence of HCV in Saudi Arabia ## Genotypes In Saudi Arabia, genotype 4 HCV is most prevalent, followed by genotype 1. In the largest genotype study on 1013 Saudi nationals, HCV G1 accounts for 25.9%, G2 for 4.3%, G3 for 2.9%, G4 for 60%, G5/G6 for 0.3% and 6.3% were of mixed genotype. In addition, 81.1% of all HCV patients are older than 41 years of age, and males account for 55.3% in G1, and 44.9% in G4 cases. [bib_ref] A systematic review of hepatitis C virus epidemiology in Asia, Australia and..., Sievert [/bib_ref] (I. Altraif et al., unpublished data). Genotypes 2a/2b has been documented in the eastern region and genotype 5 in the western region of the country, with genotypes 3 and 6 being extremely rare. [bib_ref] Hepatitis C: Prevalence and common genotypes among ethnic groups in Jeddah, Saudi..., Fakeeh [/bib_ref] [bib_ref] Hepatitis C genotypes/subtypes among chronic hepatitis patients in Saudi Arabia, Shobokshi [/bib_ref] [bib_ref] Hepatitis C virus genotypes in patients with chronic liver disease and haemodialysis..., Al-Faleh [/bib_ref] [bib_ref] Prevalence and clinical expression of HCV-genotypes in haemodialysis-patients of two geographically remote..., Bosmans [/bib_ref] [bib_ref] Hepatitis C genotypes and subtypes in Saudi Arabia, Shobokshi [/bib_ref] [bib_ref] Chronic hepatitis C. Genotypes and response to anti-viral therapy among Saudi patients, Handoo [/bib_ref] The most common subtypes of genotype 4 HCV among Saudis are 4c/4d followed by subtypes 4h, 4e, and 4a. [bib_ref] Hepatitis C genotypes/subtypes among chronic hepatitis patients in Saudi Arabia, Shobokshi [/bib_ref] [bib_ref] Management of hepatitis C virus genotype 4, Abdo [/bib_ref] ## Risk factors The primary source of HCV transmission is parenteral exposure to HCV-infected blood or blood products. ## Hemodialysis Patients on hemodialysis are particularly at risk of contracting HCV. In Saudi Arabia, hemodialysis is the most commonly used form of renal replacement therapy, and the number of patients receiving hemodialysis treatment has been increasing dramatically. [bib_ref] Hepatitis C in dialysis units: The Saudi experience, Karkar [/bib_ref] [bib_ref] High prevalence of and risk factors for hepatitis C in haemodialysis patients..., Huraib [/bib_ref] At the same time, the incidence of new infection, and the prevalence of HCV has increased in this patient population over the past three decades, and it is now estimated to be 7-9% and 15-80%, respectively. [bib_ref] Hepatitis C in dialysis units: The Saudi experience, Karkar [/bib_ref] Additionally, there was a surge in endemicity in the mid-1990s, from 41% to 55%, appearing simultaneously with the sudden expansion of hemodialysis services, due to a significant increase in the number of patients with end-stage renal disease across the country. [bib_ref] Hepatitis C in dialysis units: The Saudi experience, Karkar [/bib_ref] In recent years, based on more available data, and countrywide figures from the Saudi Centre for Organ Transplant, the HCV prevalence rate has remained constant at 50%, even though the demand for dialysis services continues to rise, perhaps as a reflection of better adherence to infection prevention and control policies and practices. [bib_ref] Hepatitis C in dialysis units: The Saudi experience, Karkar [/bib_ref] In fact, a recent singlecentre study that adopted strict infection control guidelines reported a zero incidence of infection for the entire duration of 5 years that 36 sero-negative hemodialysis patients were followed. [bib_ref] Prevention of hepatitis C virus in hemodialysis patients: Five years experience from..., Mohamed [/bib_ref] Another investigational study followed the epidemiology of HCV in a dialysis unit after methods to reduce prevalence of the virus were set in place. [bib_ref] Methods used to reduce the prevalence of hepatitis C in a dialysis..., Hussein [/bib_ref] These practices included strict adherence to universal infection control precautions, separation of HCV-positive patients from the negative ones, and using specially designated machines for the HCV-negative hemodialysis patients. Periodic testing revealed no sero-conversions and a reduced prevalence of HCV RNA-positive patients to 6.5% within the unit. A study by Abu-Aisha et al. recommended the delegation of specific hemodialysis machines for anti-HCV-positive cases. [bib_ref] The effect of chemical and heat disinfection of the hemodialysis machines on..., Abu-Aisha [/bib_ref] Soyannwo et al. also determined that machine isolation policies, rather than blood transfusions, lead to wide-spread variations in the prevalence of HCV among different dialysis centres in Saudi Arabia. [bib_ref] Hepatitis C antibodies in haemodialysis and pattern of end-stage renal failure in..., Soyannwo [/bib_ref] Several studies have also referred to patient isolation as an important factor in preventing transmission of viral hepatitis in hemodialysis units. [bib_ref] Impact of dedicated space, dialysis equipment, and nursing staff on the transmission..., Saxena [/bib_ref] [bib_ref] Hepatitis C virus infection among patients on hemodialysis in jeddah: A single..., Fadag [/bib_ref] [bib_ref] Prevention of viral transmission in HD units: The value of isolation, Karkar [/bib_ref] For instance, a specially designed centre with complete isolation of HCVnegative and HCV-positive patients resulted in the annual incidence of HCV infection dropping significantly from 2.4% to 0.2%. [bib_ref] Prevention of viral transmission in HD units: The value of isolation, Karkar [/bib_ref] Intravenous drug users Acquisition of Hepatitis C by intravenous drug users constitutes only a small percentage of the total HCV infection cases in Saudi Arabia, despite the continued rise in number of IV drug users. [bib_ref] Hepatitis C virus infections reported in Saudi Arabia over 11 years of..., Madani [/bib_ref] [bib_ref] Trend in incidence of hepatitis B virus infection during a decade of..., Madani [/bib_ref] Recent examination of the prevalence of viral infection among 344 Saudi injecting drug users reported a 38% HCV RNA detection rate with a predominant genotype of 1b. [bib_ref] Trend in incidence of hepatitis B virus infection during a decade of..., Madani [/bib_ref] An earlier study showed that the HCV infection among IV drug users in a Jeddah detoxification center was 69%. [bib_ref] Substance dependence. A hospital based survey, Iqbal [/bib_ref] Other risk factors Additional potential risk factors for HCV transmission include exposure to an infected sexual partner, or multiple sexual partners, and perinatal exposure.Few studies have been done on these topics, and the available data are conflicting. One study concluded that intrafamilial transmission was a major route of transmission among the Saudi population, [bib_ref] Hepatitis C Virus prevalence among patients infected with human immunodeficiency virus: A..., Sherman [/bib_ref] while two others showed that neither intrafamilial [bib_ref] Risk of hepatitis C virus infection among household contacts of Saudi patients..., Arif [/bib_ref] nor perinatal [bib_ref] Hepatitis C virus infections reported in Saudi Arabia over 11 years of..., Madani [/bib_ref] transmission are risk factors for HCV infection in Saudi Arabia. Further studies need to be undertaken to explore modes of transmission of HCV in the local population. Other forms of transmission such as bloodletting and traditional tattooing have been suggested. [bib_ref] Hepatitis C acquisition in Saudi Arabia: Are the majority of cases without..., Altraif [/bib_ref] In addition, a study by Al Faleh et al., has documented a history of prior blood transfusion in 14.8% of infected patients. [bib_ref] Hepatitis C genotypes/subtypes among chronic hepatitis patients in Saudi Arabia, Shobokshi [/bib_ref] The low prevalence of HIV in the Saudi population relegates it as a risk factor of marginal importance in the local setting. [bib_ref] High prevalence of and risk factors for hepatitis C in haemodialysis patients..., Huraib [/bib_ref] [bib_ref] Schistosomiasis as a possible risk factor for acquiring hepatitis C virus (HCV)..., Arif [/bib_ref] [bib_ref] Age-specific prevelance of antibody to hepatitis C virus (HCV) among the Saudi..., Bakir [/bib_ref] Other high risk group patients such as patients with thalassemia major and hemophilia have a prevalence rate of 70% and 78.6%, respectively. [bib_ref] Hepatitis C virus antibodies in high-risk Saudi groups, Bahakim [/bib_ref] [bib_ref] Schistosomiasis as a possible risk factor for acquiring hepatitis C virus (HCV)..., Arif [/bib_ref] A prevalence of 15.9% has been reported in patients with sexually-transmitted diseases [bib_ref] Age-specific prevelance of antibody to hepatitis C virus (HCV) among the Saudi..., Bakir [/bib_ref] and high risk behavior. counseled regarding prevention of the spread of the virus to others. They should be informed that transmission occurs through contact with their blood, and they should therefore be informed about how to take precautions against the possibility of such exposure (Grade B). ## Recommendations ## Natural history The HCV is one of the most important Flaviviridae infections in humans, and is the second most common cause of viral hepatitis. [bib_ref] Pegasys / RBV improves fibrosis in responders, relapsers and nonresponders with advanced..., Leiveven [/bib_ref] HCV has six major genotypes, which are indicated numerically (1 to 6) according to the international Simmonds classification. [bib_ref] A proposed system for nomenclature of hepatitis C viral genotypes, Simmonds [/bib_ref] HCV infection can present as an acute hepatitis, chronic hepatitis, extra-hepatic manifestation, or as cirrhosis and its complications. Acute hepatitis is usually asymptomatic, not commonly encountered in general clinical practice and rarely leads to hepatic failure. Natural history studies suggest that 55-85% of persons with acute hepatitis C will go on to develop chronic HCV infection, while the remaining 15-45% of patients with acute hepatitis C will spontaneously clear the virus without developing any long-term complications and require no further treatment. Those having persistent infection for more than six months are defined as chronic hepatitis C.Of these, 5-20% have been reported to develop cirrhosis over a period of 20 to 25 years. [bib_ref] The natural history of chronic hepatitis C infection, Strader [/bib_ref] [bib_ref] National institutes of health consensus development conference: Management of hepatitis C: 2002, Seeff [/bib_ref] [bib_ref] Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and..., Seeff [/bib_ref] The high figure of 20% of chronic HCV patients developing cirrhosis may not reflect the true rate in the general population of HCV-infected persons, since these studies were done in tertiary-care hospitals and may have had referral bias. A very small portion of chronic HCV patients (0.5% to 0.74% per year) spontaneously clear their virus. [bib_ref] High rate of spontaneous negativity for hepatitis C virus RNA after establishment..., Scott [/bib_ref] Patients with HCVinduced cirrhosis have a risk of about 30% over 10 years for developing end-stage liver disease, and about 1-4% risk per year for developing hepatocellular carcinoma (HCC). [bib_ref] Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in..., Fattovich [/bib_ref] [bib_ref] Chronic hepatitis C virus disease: An evaluation of procedures for diagnosis and..., Stadhouders [/bib_ref] The 10-year risk of cirrhosis is less than 10% in patients with mild chronic hepatitis, 44% in those with moderate hepatitis, and 100% in those with severe hepatitis with bridging fibrosis. [bib_ref] Serum HCV RNA levels correlate with histological liver damage and concur with..., Adinolfi [/bib_ref] Evolution of chronic HCV infection to cirrhosis is a primary concern. Factors that accelerate the rate of progression include excessive alcohol intake, existing HIV and/or HBV, a longer duration of HCV infection, males, and those patients acquiring the infection when under the age of 40, or who acquire it through blood transfusion rather than through drug use by injection. [bib_ref] Serum HCV RNA levels correlate with histological liver damage and concur with..., Adinolfi [/bib_ref] [bib_ref] Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected..., Benhamou [/bib_ref] [bib_ref] Natural history of liver fibrosis progression in patients with chronic hepatitis C...., Poynard [/bib_ref] [bib_ref] The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in..., Harris [/bib_ref] [bib_ref] Long-term clinical and histopathological follow-up of chronic post transfusion hepatitis, Bisceglie [/bib_ref] [bib_ref] Updated thresholds for alanine aminotransferase do not exclude significant histological disease in..., Sanai [/bib_ref] An important predictor of the future progression of liver disease and the need for HCV treatment is more-than-portal fibrosis on liver biopsy (Metavir ≥2 or Ishak ≥3). [bib_ref] Natural history of liver fibrosis progression in patients with chronic hepatitis C...., Poynard [/bib_ref] [bib_ref] The long-term pathological evolution of chronic hepatitis C, Yano [/bib_ref] [bib_ref] Hepatitis activity index is a key factor in determining the natural history..., Fontaine [/bib_ref] Due to the long course of hepatitis C, the exact risk of cirrhosis is very difficult to determine, and figures differ from study to study and between populations. Data from Egypt has suggested a possible relationship between HCV genotype 4 and HCC, where the vast majority of patients have genotype 4. [bib_ref] ) of the Middle East Cancer Consortium (MECC) Compared with US SEER, Freedman [/bib_ref] [bib_ref] Use of NS-4 peptides to identify type-specific antibody to hepatitis C virus..., Bhattacherjee [/bib_ref] [bib_ref] Chronic liver disease in the Alexandria governorate, Egypt: Contribution of schistosomiasis and..., Angelico [/bib_ref] [bib_ref] Clinical, virological and histopathological features: Long-term follow-up in patients with chronic hepatitis..., Kamal [/bib_ref] [bib_ref] Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in..., Lehman [/bib_ref] Such data is not available in Saudi Arabia and its relevance in the local setting needs to be further explored. The Saudi Observatory Liver Disease (SOLID) registry has recently been established through a national funding initiative termed as the National Plan for Science and Technology, under the auspices of King Abdulaziz City for Science and Technology in Riyadh. The SOLID registry functions on a nationwide basis, with a constantly expanding list of participating centers. The registry aims to prospectively accrue demographic, clinical and treatment-related data in patients with HCV and other liver diseases. It is at present the only longitudinal, hospital-based, research database in the region. Deaths related to chronic HCV are usually caused by complications of decompensated cirrhosis and HCC. The onset of decompensation is associated with a rapid decline in survival rates. The 5-year survival rate for patients with compensated cirrhosis is as high as 90%, compared to 50% for those with decompensated cirrhosis. [bib_ref] Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study..., Fattovich [/bib_ref] [bib_ref] The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and..., Hu [/bib_ref] [bib_ref] Natural history of decompensated hepatitis C virus-related cirrhosis. A study of 200..., Planas [/bib_ref] ## Clinical features of hcv infection Infection with HCV can result in both acute and chronic hepatitis, each with a different spectrum of clinical manifestations. ## Acute hcv Acute HCV infection is usually asymptomatic. However, approximately 25% of patients with acute HCV present with jaundice, and less than 33% develop non-specific symptoms such as nausea, vomiting, abdominal pain, and fatigue orarthralgia. Less common symptoms include fever and rash. In patients who experience the symptoms of acute hepatitis, the illness typically lasts for 2-12 weeks. The incubation period from infection to onset of symptoms can range from 2 to 12 weeks. [bib_ref] Current patterns of hepatitis C virus transmission in United States: The role..., Williams [/bib_ref] [bib_ref] Acute hepatitis C, Orland [/bib_ref] HCV RNA typically becomes detectable in serum 7 to 21 days after exposure, and can be detected at high levels at the onset of jaundice. [bib_ref] Acute hepatitis C, Orland [/bib_ref] Aminotransferase levels become elevated approximately 6-12 weeks after exposure, and can be more than 15 times the upper limit of normal. [bib_ref] Hepatitis C: Molecular biology, pathogenesis, epidemiology, clinical features, and prevention, Esteban [/bib_ref] Anti-HCV becomes detectable approximately 7-10 weeks after the onset of infection. Fulminant hepatic failure due to acute HCV infection is very rare. It may be more common in patients with underlying chronic hepatitis B virus infection. [bib_ref] Fulminant hepatic failure in acute hepatitis C: Increased risk in chronic carriers..., Chu [/bib_ref] Chronic HCV In chronic hepatitis C, the disease may continue to appear to resolve both biochemically and histologically, followed by intermittent or constant elevation of serum transaminases. Most patients with chronic infection are asymptomatic or have only mild nonspecific symptoms, and do not have physical signs of liver disease, as long as cirrhosis itself is not present. [bib_ref] Persistence of viremia and the importance of long-term follow-up after acute hepatitis..., Villano [/bib_ref] Extrahepatic manifestation of HCV Patients with these syndromes can be divided into those with a higher degree of association, and those with a more moderate or mild association with HCV. The most prevalent extra-hepatic diseases with the highest degree of association with HCV are the essential mixed cryoglobulins with a clinical triad of weakness, arthralgia and palpable purpura. Renal disease can also be associated with chronic HCV, particularly membranoproliferative glomerulonephritis. [bib_ref] Extrahepatic manifestations of hepatitis C virus, Sterling [/bib_ref] [bib_ref] Hepatitis C associated glomerulonephritis, Altraif [/bib_ref] The other diseases include noncryoglobulinemic systemic vasculitis, splenic lymphoma with villous lymphocytes, fatigue, porphyria cutanea tarda, sicca syndrome, and autoantibodies production. The extra-hepatic manifestations that share mild-degree certainty of association with HCV infection include B-cell non-Hodgkin lymphoma, autoimmune thrombocytopenia, pruritus, and type II diabetes mellitus. The other diseases such as autoimmune thyroiditis, lichen planus are less likely to be associated with HCV. [bib_ref] Hepatitis C virus-associated extrahepatic manifestations: A review, Sène [/bib_ref] [bib_ref] Extrahepatic manifestations of hepatitis C, Gordon [/bib_ref] Most extra-hepatic manifestations of chronic HCV infection are immunological, and a chronic level of infection seems to be necessary for their development. Molecular study of the unique way in which the HCV virus interacts with the human immune system is slowly beginning to provide plausible explanations of the pathogenic role of HCV in some of these syndromes, but many patho-genetic links remain completely obscure. [bib_ref] Extrahepatic manifestations of hepatitis C infection, Mayo [/bib_ref] ## Cirrhosis and hepatocellular carcinoma Patients with normal serum transaminases activity have a lower fibrosis progression rate (15%) than those patients with elevated enzymes. [bib_ref] Slow progression rate of fibrosis in hepatitis C virus patients with persistently..., Mathurin [/bib_ref] Cirrhosis can be missed clinically, as most cirrhotic patients are asymptomatic as long as hepatic decompensation and HCC does not occur. The HCV-related compensated cirrhosis is usually discovered during screening of blood donors, premarital screening or at the time of routine laboratory testing. [bib_ref] The long-term pathological evolution of chronic hepatitis C, Yano [/bib_ref] [bib_ref] Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study..., Fattovich [/bib_ref] A wide spectrum of nonspecific symptoms can be noted in patients with compensated and decompensated cirrhosis, including fatigue in 75%, abdominal pain in 24%, and anorexia in 13%. [bib_ref] Clinical outcomes after transfusion-associated hepatitis C, Tong [/bib_ref] Less than 50% of cirrhotic patients have clinical and laboratory results that support the presence of cirrhosis like hepatomegaly and/or splenomegaly, spider angiomata, palmar erythema, testicular atrophy, or gynaecomastia, caput medusa, elevated serum bilirubin concentration, hypoalbuminemia, or low platelet counts. Among patients with compensated cirrhosis, the annual risk of decompensation is 3.9%. The clinical presentation can be dramatic after hepatic decompensation, and manifests itself with ascites in 48%, variceal bleeding in 22-32%, hepatic encephalopathy in 5-8%, jaundice in 6%, or a combination of these complications in 17% of patients. Patients with hepatic decompensation may also develop lower extremity edema, pruritus, sexual dysfunction, easy bruising, muscle wasting and muscle cramps. Patient with HCV-related cirrhosis are at risk of HCC, and the estimated risk, described in various reports, has varied from 0-3% per year. The suspicion of HCC development should be high in those patients who present with rapid clinical decompensation with ascites, hepatic encephalopathy and bleeding from portal hypertension. Ultrasound of the abdomen at 6 months intervals is the recommended test that can be used for early detection of HCC in patients with HCV cirrhosis. [bib_ref] Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study..., Fattovich [/bib_ref] ## Recommendations ## Laboratory testing alanine aminotransferase and aspartate aminotransferase Liver chemistries are an insensitive means of assessing fibrosis. Elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may indicate the presence of liver disease, but does not determine the type, the cause of the liver disease, or correspond to the degree of damage on liver biopsy.Additionally, viral genotype and/or viral load do not correlate with the amount of liver injury. [bib_ref] Chronic hepatitis C in patients with persistently normal alanine transaminase levels, Shiffman [/bib_ref] In 341 anti-HCV positive patients in the study by Silini et al., 49% had persistently normal or nearly normal ALT levels and of those 70% had circulating HCV RNA; while on histology a large number of them had mild chronic hepatitis. [bib_ref] Differential distribution of hepatitis C virus genotypes in patients with and without..., Silini [/bib_ref] Therefore, if there is a suspicion of HCV infection in patients with a persistently normal ALT level, they should be tested for HCV-RNA. The use of routine liver tests to screen for chronic hepatitis C virus infection is of limited value in cases of anti-HCV and PCR positives. [bib_ref] Hepatitis C viraemia and liver disease in symptom-free individuals with anti-HCV, Alberti [/bib_ref] Other studies have shown that transaminase levels can be helpful in predicting the severity of liver disease, with higher levels associated with more advanced histology, but they are usually of limited value in an individual patient. [bib_ref] Updated thresholds for alanine aminotransferase do not exclude significant histological disease in..., Sanai [/bib_ref] [bib_ref] Relationship of aminotransferases to liver histologicalstatus in chronic hepatitis C, Haber [/bib_ref] With levels fluctuating from normal to abnormal over time, the value of monitoring transaminases is limited. Additionally, the results of routine liver tests correlate poorly with both necro-inflammatory and fibrosis scores found on liver biopsy. ## Serologic assays Detection of the anti-HCV antibody is used for screening for HCV infection. The two enzyme immunoassays (EIAs) commonly used are Abbott HCV EIA 2.0 (Abbott Laboratories, Abbott Park, IL) and ORTHO  HCV Version 3.0 ELISA (Ortho-Clinical Diagnostics, Raritan, NJ). The enhanced chemi-luminescence immunoassay (CIA) VITROS  Anti-HCV assay, (Ortho-Clinical Diagnostics, Raritan, NJ) is also used for the same purpose. The specificity of third generation EIAs for detection of anti-HCV is greater than 99%; [bib_ref] Sensitivity and specificity of third-generation hepatitis C virus antibodydetection assays: An analysis..., Colin [/bib_ref] at the same time, they are reproducible and inexpensive.The recombinant immunoblot assay, Chiron RIBA HCV 3.0 SIA (Chiron Corporation, Emeryville, CA) is more specific, and is a supplemental assay to confirm the results of EIA testing. [bib_ref] Low-positive anti-hepatitis C virus enzyme immunoassay results: An important predictor of low..., Dufour [/bib_ref] [bib_ref] Guidelines for laboratory testing and result reporting of antibody to hepatitis C..., Alter [/bib_ref] The specificity is extremely high for third generation EIA, that exceeds particular signal/ cutoff ratios (e.g., >3.8 for the above mentioned Ortho and Abbott EIA tests). [bib_ref] What strategy should be used for diagnosis of hepatitis C virus infection..., Pawlotsky [/bib_ref] [bib_ref] NAT of the United States and Canadian blood supply, Stramer [/bib_ref] Its high sensitivity and specificity may obviate the need for a confirmatory immunoblot assay in the patient with HCV infection. However, a positive RIBA is not diagnostic of active HCV infection, since up to 45% of patients will clear HCV spontaneously after acute infection, while remaining anti-HCV positive.The hepatitis C virus antibodies revealed by ELISA are detectable within three to 15 weeks of infection. The thirdgeneration anti-HCV enzyme immunoassay (EIA) can detect HCV antibodies as early as 6-8 weeks after exposure. [bib_ref] Distribution of hepatitis C virus genotypes in the Middle East, Ramia [/bib_ref] Anti-HCV antibodies can be detected in 80% of HCV patients within 15 weeks after exposure, in > 90% within 5 months after exposure, and in > 97% up to 6 months after exposure. Overall, HCV antibody tests have a strong positive predictive value for exposure to the hepatitis C virus. One of the newest assays, the Murex HCV Ag/Ab combination assay combines the detection of anti-HCV antibodies with the detection of core antigen in a single assay, which significantly reduces the window period from infection to detection when compared with conventional serological HCV antibody screening assays.Second-and third-generation tests, which have included more antigens from the better-conserved regions of the viral genome, have high sensitivity and specificity for detection for all genotypes. Use of this technique runs the risk of false-negative results of less than 5%. [bib_ref] Sensitivity and specificity of three third-generation antihepatitis C virus ELISAs, Vrielink [/bib_ref] If a reaction with two or more of the antigens is seen, the RIBA test is considered positive. [bib_ref] Serologic diagnosis of viral hepatitis, Sjogren [/bib_ref] Reaction with only one antigen gives an indefinite test result; only about 10% of these patients are HCV-RNA-positive. [bib_ref] Recombinant immunoblot assay first and second generations on 732 blood donors reactive..., Courouce [/bib_ref] The recombinant viral antigens from HCV are used in all commercial assays, and consequently false-negative results are less likely, due to amino-acid heterogeneity. False positive results are more likely to occur when testing is performed among populations where the prevalence of hepatitis C is low. False negative results are more likely in patients who have not yet developed antibodies (seroconversion), have an insufficient level of antibodies to be detected, immunocompromised individuals who may never develop antibodies to the virus, in the presence of hypo-or aggammaglobulinemia, and in patients on hemodialysis. [bib_ref] Screening for hepatitis C virus in human immunodeficiency virusinfected individuals, Thio [/bib_ref] [bib_ref] Diagnostic discordance for hepatitis C virus infection in hemodialysis patients, Kalantar-Zadeh [/bib_ref] [bib_ref] Loss of antibodies against hepatitis C virus in HIV-seropositive intravenous drug users, Chamot [/bib_ref] ## Molecular assays The presence of the virus is tested by using molecular nucleic acid testing methods, such as polymerase chain reaction (PCR), transcription mediated amplification (TMA), or branched DNA (b-DNA). All HCV nucleic acid molecular tests have the capacity to detect the presence of the virus and to measure the amount of the virus present in the blood (the HCV viral load). Historically, qualitative assays have been shown to be more sensitive than quantitative assays. Most recently, available real-time polymerase chain reaction (PCR) has shown the ability to detect even a small amount of HCV RNA (<10 (IU)/ml) and to accurately quantify HCV RNA levels up to 10 7 IU/ml. Their dynamic quantification range adequately covers clinical needs for diagnosis and monitoring. [bib_ref] Differences between two real-time PCR-based hepatitis C virus (HCV) assays (RealTime HCV..., Vermehren [/bib_ref] [bib_ref] Performance of the Abbott Real-Time PCR assay using m2000(sp) and m2000(rt) for..., Chevaliez [/bib_ref] [bib_ref] Frequency of very low HCV viremia detected by a highly sensitive HCV-RNA..., Fytili [/bib_ref] With transcription mediated amplification (TMA) assays, the sensitivity is up to 10-50 IU/mL. [bib_ref] Molecular diagnosis of viral hepatitis, Pawlotsky [/bib_ref] A highly sensitive assay with a lower detection limit is considered appropriate for monitoring during therapy. All available assays have excellent specificity, namely in the range of 98% to 99%. The international standard for HCV RNA nucleic acid is well accepted for uniformity, [bib_ref] Pegasys / RBV improves fibrosis in responders, relapsers and nonresponders with advanced..., Leiveven [/bib_ref] and is now preferred over viral copies. [bib_ref] Establishment of the first international standard for nucleic acid amplification technology (NAT)..., Saldanha [/bib_ref] [bib_ref] Standardization of hepatitis C virus RNA quantification, Pawlotsky [/bib_ref] The hepatitis C virus is usually detectable in the blood by PCR within one to three weeks of infection. [bib_ref] Distribution of hepatitis C virus genotypes in the Middle East, Ramia [/bib_ref] However, more recently HCV antigen assays (HCV core antigen) has significantly reduced the window period (i.e., period prior to the detection of an antibody). [bib_ref] Efficacy of HCV core antigen detection during the preseroconversion period, Courouce [/bib_ref] [bib_ref] Detection of hepatitis C virus core antigen in blood donors using a..., Alzahrani [/bib_ref] [bib_ref] Analysis of HCV core antigenemia in Saudi Drug users, Alzahrani [/bib_ref] [bib_ref] Novel assay using total hepatitis C virus (HCV) core antigen quantification for..., Fabrizi [/bib_ref] [bib_ref] Benefit of hepatitis C virus core antigen assay in prediction of therapeutic..., Takahashi [/bib_ref] The assay based on the detection of the HCV core protein (Trak-C; Ortho Clinical Diagnostics) has proposed an alternative to PCR, but it suffers from lack of sensitivity. [bib_ref] Clinical assessment of Monolisa HCV Ag-Ab ULTRA (Bio-Rad) in a general hospital, Alados-Arboledas [/bib_ref] For monitoring purposes, it is important to use the same laboratory test before and during therapy. Traditionally, qualitative tests are more sensitive, but with a lower limit of detection 5 IU/mL [ [fig_ref] Table 1: Qualitative assays for detection of HCV RNA [/fig_ref] ]. [bib_ref] AASLD practice guidelines, diagnosis, management and treatment of hepatitis C: An update, Ghany [/bib_ref] Viral RNA testing is indicated when there is clinical suspicion of HCV, transaminase levels are high, and antibody testing is negative. [bib_ref] Chronic hepatitis C in patients with persistently normal alanine transaminase levels, Shiffman [/bib_ref] An approach based on the HCV core protein and specific anti-HCV antibody detection (Monolisa HCV Ag-Ab Ultra; Bio-Rad Laboratories, Marnesla-Coquette, France) has recently been developed for the diagnosis of hepatitis C. [bib_ref] Simultaneous detection of hepatitis C virus (HCV) core antigen and anti-HCV antibodies..., Laperche [/bib_ref] [bib_ref] Combination hepatitis C virus antigen and antibody immunoassay as a new tool..., Ansaldi [/bib_ref] Reverse transcription of the viral RNA, followed by amplification of complementary DNA (RT-PCR) has a role in diagnosis, monitoring and evaluation of therapy. Its disadvantages are the risk of contamination, and falsenegative results when samples are not handled correctly. Quantitative measurements have revealed that the level of viraemia correlates with the severity of disease and reacts inversely with the response to therapy. Quantification can be done by quantitative PCR assays or by branched DNA (bDNA) techniques. [bib_ref] Assessment of hepatitis C viremia using molecular amplification technologies: Correlations and clinical..., Gretch [/bib_ref] In PCR, sensitivity is higher, but bDNA has better reproducibility. [bib_ref] Assessment of hepatitis C viremia using molecular amplification technologies: Correlations and clinical..., Gretch [/bib_ref] The lower limit of detection for earlier versions of these PCR tests has been around 600 IU/mL. More recent versions are more sensitive, with a broader dynamic range from around 5-25 IU/mL to > 108 IU/mL, depending on the laboratory of origin. ## Genotype assay HCV genotype and subtype can be determined via various methods, including direct sequence analysis, reverse hybridization, and genotype-specific real-time PCR. [bib_ref] Diagnosis and management of chronic viralhepatitis: Antigens, antibodies and viral genomes, Chevaliez [/bib_ref] Genotyping is useful in epidemiological studies, selecting therapy, predicting likelihood of response to therapy and determining the optimal duration of treatment. Up to 80% of patients with HCV genotype 2 and 3 respond favorably to antiviral therapy. Several methods are available for genotyping: (a) serologically identifying the specific peptide by ELISA, [bib_ref] Mapping of serotype-specific, immunodominant epitopes in the NS-4 region of hepatitis C..., Simmonds [/bib_ref] (b) sequencing of PCR products, (c) use of type-specific primers and (d) restriction fragment length polymorphism. Several commercial assays are available to determine HCV genotypes, using direct sequence analysis of the 5´ non-coding region. These include the Trugene 5´NC HCV Genotyping kit (Siemens Healthcare Diagnostics Division, Tarrytown, NY). A reverse hybridization analysis using genotype specific oligonucleotide probes located in the 5´non-coding region, INNO-LiPa HCV II, (Innogenetics, Ghent, Belgium), and Versant HCV Genotyping Assay 2.0 (Siemens Healthcare Diagnostics Division, Tarrytown, NY). The analysis of conserved 5´NCR allows the determination of 3 major groups, types 1, 2, and 3, [bib_ref] At least 12 genotypes of hepatitis C virus predicted by sequence analysis..., Bukh [/bib_ref] [bib_ref] Identification of genotypes of hepatitis C virus by sequence comparisons in the..., Simmonds [/bib_ref] with type specific primers, [bib_ref] Typing hepatitis C virus by polymerase chain reaction with type-specific primers: Application..., Okamoto [/bib_ref] on the basis of restriction fragment length polymorphisms (RFLP's) [bib_ref] Detection of three types of hepatitis C virus in blood donors: Investigation..., Mcomish [/bib_ref] or with sequence specific DNA probes (genotyping). [bib_ref] Typing of hepatitis C virus isolates and characterization of new subtypes using..., Stuyver [/bib_ref] Phylogenetic analysis of the NS5 region has allowed the classification of HCV into 6 major genetic types and a number of subtypes. So far, there has been no overlap in sequence variability between the different classes with nucleotide homologies of 88-100% between isolates, 74-86% between subtypes, and 56-72% between types. Incorrect typing among the major genotypes is rare (< 3%) and mixed genotypes are known to occur, but are uncommon. Occasionally (< 5%), tested samples cannot be genotyped. This usually results from low viral levels, issues with the PCR amplification step of the assay, or extreme nucleotide variability within the HCV genome. [bib_ref] Determination of hepatitis C virus genotype by direct sequence analysis of products..., Germer [/bib_ref] Noninvasive tests to asssess liver fibrosis The use of non-invasive tests to assess liver fibrosis is not yet recommended. However, various non-invasive tests are being investigated for staging the degree of liver fibrosis. These tests may be used to decide whether or not to initiate antiviral therapy, and to monitor the effects of such therapy. [bib_ref] Evaluation of liver fibrosis: A concise review, Afdhal [/bib_ref] Standard liver biochemical tests (liver function and coagulation studies) and radiological imaging of the liver are not sufficiently sensitive to diagnose evolving hepatic fibrosis and early stages of cirrhosis, though it may be helpful in advanced cirrhosis. [bib_ref] Evaluation of liver fibrosis: A concise review, Afdhal [/bib_ref] A number of studies employing a variety of indirect markers of liver fibrosis (FibroSure and FibroStat), including standard liver chemistries, platelet count, prothrombin index, and lipoprotein A1 concentrations, have been published recently. These tests have gained acceptance in Europe as alternatives to liver biopsy. [bib_ref] Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest,..., Poynard [/bib_ref] [bib_ref] Prospective analysis of discordant results between biochemical markers and biopsy in patients..., Poynard [/bib_ref] The commonly used non-invasive tests are 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] the Forns index, [bib_ref] Identification of chronic hepatitis C patients without hepatic fibrosis by a simple..., Forns [/bib_ref] FIB-4, [bib_ref] FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. Comparison..., Vallet-Pichard [/bib_ref] [bib_ref] Development of a simple noninvasive index to predict significant fibrosis in patients..., Sterling [/bib_ref] Fibroindex, [bib_ref] Fibroindex, a practical index for predicting significant fibrosis in patients with chronic..., Koda [/bib_ref] FibroTest,FibroMeter, [bib_ref] A novel panel of blood markers to assess the degree of liver..., Calès [/bib_ref] and Hepascore. [bib_ref] Hepascore: An accurate validated predictor of liver fibrosis in chronic hepatitis C..., Adams [/bib_ref] The main advantage of APRI, the Forns index, and FIB-4 over other non-invasive tests is that they are based on readily available blood tests, and are easily accessible. The Forns index is based on platelet count, gamma glutamyl transpeptidase (GGT), age, and cholesterol. The Forns index was found to be slightly more accurate than the aspartate aminotransferase-platelet ratio index and FIB-4 in predicting significant fibrosis and cirrhosis. [bib_ref] Fibroindex, a practical index for predicting significant fibrosis in patients with chronic..., Koda [/bib_ref] The APRI Score (AST platelets ratio index) is a serological marker alternative to liver biopsy, and it has been found to be both satisfactorily sensitive and specific. [bib_ref] Use of AST platelet ratio index (APRI Score) as an alternative to..., Viana [/bib_ref] The APRI formula was proposed by Wai et al. [bib_ref] FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. Comparison..., Vallet-Pichard [/bib_ref] and the APRI score is calculated as follows: [(AST/upper normal limit of AST) ×100) / number of platelets (10 9 /L). [bib_ref] Fib4 is an independent predictor of serious liver disease among HIV-infected patients..., Cozzi Lepri [/bib_ref] The results obtained are then used to plot two Receiver Operating Characteristic (ROC) curves to determine the best cutoff point for advanced fibrosis (F3 and F4). A second point on the curve is established for moderate and advanced fibrosis (F 2, 3, and 4). The FIB-4 was originally developed to predict significant fibrosis and cirrhosis among human immunodeficiency virus (HIV)/HCV co-infected patients in the APRICOT study. [bib_ref] Development of a simple noninvasive index to predict significant fibrosis in patients..., Sterling [/bib_ref] The FIB-4 formula includes the alanine aminotransferase (ALT) level, the aspartate aminotransferase (AST) level, platelet count and age: FIB-4 score = [age (years) × AST (U/L)]/(number of platelets (10 9 /L) × ALT (U/L) ½], [bib_ref] FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. Comparison..., Vallet-Pichard [/bib_ref] [bib_ref] Development of a simple noninvasive index to predict significant fibrosis in patients..., Sterling [/bib_ref] and appears to be a strong predictor of de-compensated cirrhosis or death. [bib_ref] Fib4 is an independent predictor of serious liver disease among HIV-infected patients..., Cozzi Lepri [/bib_ref] In fact, both FIB-4 and APRI have been shown to have the highest positive predictive value only in cases with the most severe stages of liver fibrosis (LF). [bib_ref] Accuracy of simple biochemical tests in identifying liver fibrosis in patients co-infected..., Tural [/bib_ref] For these reasons, rather than using FIB-4 and APRI as substitutes for liver histology at a single time-point for comparison of LF among different individuals, these markers can be used to determine associated risk factors for possible LF progression. [bib_ref] Evaluation of liver fibrosis: Concordance analysis between noninvasive scores (APRI and FIB-4)..., Mendeni [/bib_ref] In a study by Güzelbulut et al., the Forns index, APRI and FIB-4 were all found to be accurate noninvasive blood tests for the prediction of the presence or absence of significant fibrosis and cirrhosis in half of the patients studied. Although they all demonstrated similar levels of accuracy, the Forns index performed slightly better than the APRI and the FIB-4 both in the prediction of significant fibrosis and cirrhosis. The main advantage of these tests is that they are easily reproducible, with readily available blood tests. Consequently, the use of a combination of some or all of these tests may circumvent the need for liver biopsy. [bib_ref] AST-platelet ratio index, Forns index and FIB-4 in the prediction of significant..., Güzelbulut [/bib_ref] FibroTest/ActiTest FibroTest/ActiTest estimates liver fibrosis and necrotic inflammation. These tests are validated, [bib_ref] FibroTest-ActiTest as a non-invasive marker of liver fibrosis, Halfon [/bib_ref] and recommended in Europe. ActiTest is a modification of the FibroTest that incorporates ALT, and measures both necro-inflammatory activity, and liver fibrosis of viral origin (HBV and HCV). [bib_ref] Biomarkers of liver injury for hepatitis clinical trials: A meta-analysis of longitudinal..., Poynard [/bib_ref] The diagnostic value of FibroTest/ActiTest is the same for the intermediate and extreme grades of liver fibrosis. The diagnostic value is independent of ethnic origin, sex, genotype, viral load, or presence of co-morbidities. ActiTest is validated for the initial diagnosis, monitoring both treated and untreated patients. The ActiTest result is presented as a score of 0 to 1, proportional to the significance of the activity, with a conversion to the METAVIR system (from A0 to A3). To facilitate the visual interpretation, the result is accompanied by a colored graph showing the level of severity as follows: [formula] - Green (minimal or absent) - Orange (moderate) - Red (significant) [/formula] The use of FibroTest has been validated for the diagnosis of fibrosis in both treated and untreated patients. In 2006, the French National Authority for Health (HAS) recommended the use of FibroTest as a first-line assessment tool for fibrosis in patients with untreated chronic hepatitis C. When serological markers and transient elastography are used alone or together, the results obtained are comparable to those of the liver biopsy itself. [bib_ref] Biomarkers of liver injury for hepatitis clinical trials: A meta-analysis of longitudinal..., Poynard [/bib_ref] [bib_ref] Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients..., Castera [/bib_ref] The use of biochemical markers of liver fibrosis (FibroTest) and necrosis (ActiTest) can be recommended as an alternative to liver biopsy for the assessment of liver injury in patients with chronic hepatitis C and both have been shown to accurately identify patients with mild fibrosis or cirrhosis. However, they have been shown to be less effective in discriminating moderate and severe fibrosis. [bib_ref] Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest,..., Poynard [/bib_ref] Histology Liver biopsy still remains the only gold standard test for evaluating stages of fibrosis, and, when combined with clinical and laboratory findings, is also a reliable means of assessing prognosis, thus helping to provide information about the need to initiate therapy. Currently, the American Association for the Study of Liver Disease (AASLD) recommends that, regardless of the level of ALT, a liver biopsy is advised for patients with genotypes 1 and 4. However, biopsy is not mandatory in order to initiate therapy. [bib_ref] A proposed system for nomenclature of hepatitis C viral genotypes, Simmonds [/bib_ref] Histology outcomes can vary from showing only mild changes to those of chronic active hepatitis and cirrhosis, [bib_ref] Histopathology of hepatitis C virus infection, Goodman [/bib_ref] depending on the duration and severity of the disease. Histological changes indicative of chronic HCV disease are lymphoid aggregates in portal and bile duct areas, together with steatosis of hepatocytes. A combination of at least two of these features is seen in about 70% of all cases. Immunohistochemical techniques can detect HCV proteins in liver biopsy, and HCV-RNA can be detected with in situ PCR or bDNA techniques. For evaluation of histo-pathological abnormalities and progression, quantitative scores have been developed for estimating the degrees of inflammation (grading) and of fibrosis (staging). The 'histological activity index' (HAI) of Knodell [bib_ref] Formulation and application of a numerical scoring system for assessing histological activity..., Knodell [/bib_ref] is widely used, but has some drawbacks. Several adaptations have been proposed, (e.g., Scheuer [bib_ref] Classification of chronic viral hepatitis: A need for reassessment, Scheuer [/bib_ref] , mainly to separate inflammation from fibrosis scores, as each of these parameters has a distinct value for the prognosis of the disease and for evaluating the effect of therapy. ## Metavir score stage assessment for fibrosis classification in chronic hepatitis c The scores are as follows: ## Necroinflammatory activity The activity (or grade) estimates the lesions by measuring portal inflammation and hepatocellular necrosis. METAVIR score assesses grading for activity as follows: ## Treatment of chronic hcv patients Since interferon-alpha (IFN-a) was first introduced for treatment of non-A and non-B hepatitis 2 decades ago, therapy for chronic carriers of the hepatitis C virus has improved dramatically. Historically, standard IFN monotherapy will lead to a sustained virological response (SVR) in less than 15% of patients. With the addition of ribavirin (RBV), and later the substitution of pegylated IFN-alpha (peg-IFN-a) for the standard IFN, the SVR rate significantly improved. Treatment with combined peg-IFN and RBV may result in SVR in 42% to 52% of genotype 1 infected patients, 70% to 80% of genotype 2 or 3 infected patients and 54-68% of genotype 4 infected patients. The use of combinations of peg-IFN and RBV are thus considered the current standard of care for the treatment of chronic hepatitis C (CHC). The purpose of anti-HCV therapy is the eradication of HCV infection, in order to prevent the occurrence of complications and death. All HCV patients with compensated chronic liver disease who have had no previous treatment for HCV, are willing to be treated, and have no contra-indication to peg-IFN-a or RBV should be considered for treatment, regardless of their baseline ALT level. Pre-treatment predictors of response are useful for advising patients on their chance of viral eradication. Positive pre-treatment predictors of response to peg-IFN and RBV include the HCV genotypes 2 and 3, low baseline HCV RNA levels (genotypes 1 and 4 < 600,000 IU/mL, genotypes 2 and 3 < 400,000 IU/mL), IL-28B polymorphism CC type, absence of bridging fibrosis or cirrhosis, younger age (< 40 years), and those with a body mass index of < 30 Kg/m 2 . Negative pre-treatment predictors include advanced hepatic fibrosis, HIV coinfection, and the presence of insulin resistance with or without diabetes, obesity, non-viral hepatic steatosis and possibly low vitamin D levels. [bib_ref] Treatment predictors of a sustained virologic response in hepatitis B and C, Kau [/bib_ref] [bib_ref] Genetic variation in IL28B is associated with chronic hepatitis C and treatment..., Rauch [/bib_ref] ## Indications and contraindications of antiviral therapy Treatment with peg-IFN-a and RBV is cost effective, even for patients showing early stages of liver fibrosis. [bib_ref] Cost effectiveness of interferon or peginterferon with ribavirin for histologically mild chronic..., Grieve [/bib_ref] [bib_ref] Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C, Sroczynski [/bib_ref] A reasonable candidate for HCV therapy is an adult patient who is 18 years old or older, has HCV viremia, and displays evidence of chronic hepatitis with at least F2 fibrosis, or a well-compensated cirrhosis (total serum bilirubin < 25 µmol/l; INR < 1.5; serum albumin > 34 g/L, no hepatic encephalopathy or ascites). Candidates should also have good hematological indices before starting antiviral therapy. Preferable pre-treatment hematological indices should be the following: hemoglobin level above 12 g/dl; neutrophil count above 1500 /mm [bib_ref] Viral hepatitis in HIV infection, Koziel [/bib_ref] ## Treatment regimen and antiviral side effects Two pegylated IFN-a are available in Saudi Arabia, namely, peginterferon alfa-2b (PegIntron  ), with a 12-kd linear polyethylene glycol (PEG) covalently linked to the standard interferon alfa-2b molecule, and peginterferon alfa-2a (Pegasys  ) with a 40-kd branched PEG covalently linked to the standard interferon alfa-2a molecule. [bib_ref] Pharmacokinetics of peginterferon, Zeuzem [/bib_ref] In the Individualized Dosing Efficacy versus Fixed Dosing to Assess Optimal Peg-IFN Therapy (IDEAL) trial, 3070 genotype 1 infected patients were randomized to one of the two-pegylated IFN, and no difference in SVR was obtained between the two formulations. The rate of SVR was 40.9% with peg-IFN-a2a (Pegasys  ) and 39.8% with peg-IFN-a2b (PegIntron  ). [bib_ref] Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection, Mchutchison [/bib_ref] The preference as to which of them to use will therefore depend on their availability at a particular hospital or patient preference. Ribavirin (a guanosine nucleoside analogue) is an important component of HCV dual and triple (direct-acting antiviral agents) therapy. It improves viral clearance, decreases relapse rates, and improves rates of SVR when used in combination with peginterferon, as compared with peginterferon monotherapy. When a patient is being evaluated for HCV therapy, it is important to assess all pre-existing medical problems, such as diabetes, hypertension, and weight, and to screen all candidates for symptoms of depression and coronary artery disease. An acceptable plan for monitoring patients on antiviral therapy would include monthly visits during the first 12 weeks of treatment, followed by visits at threemonth intervals until the end of therapy. At each visit, adherence to treatment, and the presence of any side effects should be reviewed. Laboratory monitoring should include measurements of the complete blood count and differential (if leucopenia has developed), ALT, AST, ALP, bilirubin (total and direct), INR, and Albumin every 4 weeks on treatment. A sensitive real-time PCR-based assay with a lower limit of detection of 50 IU/ml should be used. The same assay should be used in each patient to determine HCV RNA at different time points, in order to ensure consistency of results. [bib_ref] Overestimation and under-estimation of hepatitis C virus RNA levels in a widely..., Chevaliez [/bib_ref] The Saudi Journal of Gastroenterology ## Recommendations 1. In chronic HCV non-genotype 1 infected patients with normal renal function, combination therapy with pegylated IFN-a and ribavirin is considered the standard of care (Grade A). ## After initiating combination antiviral therapy, patients should be seen at monthly intervals in the first three months, and then every two to three months until the end of treatment. Patients who have completed the treatment regimen should be seen six months after the end of treatment. Individualized close follow up should be planned, based on the severity of any adverse events (Grade D). ## Adverse events associated with pegylated interferon and ribavirin Pegylated interferon-related adverse events are the primary reason for patients discontinuing treatment. It is estimated that 10% to 14% of patients may discontinue treatment due to adverse events associated with the use of IFN. [bib_ref] Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial..., Manns [/bib_ref] [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] The most common of these are influenza-like side effects such as fatigue, headache, aching bones, myalgia, fever and rigors. Neuropsychiatric side effects may also manifest them selves in 22% to 31% of patients. These side effects include depression, anxiety, irritability and rarely psychosis. In addition, neutropenia (absolute neutrophil count (ANC) below 1500 mm 3 ) is a frequent laboratory abnormality, occurring in 18% to 20% of patients, and severe neutropenia, that is, ANC < 500 mm 3 , may be observed in 4% of patients. Despite the decline of the neutrophil count, serious infections are not related to the degree of neutropenia. [bib_ref] Risk factors for infection during treatment with peginterferon alfa and ribavirin for..., Roomer [/bib_ref] [bib_ref] Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis..., Soza [/bib_ref] The use of peg-IFN can also induce autoimmune disorders, such as autoimmune thyroiditis, [bib_ref] Thyroid abnormalities in chronic viral hepatitis and their relationship to interferon alfa..., Deutsch [/bib_ref] or could aggravate preexisting autoimmune disorders. The most common side effect related to RBV is hemolytic anemia. Anemia can be observed in approximately onethird of patients. Dose adjustment for anemia (hemoglobin level < 10 g/dL) may be required in 9% to 15%. Other side effects associated with RBVcould include mild lymphopenia, hyperuricemia, itching, rash, cough and nasal stuffiness. RBV is teratogenic in animals, and therefore strict birth control should be practised in patients being treated with peg-IFN-a and RBV during treatment and for six months following its discontinuation. [fig_ref] Table 3: Summary of management of other adverse effects of Peginterferon/RibavirinSource [/fig_ref] summarizes common strategies used in ameliorating antiviral adverse events. Neutropenia and thrombocytopenia are common adverse events reported when peg-IFN-a is administrated. The dose of pegylated interferon should be reduced if the ANC falls below 750/mm 3 , or if the platelet count falls below 50,000/mm 3 . When using peg-IFN-a 2a, the dose may be reduced from 180 to 135 µg/week, and then to 90 µg/week. When using pegylated IFN-a 2b, the dose may be reduced from 1.5 to 1.0 µg/kg/week and then to 0.5 µg/kg/ week. Peg-IFN-a 2b should be stopped if the platelet count is < 25,000. Once neutrophil or platelet counts rise again, treatment can be re-started, but a reduced dose should be administered. There is no evidence to support the routine use of granulocyte colony stimulating factor (G-CSF, Filgrastim) to reduce the rate of infections or improve SVR rates. Serious infections may occur in 3% to 5% of patients, irrespective of neutrophil count. [bib_ref] Risk factors for infection during treatment with peginterferon alfa and ribavirin for..., Roomer [/bib_ref] [bib_ref] Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis..., Soza [/bib_ref] The use of granulocyte colony-stimulating factors should therefore be reserved for managing only the most severe neutropenia which is not initially responsive to peg-IFN dose reduction. ## Management of adverse events related to antiviral therapy Eltrombopag is an orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. [bib_ref] Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C, Mchutchison [/bib_ref] It allowed successful treatment of HCV when given for 12 weeks to patients who had baseline thrombocytopenia (20,000 to 70,000 mm 3 ). However, thrombopoiesis-stimulating drugs are not generally recommended for the management of thrombocytopenia, as there is still a lack of sufficient data on their role in improving SVR rates, as well as a potential risk of precipitating portal vein thrombosis. Although anemia is most commonly related to RBV, Peg-IFN also contributes to anemia by its effect on bone marrow suppression. It manifests itself early, within the first 2 weeks of administration, with a mean maximum hemoglobin reduction of 3 g/dL in first 6-8 weeks that could be associated with an improved chance of achieving SVR. [bib_ref] Hepatitis C virus treatment-related anemia is associated with higher sustained virologic response..., Sulkowski [/bib_ref] A decrease in hemoglobin of 1.5 g/dL at week 2 of therapy has been associated with the risk of severe anemia and the need for treatment interruption. If significant anemia occurs (hemoglobin < 10 g/ dl) the dose of RBV should be adjusted downward, by 200 mg at a time. RBV administration should be stopped if the hemoglobin level falls below 8.5 g/dl. However, RBVdose reductions to levels less than 60% will significantly decrease the likelihood of obtaining SVR. Recombinant erythropoietins (rEPO) can therefore be used to maintain or improve hemoglobin levels, in order to avoid significant ribavirin dose reductions or interruptions. rEPO can be administered when the hemoglobin level falls below 10 g/dl. The hemoglobin level should be assessed 2 weeks after initiating rEPO. The rEPO dose should be reduced if the increase in hemoglobin is more than 1 g/dl, and stopped if the hemoglobin level rises to over 12 g/dl. The hemoglobin level should then be re-assessed 4 weeks later. The dose should again be reduced if the hemoglobin increase is more than 2 g/dl, compared to 4 weeks earlier. If the hemoglobin level falls again below 12 g/dl, erythropoietin therapy can be restarted at 50% of the initial dose. If the hemoglobin level rise is less than 1 g/dl at 4 weeks of administration and no other cause of anemia is found, the rEPO dose can be increased. The Saudi Journal of Gastroenterology Antidepressant therapy maybe prescribed in a prophylactic approach to patients in whom pre-treatment screening indicates possible positive symptoms of depression. Success in reducing the incidence of depression without an impact on the SVR during treatment has been reported. [bib_ref] Escitalopram for the prevention of peginterferon-a2a-associated depression in hepatitis C virus-infected patients..., Schaefer [/bib_ref] IFN-induced sleep deprivation manifested together with irritability and anxiety should not be confused with depression, and should be managed with anxiolytics. [bib_ref] Hepatitis C treatment in patients with drug addiction: Clinical management of interferon-alpha-associated..., Schaefer [/bib_ref] Early consultation and follow up with a psychiatrist is desirable whenever psychiatric symptoms are suspected. ## Recommendations 1. The peg-IFN-a and RBV should be temporarily interrupted if the ANC falls below 500/mm 3 , or hemoglobin falls below 8.5 g/dl respectively (Grade A). The combination of peg-IFN-a and RBV should be stopped if severe hepatitis flare or severe sepsis occur (Grade C). 2. The use growth factors is associated with an increased cost of therapy and a lack of sufficient evidence towards improvement of sustained virologic response (SVR) (Grade B). When deciding to use recombinant erythropoietin (EPO) and G-CSF, an 80% or more of RBV and peg-IFN-a dose should be maintained during the course of therapy so that the benefit of adherence However, few studies have prospectively evaluated the impact of rEPO on SVR rates. rEPO use was associated with an improved rate of SVR when higher doses of RBV(~15 mg/ kg/day, 1,000-1,600 mg/day) were initiated, but showed no impact on SVR with standard ribavirin dosing. [bib_ref] Epoetin alfa improves quality of life in anemic HCV infected patients receiving..., Pockros [/bib_ref] [bib_ref] Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and..., Shiffman [/bib_ref] The use of hematological growth factors is associated with increased cost of treatment for chronic hepatitis C. [bib_ref] Cost-effectiveness of hematologic growth factors for anemia occurring during hepatitis C combination..., Rio [/bib_ref] In addition, rEPO has been associated with serious side effects, including cardiovascular and/or thromboembolic events, pure red cell aplasia, progression of certain cancers, and death. [bib_ref] Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for..., Bennett [/bib_ref] Antiviral treatment should be stopped immediately in cases of a hepatitis flare (ALT levels above 10 times normal), or if a serious bacterial infection occurs at any site in the body, regardless of neutrophil counts. Interferons can induce or exacerbate depression. There are two distinct depressive syndromes that can develop while receiving interferon, namely, a depression-specific syndrome (mood, anxiety, cognitive complaints), and neurovegetative syndrome, (fatigue, anorexia, pain and psychomotor slowing). Depression-specific symptoms are responsive to serotonergic antidepressants, whereas neurovegetative symptoms are not. can be achieved (Grade D). ## Peg-ifn-a-induced neutropenia does not correlate with increased frequency of infection episodes (grade c). the use of granulocyte colony-stimulating factor (g-csf) does not reduce the rate of infections (grade c) ## Improving treatment success rates Before starting antiviral therapy, patients must be instructed about the schedule and the side effects to be expected during treatment. Patients should also be instructed about preventive and therapeutic measures to ease these side effects. Adherence to an antiviral treatment regimen is generally defined as taking ≥80% of treatment regimen for ≥80% duration of therapy. In order to maintain maximum exposure to each drug after dose reductions and hence, improve the response rate, a full dose should be resumed whenever possible. [bib_ref] Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic..., Mchutchison [/bib_ref] Diabetes control, weight reduction for obese [bib_ref] High body mass index is an independent risk factor for non-response to..., Bressler [/bib_ref] and reduction of or abstention from alcohol intake are important measures to consider before initiating antiviral therapy. ## Recommendations 1. In order to optimize SVR rates, complete adherence to both peg-IFN-a and RBV regimens should be emphasized (Grade B). 2. Pre-treatment weight reduction in obese individuals and good control of diabetes mellitus may increase the chance of SVR (Grade B). ## Treatment of chronic hcv naïve patients ## Genotypes 1 and 4 hcv infection The SVR reported by registration trials for peg-IFN-a was 46% and 42% in patients with HCV genotype 1 treated with peg-IFN-a 2a or peg-IFN-a 2b and RBV, respectively. [bib_ref] Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial..., Manns [/bib_ref] [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] The reported SVR rates using peg-IFN-a and weight based RBV in large prospective trials of genotype 4 were 54% to 68%. [bib_ref] Insulin resistance and geographical origin: Major predictors of liver fibrosis and response..., Moucari [/bib_ref] [bib_ref] Insulin resistance predicts rapid virologic response to peginterferon/ ribavirin combination therapy in..., Khattab [/bib_ref] [bib_ref] Viral kinetic of HCV genotype-4 during pegylated interferon alpha 2a: Ribavirin therapy, Derbala [/bib_ref] The optimal treatment regimen for HCV infection with genotypes 1 and 4 is peg-IFN-a based RBV (13-15 mg/Kg/day) divided into two doses, for a duration of 48 weeks. The dose of peginterferon alfa-2a (Pegasys  ) is 180 µg subcutaneously per week, and the dose of peginterferon alfa-2b (PegIntron  ) is 1.5 µg/kg subcutaneously per week. Direct acting antiviral agents (Boceprevir and Telaprevir) have recently been approved for use as triple therapy in chronic HCV genotype 1 infected patients [bib_ref] SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection, Poordad [/bib_ref] [bib_ref] Telaprevir for previously untreated chronic hepatitis C virus infection, Jacobson [/bib_ref] (See section on triple therapy of HCV genotype 1). ## Recommendations 1 Treatment with peginterferon plus ribavirin should be planned for 48 weeks; the dose for peg-IFN-a 2a (Pegasys  ) is 180 µg subcutaneously per week, and for peg-IFN-a 2b (PegIntron  ) is 1.5 µg/kg subcutaneously per week together with weight-based (13-15mg/kg/day) RBV (Grade A). ## Genotypes 2 and 3 hcv infection In patients infected with HCV genotypes 2 and 3, the reported SVR is 76% and 82% of cases treated with peg-IFN-a 2a plus RBV, and peg-IFN-a 2b plus RBV, respectively. [bib_ref] Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial..., Manns [/bib_ref] [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] A recent meta-analysis showed higher SVR rates in genotype 2 than in genotype 3 infected patients treated for 24 weeks (74% vs. 69%, respectively). [bib_ref] Meta-analysis: The outcome of anti-viral therapy in HCV genotype 2 and genotype..., Andriulli [/bib_ref] Treatment with peg-IFN plus RBV should be administered for 24 weeks, using a fixed dose of RBV at 800 mg per day. However, those with a BMI beyond 25 or those who have baseline factors suggesting low responsiveness (high viral load, insulin resistance, metabolic syndrome, severe fibrosis or cirrhosis) should receive a weight-based dose of RBV, similar to genotypes 1 and 4.Recommendations ## Genotype 5 and 6 hcv infection Patients with genotypes 5 and 6 infections are under-represented in trials of peg-IFN and RBV, due to their limited distribution globally. In the non-randomized retrospective studies of genotype 5 that are limited to small numbers of patients, the reported SVR, using 24-48 weeks non-pegylated and pegylated IFN and RBV, was 48% to 60%. [bib_ref] Efficacy of interferon-based antiviral therapy in patients with chronic hepatitis C infected..., D'heygere [/bib_ref] [bib_ref] Efficacy of interferon plus ribavirin in the treatment of hepatitis C virus..., Antaki [/bib_ref] [bib_ref] Effectiveness of interferon plus ribavirin combination in the treatment of naive patients..., Bonny [/bib_ref] The reported SVR rate in HCV-6 patients treated with a 48-week regimen of peg-IFN and RBV varies between 66% and 86%. [bib_ref] Higher rate of sustained virologic response in chronic hepatitis C genotype 6..., Nguyen [/bib_ref] [bib_ref] High response rate of combination therapy of pegylated interferon and ribavirin in..., Li [/bib_ref] [bib_ref] What is the safe duration of therapy for patients infected with HCV..., Antaki [/bib_ref] There are insufficient data to determine the optimal treatment regimen for genotypes 5/6, and further studies are needed. Until robust data are available, the treatment regimen for patients with genotype 5 / 6 infections should follow the recommendations for patients with genotype 1 and 4 infections, using peg-IFN and a weight-based dosage of RBV, over a period of 48 weeks. ## Recommendations ## Direct-acting antivirals in treatment naïve patients In many patient populations, the outcome of standard HCV therapy with peg-IFN-a and RBV is not satisfactory. The advanced knowledge of the structures of HCV polymerases and proteases has meant that structure-based drug design can be used to develop direct inhibitors to these enzymes. This category of antivirals is called "direct-acting antivirals" (DAAs). Currently, many drugs at different stages of development are under investigation. Of these, Telaprevir and Boceprevir are NS3/4A protease inhibitors. Each has been the subject of several large recently completed multicenter phase 3 clinical trials, and they have subsequently been added to some international institutional guidelines for the treatment of HCV genotype 1. The efficacy of telaprevir in combination with peg-IFN-a 2a and RBV in the treatment of naïve HCV genotype 1 patients has been evaluated in several phase 2 and 3 studies. A landmark phase 3 (ADVANCE) trial, [bib_ref] Telaprevir for previously untreated chronic hepatitis C virus infection, Jacobson [/bib_ref] evaluated the efficacy of telaprevir with peg-IFN-a 2a and RBVin 1088 treatment-naïve patients with genotype 1 chronic HCV. Patients were randomly assigned to one of three different treatment regimens. SVR rates were significantly higher (69% to 75%, versus 44%) in patients who received a regimen containing telaprevir, in comparison with a standard of care treatment regimen. The most commonly encountered adverse events in the telaprevir-based groups were pruritus, rash, and anemia. Another (ILLUMINATE) trial, [bib_ref] Response-guided telaprevir combination treatment for hepatitis C virus infection, Sherman [/bib_ref] was a phase 3 noninferiority trial, designed to evaluate differences in SVR rates between a 24-week period and a 48-week period of telaprevir-based therapy in patients who had an extended rapid virologic response (eRVR; HCV RNA < 25 IU/mL at both weeks 4 and 12). In this trial, a total of 540 treatmentnaïve patients with HCV genotype 1were included. The overall SVR rate was 72%, and an eRVR was achieved in 65%. Among patients with an eRVR, the SVR rate in the 24-week treatment group (92%) was non-inferior to the SVR rate in the 48-week treatment group (88%). Boceprevir is another NS3/ 4A protease inhibitor. Its efficacy against HCV genotype 1 was evaluated in several trials. A phase 3 SPRINT-2 trial studied boceprevir in combination with peg-IFN-a 2b and RBV in 1097 treatment naive genotype 1 HCV patients. [bib_ref] SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection, Poordad [/bib_ref] All patients received a 4-week lead-in of peg-IFN-a 2b and RBV. They were subsequently randomly assigned to 3 groups: group 1 (the control group) received placebo plus peg-IFN/RBV for an additional 44 weeks, group 2 received boceprevir plus peg-IFN/RBV for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peg-IFN/ RBV for an additional 20 weeks, group 3 received boceprevir plus peg-IFN/RBV for 44 weeks. SVR was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P < 0.001), and in 213 of the 311 patients (68%) in group 3 (P < 0.001). These drugs appear promising in the treatment of HCV genotype 1. However, they are limited by their proven efficacy against HCV genotype 1 only; in addition, concerns about their side effects and long term resistance profile exist. Preclinical data suggests that, with the currently used dosages, boceprevir might not be effective in HCV genotype 4. In a proof-of-concept study, telaprevir has shown activity against HCV genotype 4 during 15 days monotherapy or in combination with peg-IFN and RBV when compared to peg-IFN, RBV and placebo. [bib_ref] Management of hepatitis C virus genotype 4: Recommendations of an international expert..., Khattab [/bib_ref] Recommendations 1. The combination of peg-IFN/RBV is the approved standard of care for chronic hepatitis C, especially non-genotype1 (Grade A) 2. The most effective regimen for treating HCV genotype 1 is the use of triple therapy, with boceprevir or telaprevir in combination with peg-IFN/RBV (Grade A) ## Clinical trials of hcv antiviral therapy in saudi arabia When ## Response-guided therapy of chronic hcv infection The rapidity with which a patient clears HCV RNA during therapy has very important implications for predicting the likelihood of a response to treatment, for determining the optimal duration of treatment, and as a stopping rule for antiviral therapy. In patients infected with HCV genotype1 and 4-6, HCV RNA levels should be assessed at the following times: baseline, week 4, week 12, and at the end of treatment. Week 24 HCV RNA testing is indicated in patients who do not obtain negative HCV RNA at week 12, i.e., in partial early virological responders (pEVR). In patients infected with HCV genotypes 2 and 3, HCV RNA levels should be obtained at baseline, week 4 and week 24. Week 12 HCV RNA level should be tested in patients who do not achieve rapid virological response (RVR). All HCV patients who achieve end of treatment response (ETR) should have their HCV RNA level tested six months after completing antiviral therapy, in order to establish whether SVR has been achieved, or relapse has taken place. ## Rapid virological response A rapid virologic response (RVR) is defined as having undetectable HCV RNA in serum after the first 4 weeks of antiviral therapy. The achievement of an RVR identifies those patients who are most sensitive to IFN, and is highly predictive of obtaining an SVR, independent of genotype and treatment regimen; an SVR rate of 91% is reported. [bib_ref] Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon..., Ferenci [/bib_ref] Approximately 20% of persons with HCV genotypes 1 and 4 infections and 66% with HCV genotype 2 and 3 infections achieve an RVR. [bib_ref] Austrian Hepatitis Study Group. Peginterferon alfa-2a and ribavirin for 24 weeks in..., Ferenci [/bib_ref] [bib_ref] Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients..., Dalgard [/bib_ref] ## Early virologic response and delayed virological response Early virologic response (EVR) is defined as a greater than 2-log drop in viral load at 12 weeks of therapy. An EVR is sub-classified into a complete EVR (cEVR), defined as undetectable HCV RNA in serum at 12 weeks of therapy, and a partial EVR (pEVR), defined as a greater than 2-log decrease in the level of HCV RNA in serum at week 12 of therapy. Approximately 97% to 100% of treatment-naive patients with HCV genotype 1 infection who do not achieve EVR, fail to obtain an SVR. [bib_ref] Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon..., Jensen [/bib_ref] [bib_ref] Prediction of treatment outcome in patients with chronic hepatitis C: Significance of..., Berg [/bib_ref] In contrast, an EVR is less accurate in predicting an SVR. A complete EVR is a better predictor of an SVR than a 2-log reduction in HCV RNA. The clinical utility of an EVR is less useful in persons with HCV genotype 2 and 3 infections, since the majority clear virus by week 12 and respond to treatment. In patients with detectable HCV RNA (≥50 IU/ml) at week 24, i.e., partial virological response, treatment should then also be stopped, due to a small chance of SVR (1-3%). [bib_ref] Prediction of treatment outcome in patients with chronic hepatitis C: Significance of..., Berg [/bib_ref] [bib_ref] Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients..., Davis [/bib_ref] Delayed virological response (DVR), also known as slow virological response, is defined as a more than 2 Log 10 drop in HCV RNA level at week 12 (pEVR) but with an undetectable level at week 24, and maintained undetectability to the end of treatment. ## Stopping rules for combination therapy with peginterferon and ribavirin All HCV patients who have null response [defined as > 2 log reduction in HCV RNA level at week 12 but detectable viral load (>50 IU/ml) at week 24] must abandon antiviral therapy. ## Individualized treatment duration according to on-treatment virologic response ## Shortening the duration of antiviral therapy based on rvr It may be possible to shorten the duration of treatment for patients with genotypes 1 or 4 who achieve an RVR, from 48 to 24 weeks. [bib_ref] Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients..., Zeuzem [/bib_ref] [bib_ref] Pegylated interferon alpha-2b plus ribavirin in patients with genotype 4 chronic hepatitis..., Kamal [/bib_ref] Treatment for those patients with genotypes 2 or 3 who achieve an RVR, could possibly be shortened to 16 weeks from 24. [bib_ref] Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype..., Mangia [/bib_ref] [bib_ref] A randomized study of peginterferon and ribavirin for 16 versus 24 weeks..., Yu [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype..., Shiffman [/bib_ref] However, a large,multicenter international trial [bib_ref] Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype..., Shiffman [/bib_ref] randomly assigned 1469 patients with HCV genotypes 2 or 3 to receive 180 µg of peg-IFN-a 2a weekly, plus 800 mg of RBV daily for a period of either 16, or 24 weeks. The SVR rate was significantly lower in patients treated for 16 weeks than in those treated for 24 weeks (62% vs. 70% respectively). In addition, among those patients treated for 16 weeks only, there was a higher relapse rate (31% versus 18%). Shortening the duration of antiviral therapy across all genotypes should not be attempted if patients have any of the following negative predictors: high viral load (genotypes 1 and 4 > 600,000 IU/ mL, genotypes 2 and 3 >400,000 IU/mL), advanced fibrosis of ≥F3 on metavir, insulin resistance, metabolic syndrome, and non-viral steatosis or HIV co-infection. ## Extension of duration of antiviral therapy based on dvr Strategies to improve SVR rates in patients who achieve undetectable HCV RNA between weeks 12 and 24 of therapy, delayed virologic response (DVR), or so-called slow responders, may include extension of duration of therapy for another 24 weeks. For patients with genotypes 1 and 4 infection who have DVR, consideration could be given to extending treatment to a duration of 72 weeks, with the intention of minimizing the risk of relapse. [bib_ref] Extended treatment duration for hepatitis C virus type 1: Comparing 48 versus..., Berg [/bib_ref] [bib_ref] Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C..., Pearlman [/bib_ref] [bib_ref] Meta-analysis shows extended therapy improves response of patients with chronic hepatitis C..., Farnik [/bib_ref] [bib_ref] Peginterferon a-2a/ribavirin for 72 weeks reduces relapse among Hepatitis C type 1..., Ferenci [/bib_ref] [bib_ref] Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable..., Sanchez-Tapias [/bib_ref] However, in the era of direct acting antiviral therapy, all genotype 1 infected patients are expected to undergo triple therapy, and therefore extension of the treatment for another 24 weeks would probably not be necessary, due to the normally impressive SVR rate obtained with triple therapy. In patients with genotypes 2/3 infection with no RVR, treatment of 48 weeks duration is advised.Insufficient data exist for other genotypes. ## Recommendations ## Re-treatment of experienced chronic hcv patients Poor adherence to antiviral regimen by patients, and inappropriate dose reductions can both contribute to low response rates. Significantly, 20% to 50% of patients treated with peg-IFN and RBV will not achieve an SVR. ## Null responder and partial responder Approximately one third of patients treated with peg-IFN and RBV are unable to obtain negative viremia before week 24. These patients may be either null responders, or partial responders. The decision to engage on a repeated course of therapy must be individualized for each patient in the light of potential benefits, when options are limited, and the chances for success quite low. Non-responders to previous non-peg-IFN can be retreated with peg-IFN-a -2a or 2b and RBV. Re-treatment with peg-IFN and RBV has been shown to result in an SVR rate of 40% among patients who were previously treated with IFN monotherapy, but this rate dropped to 10% in those who had previously received combination therapy with non-peg-IFN and RBV. [bib_ref] Pegylated interferon alfa-2b plus ribavirin in the re-treatment of interferon-ribavirin non-responder patients, Taliani [/bib_ref] [bib_ref] Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have..., Shiffman [/bib_ref] [bib_ref] A randomized trial of pegylated interferon alpha-2b plus ribavirin in the re-treatment..., Jacobson [/bib_ref] Re-treatment of patients who failed to respond fully to a previous full treatment regimen of peg-IFN-a/ RBV with the same or a different peg-IFN regimen, showed disappointing results, and is not recommended. [bib_ref] Pegylated interferon and ribavirin failures: Is re-treatment an option?, Cheruvattath [/bib_ref] Given the unfortunate SVR rate for retreatment of HCV patients, all non-responders genotype 1 and relapsers to previous peg-IFN treatment should be considered for triple therapy using protease inhibitors. [bib_ref] Boceprevir for previously treated chronic HCV genotype 1 infection, Bacon [/bib_ref] [bib_ref] Telaprevir for previously treated chronic HCV infection, Mchutchison [/bib_ref] Re-treating non-responders for a longer duration improved response rates, although in general the rates remained disappointingly low. In the REPEAT trial, [bib_ref] Re-treatment with peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C..., Yoshida [/bib_ref] extension of peg-IFN-a 2a therapy to 72 weeks in patients who had previously been treated with peg-IFN-a 2b (the study included all genotypes, but genotype1 was the predominant one) showed an SVR rate of 16%, compared with 8% of those who received 48 weeks of treatment. The major limitation of the REPEAT study was that 64% of patients had an unknown response to their previous peg-IFN therapy. Non-genotype 1 patients with DVR in the first cycle of treatment who have evidence of inadequate exposure to either peg-IFN-a or RBV (due to dose adjustments or poor adherence during the first course of therapy) could be considered for retreatment with peg-IFN-a and RBV. Non-responders to peg-IFN and RBV with baseline cirrhosis should generally undergo screening and surveillance for HCC and varices. ## Relapsers The reported relapse rate after treatment with peg-IFN-a and RBV is approximately 15-25%. Patients who relapsed after treatment with standard IFN-based regimens responded to re-treatment with peg-IFN-a and RBV in 32-53% of cases. [bib_ref] Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have..., Shiffman [/bib_ref] Re-treatment with peg-INF-a 2a of patients who relapsed after prior peg-IFN and RBV was reported in a small, open-label, multicentre trial, which included 28 relapsers, of whom 68% then achieved SVR. [bib_ref] Re-treatment with peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C..., Yoshida [/bib_ref] All genotype 1 patients who have relapsed after a previous peg-IFN course should be considered for re-treatment with triple therapy using protease inhibitors. [bib_ref] Pegylated interferon and ribavirin failures: Is re-treatment an option?, Cheruvattath [/bib_ref] [bib_ref] Boceprevir for previously treated chronic HCV genotype 1 infection, Bacon [/bib_ref] Recommendations 1. HCV patients with non-genotype 1infection experiencing prior non-response or relapse after non-peg-IFN therapy with or without RBV, or previously treated with peg-IFN monotherapy, may be considered for a second course of therapy with peg-IFN plus RBV (Grade B). 2. HCV patients with non-genotype 1 infection who had previously shown a null or partial response pattern, where an adequate dose of peg-IFN and RBV had been administered during the first course of antiviral therapy, should not be subjected to another course of combination therapy using same or different peg-IFNs (Grade B). These patients should be followed up for progression of liver disease and could wait for new, more effective protease inhibitors (Grade C) 3. Non-responder or relapsers patients with genotype 1 HCV infection after treatment with either peg-IFN or non-peg-IFN should be considered for re-treatment with a triple therapy regimen, using direct acting antiviral agents (Grade A). ## Role of maintenance antiviral therapy in non-responders Studies assessing the role of peg-IFN as a maintenance strategy for non-responders [bib_ref] Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon, Dibisceglie [/bib_ref] [bib_ref] EPIC3 Study Group. Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular..., Bruix [/bib_ref] failed to demonstrate any significant reduction in the clinical endpoints such as progression of fibrosis, HCC, or death. ## Direct-acting antivirals in treatment-experienced hcv patients With the arrival of new, direct-acting antiviral (DAA) drugs like telaprevir and boceprevir, which have been shown to be more effective than re-treatment with a standard regimen, re-treatment of prior non-responders is now promising. Recently, two phase 3 studies have evaluated telaprevir. The first was in a prior non-responders, PROVE 3 (Protease Inhibition for Viral Evaluation) study, and the second, the REALIZE study (Re-treatment of Patients with Telaprevirbased Regimen to Optimize Outcomes). [bib_ref] Telaprevir for previously treated chronic HCV infection, Mchutchison [/bib_ref] In both trials, results after re-treatment of prior non-responders with different telaprevir regimens in combination with peg-IFN-a 2a and RBV were superior to those for re-treatment with peg-IFN-a 2a and RBV alone. The SVR rates ranged from 51% to 66% in the regimens containing triple therapy (telaprevir, peg-IFN and RBV), and better response rates were demonstrated in relapsers when compared to non-responders. In these trials, the SVR rates ranged from 69% to 88% in prior relapsers, while lower SVR rates in non-responders of 29% to 39% were observed. The majority of patients in these trials had genotype 1 infection. Boceprevir addition also showed similar improvements in response rates for treatment-experienced individuals. The addition of boceprevir to peg-IFN and RBV resulted in significantly higher rates of SVR in previously treated patients with chronic HCV genotype 1 infection, when compared with those on a regimen of peg-IFN and RB Valone. [bib_ref] Boceprevir for previously treated chronic HCV genotype 1 infection, Bacon [/bib_ref] In a phase 3 trial (RESPOND-2), boceprevir was evaluated in prior partial responders or relapsers with peg-IFN and RBV; however, null responders were not included in this trial. A 4-week lead-in phase of peg-IFN and RB Vand responseguided therapy was required with different regimens of boceprevir and with peg-IFN-a 2b and RBV. SVR rates were higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P < 0.001). A retrospective analysis of null responders (defined as < 1.0 log10 IU/mL reduction in HCV RNA after 4 weeks of peg-IFN-a 2b/RBV) to peg-IFN and RBV from the two lead-in groups of the SPRINT-1 trial was conducted. Following the lead-in phase, patients received 24 or 44 weeks of boceprevir plus peg-IFN-a 2b/RBV. An SVR was achieved in 25% and 55% of null responder patients treated with 24 or 44 weeks of triple therapy. Although this analysis pertains to null responders assessed after only 4 weeks of peg-IFN and RBV, the majority of these patients would have failed to achieve an SVR. These findings suggest that the additional use of protease inhibitors are not the answer for this difficult-to-treat population. There are ongoing trials with other DAAs that could suggest further solutions for the treatment of non-genotype 1 HCV patients with prior non-response. [bib_ref] Dual therapy with the NS5A inhibitor BMS-790052 and the NS3 protease inhibitor..., Chayama [/bib_ref] [bib_ref] High rates of early viral response, promising safety profile and lack of..., Jensen [/bib_ref] Recommendations 1. Patients with HCV genotype-1 who have failed prior standard therapy with peg-IFN-a and RBV, can be treated with triple therapy with boceprevir or telaprevir, together with peg-IFN-a and weight-based RBV (Grade A). ## Treatment of acute hepatitis c Identification of clinical acute HCV infection is uncommon, since, most of the time it has a subclinical course with mild or no symptoms. When clinically suspected, a patient with possible acute HCV should be tested as soon as possible for HCV RNA, since the antibody testing requires several weeks for sero-conversion. In the absence of a recent negative HCV test, discriminating between acute HCV and recently discovered chronic HCV is difficult. Spontaneous clearance of acute HCV infection can occur in up to 30% of cases, so the decision to treat or to delay treatment should weigh the possible chance of spontaneous resolution and the cost and possible side effects of treatment. In most instances, clearance will occur in the first 12 weeks, and the presence of symptoms predictive of spontaneous clearance can occur in about 30% of patients. [bib_ref] Acute hepatitis C: High rate of both spontaneous and treatment-induced viral clearance, Gerlach [/bib_ref] [bib_ref] Natural course of acute hepatitis C: A long-term prospective study, Santantonio [/bib_ref] Treatment of acute HCV has been shown to reduce the development of chronic HCV infection; however, there is no consensus on the optimal treatment regimen. Therapy begun before 12 weeks have passed since diagnosis is associated with a better chance of SVR. [bib_ref] Peginterferon alfa-2b therapy in acute hepatitis C: Impact of onset of therapy..., Kamal [/bib_ref] Standard IFN alfa is effective in improving biochemical outcomes, and achieving sustained virologic clearance in 32% of IFN-treated patients, versus only 4% of control group patients. [bib_ref] Interferon for acute hepatitis C, Poynard [/bib_ref] Several clinical trials have shown that the treatment of hepatitis C infection during the acute phase is associated with high SVR rates ranging between 75% and 95%. [bib_ref] Acute hepatitis C: A systematic review, Kamal [/bib_ref] Twelve trials were analyzed (414 patients) in a meta-analysis. The use of standard interferon appeared to significantly increase the SVR (risk difference 49%; 95% confidence interval 32.9-65%) in comparison to patients on no treatment. [bib_ref] When and how to treat acute hepatitis C?, Licata [/bib_ref] Volume 18, Number 5 Shawwal 1433 September 2012 Supplement 1 The Saudi Journal of Gastroenterology Several studies have evaluated the use of peg-IFN. Once weekly peg-IFN-a 2b monotherapy (1.5 µg /kg per week) for a period of 12 weeks was evaluated in a major study of 129 subjects with acute HCV. The SVR rates were 95%, 92%, and 76% with treatment onset at 8, 12, and 20 weeks, respectively. The overall SVR rate was 87%. [bib_ref] Peginterferon alfa-2b therapy in acute hepatitis C: Impact of onset of therapy..., Kamal [/bib_ref] Patients infected with genotypes 2, 3, and 4 showed better SVR rates than those infected with genotype 1. The role of combination therapy with RBV is not well established, and probably does not improve SVR; however, it might be considered in cases where chronic infection is suspected. [bib_ref] The Hep-Net Acute-HCV Study group. Early versus delayed treatment of acute hepatitis..., Deterding [/bib_ref] [bib_ref] Acute hepatitis C: Current status and remaining challenges, Santantonio [/bib_ref] The impact of the duration of therapy with 12 weeks vs. 24 weeks on SVR rate has also been evaluated in several case series, but no definitive recommendation can be made about the optimal length of treatment needed for acute hepatitis C. It is however, advisable to treat for 24 weeks. [bib_ref] Duration of peginterferon therapy in acute hepatitis C: A randomized trial, Kamal [/bib_ref] Recommendations 1. There is no clear evidence on the optimum timing for the start of acute HCV therapy, but treatment can be delayed up to 12 weeks after acute onset of hepatitis to allow for spontaneous resolution (Grade B). 2. Treatment with either standard IFN or peg-INF-a monotherapy for 24 weeks is recommended; however, peg-INF-a is preferable because of its convenience in administration (Grade B) ## Treating special populations ## Treatment of patients with severe liver disease Patients with hepatitis C-compensated cirrhosis need to be treated to prevent complications, especially in the absence of contraindications. Indeed both large cohort studies and metaanalyses have shown that an SVR in patients with advanced fibrosis is associated with a significantly decreased incidence of clinical decompensation and HCC. However, the SVR rates with interferon-based therapy are lower in patients with advanced fibrosis than in those with mild to moderate fibrosis. [bib_ref] Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial..., Manns [/bib_ref] [bib_ref] Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection, Fried [/bib_ref] [bib_ref] PEGASYS international study group. Peginterferon-alpha 2a and ribavirin combination therapy in chronic..., Hadziyannis [/bib_ref] In the study done by Heathcote et al. on patients with compensated cirrhosis, it appeared that the SVR was reached in 30% of those treated with peg-IFN-a 2a alone, [bib_ref] Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis, Heathcote [/bib_ref] and in another study by Helbeling et al. after they added two different doses of RBV (1,000 to 1,200 mg per day or 600 to 800 mg. per day), an SVR was achieved in 52% and 38% of patients respectively. [bib_ref] HCV-related advanced fibrosis/cirrhosis: Randomized controlled trial of pegylated interferon alpha-2a and ribavirin, Helbling [/bib_ref] Dose reduction was necessary in 78% and 57% of subjects, and serious adverse events developed in 14% and 18% respectively of the two groups. Patients with advanced fibrosis usually have low leukocyte and platelet counts secondary to portal hypertension and hypersplenism and need close monitoring for side effects of medication. Medication-related hematological side effects may contraindicate therapy, and it is more evident (vs. frequent) and anticipated in cirrhotic than in non-cirrhotic patients. [bib_ref] Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon..., Schmid [/bib_ref] The use of growth factors might be useful in treating patients with advanced fibrosis, which offers the possibility of treatment with full doses of interferon-based therapy, the eradication of pre-transplantation HCV, and the lower likelihood of post-transplantation infection. [bib_ref] Hepatitis C virus kinetics during and immediately after liver transplantation, Garcia-Retortillo [/bib_ref] [bib_ref] A 10-year experience of liver transplantation for hepatitis C: Analysis of factors..., Ghobrial [/bib_ref] [bib_ref] Long-term outcome of liver transplants for chronic hepatitis C: A 10-year follow-up, Neumann [/bib_ref] Some studies on patients with decompensated cirrhosis preliminary to liver transplantation have been done. In the earliest reported study, done by Crippin et al. in 2002, over half of considered patients were found ineligible because of cytopenias. [bib_ref] A pilot study of the tolerability and efficacy of antiviral therapy in..., Crippin [/bib_ref] In 2007, Iacobellis et al. carried out a controlled study, [bib_ref] Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated..., Iacobellis [/bib_ref] in which peg-IFN-a 2b, was given in doses of 1.0 µg /kg body weight per week, and RBV in doses of 800 to 1000 mg daily for 24 weeks; 44% and 7% of patients with genotypes 2 or 3 and genotypes 1 or 4, respectively developed SVR. Treatment was tolerated in 41% reduced in 39% and discontinued in 20%. Over a 30-month follow-up period, only 23% of patients with an SVR decompensated, while 83% of the control group and 62% of the non-responder group developed decompensation. The conclusion of this study was that in decompensated cirrhotics, HCV clearance by therapy is lifesaving and reduces disease progression. [bib_ref] Hepatitis C virus kinetics during and immediately after liver transplantation, Garcia-Retortillo [/bib_ref] [bib_ref] Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis..., Forns [/bib_ref] [bib_ref] Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients..., Carrion [/bib_ref] Approximately 75% of patients rendered HCV RNA negative at the time of transplantation, remain negative post-transplantation. Surveillance for HCC and portal hypertension should be done regularly, irrespective of SVR achievement, which in turn translates to a decreased rather than an abolished risk when HCV infection has been eradicated. ## Recommendations 1. Compensated cirrhotics should be treated to prevent future complications (Grade A). 2. Treatment should be started carefully, with close monitoring for side-effects, and lower dosages might be used once the patient has been placed on a liver transplant list, aiming for HCV clearance prior to transplantation. However, this approach is applicable in only around 50% of patients, and tolerance is poor, particularly in patients with decompensated cirrhosis (Grade C). 3. Cirrhotics should undergo regular surveillance for HCC, irrespective of SVR (Grade B). ## Post-liver transplantati on recurrence Treatment of established graft lesions with peg-IFN and RBV combination therapy results in a SVR in around 30% of patients. [bib_ref] Hepatitis C virus treatment pre-and post-liver transplantation, Roche [/bib_ref] Most studies initiated therapy at least 6 months post-operatively, in order to optimise patient tolerance and to enable the addition of RBV. [bib_ref] Management of hepatitis C infection after liver transplantation, Alsatie [/bib_ref] Since the first deceased donor liver transplantation (DDLT) took place in 1990, more than 300 DDLTs have been performed in Saudi Arabia. More recently, more than 200 living donor liver transplantations (LDLTs) have been performed in Saudi Arabia. However, there is inadequate documentation of the natural history of HCV re-infection after liver transplantation in the Kingdom and worldwide. [bib_ref] Experience with 122 consecutive liver transplant procedures at king faisal specialist hospital..., Al-Sebayel [/bib_ref] HCV infection recurrence is universal in patients, and tends to be more aggressive when there is detectable HCV RNA at the time of liver transplantation. [bib_ref] Hepatitis C virus kinetics during and immediately after liver transplantation, Garcia-Retortillo [/bib_ref] The course of HCV-related liver disease is accelerated in liver transplant recipients, and almost 6% to 23% of patients develop cirrhosis after a median of 3.4 years. [bib_ref] HCVrelated fibrosis progression following liver transplantation: Increase in recent years, Berenguer [/bib_ref] [bib_ref] Fibrosis progression after liver transplantation in patients with recurrent hepatitis C, Neumann [/bib_ref] [bib_ref] A prospective evaluation of fibrosis progression in patients with recurrent hepatitis C..., Yilmaz [/bib_ref] Successful therapy has been shown to have a positive impact on both graft and patient survival. [bib_ref] Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following..., Berenguer [/bib_ref] Rates of SVR have been lower than those achieved in the non-transplant setting. Possible reasons for this difference include high HCV viral load post-LT, a higher frequency of genotype 1 patients, poor tolerance of treatment after LT, and the need for frequent dose reductions. Treating a patient pre-emptively before the biochemical and histological recurrence of hepatitis seems attractive theoretically, because of low viral levels but the results were not encouraging. The safety efficacy and patient tolerance of peg-IFN-a alone, or associated with RBV, given pre-emptively, have been evaluated in two randomized trials, with SVR rates of 8% [bib_ref] Peginterferon alfa-2a for hepatitis C after liver transplantation: Two randomized, controlled trials, Chalasani [/bib_ref] and 18%, [bib_ref] Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C infected..., Shergill [/bib_ref] respectively. Although peg-IFN-a 2a [bib_ref] Pegylated interferon-alpha2b: Pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention..., Glue [/bib_ref] or 2b [bib_ref] Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C infected..., Shergill [/bib_ref] plus RBV were deemed safe and were reasonably well tolerated, both demonstrated very poor efficacy early post-LT. Only 40% to 60% of patients are candidates because of the high doses of immunosuppressive drugs used, underlying cytopenias, mild renal dysfunction and the presence of other medical problems during this early period post-liver transplantation, all of which can have an impact on efficacy. Monotherapy with standard or pegylated IFN is not advised because of poor SVR rates, as reported in several randomized controlled trials. [bib_ref] Peginterferon alfa-2a for hepatitis C after liver transplantation: Two randomized, controlled trials, Chalasani [/bib_ref] [bib_ref] The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after..., Sheiner [/bib_ref] [bib_ref] Interferon-alpha for prophylaxis of recurrent viral hepatitis C in liver transplant recipients:..., Singh [/bib_ref] Small, uncontrolled, trials of peg-IFN plus RBV report SVR rates of 18% to 19%. The presence of significant fibrosis or portal hypertension one year after transplantation is predictive of rapid disease progression and graft loss. [bib_ref] Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C infected..., Shergill [/bib_ref] Most transplant centers prefer to delay therapy until recurrent disease is confirmed, either by persistently raised ALT levels unexplained by other causes, or by the demonstration of significant fibrosis on liver biopsy (Metavir and IASL stage ≥2 or Batts-Ludwig and Ishak stage ≥3). [bib_ref] A randomized study comparing ribavirin and interferon alfa monotherapy for hepatitis C..., Gane [/bib_ref] The decision to treat should therefore take into consideration the benefit of good SVR rates versus the risks inherent in achieving these (precipitate acute cellular rejection and side effect of therapy). The threshold for performing a liver biopsy should be low, in order to assist treatment decisions, and whenever liver tests worsen during the course of antiviral therapy, to diagnose this, and to use it to further influence treatment decisions. Data on posttransplant HCV genotype 4 treatment is scarce. A single center in Saudi Arabia reported twenty-five patients infected with HCV genotype 4 infections that were treated with peg-IFN-a 2a at a dose of 180 µg/week in addition to 800 mg/ day of RBV (the dose was adjusted within the tolerated range of 400-1,200 mg). Pre-treatment liver biopsies were obtained from all patients. Biochemical and virological markers were assessed before, during, and after treatment. Twenty-two patients (88%) achieved EVR (12 patients tested negative for HCV-RNA). Fifteen (60%) and fourteen patients (56%) achieved an ETR, and a SVR, respectively. Five patients had advanced pre-treatment liver fibrosis. Pre-treatment ALT was elevated in 24 patients (96%). The most common adverse effects were flu-like symptoms and cytopenia. Eighteen patients (72%) required erythropoietin alpha and/or granulocyte-colony stimulating factors as a supportive measure. One patient developed severe rejection complicated by sepsis, renal failure, and death. Other adverse effects included depression, mild rejection, impotence, itching, and vitiligo. [bib_ref] Treatment of genotype 4 hepatitis C recurring after liver transplantation using a..., Al-Hamoudi [/bib_ref] No studies using protease inhibitors in the post-transplant setting have yet been published but are ongoing; however, other drug interactions with immunosuppressants is of major concern and needs to be taken into consideration. [bib_ref] Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus, Garg [/bib_ref] Recommendations 1. Once chronic hepatitis C recurrence has been documented histologically after liver transplantation, cautious treatment by an experienced physician should be started (Grade A). ## Urgent initiation of treatment in patients with significant fibrosis one year after transplantation that predicts rapid disease progression and graft loss (Grade B). 3. Liver biopsy while on treatment is indicated, if liver enzymes worsen, to rule out graft rejection, although it is rare (Grade C). ## Hiv co-infection Approximately 25% of HIV-infected persons in the western world have chronic HCV infection. [bib_ref] Hepatitis C Virus prevalence among patients infected with human immunodeficiency virus: A..., Sherman [/bib_ref] No clear data from Saudi Arabia on treating such group seems to exist. Progression of liver disease is accelerated in patients with HIV-HCV co-infection, in particular in those with a low CD4-positive cell count and impaired immune function. For this reason, early antiretroviral therapy should be considered in patients with HIV HCV co-infection. [bib_ref] Effect of antiretroviral therapy on liver-related mortality in patients with HIV and..., Qurishi [/bib_ref] Patients with HIV should be tested for the presence of HCV by doing anti-HCV and HCV RNA tests, especially in those patients with HIV and unexplained abnormalities in liver function tests and enzymes. The treatment regimen is the same as that for patients without HIV co-infection. The dose of RBV should always be weight-based, and the duration of treatment up to 48 weeks, which could be extended in some genotype 1 patients to 72 weeks. Coadministration of RBV with didanosine (ddI) should be avoided to prevent mitochondrial toxicity and fatal lactic acidosis. Anemia is more pronounced during therapy with IFN plus RBV when the patient is also taking zidovudine (AZT). This suggests that there is a cumulative myelosuppressive effect of IFN plus AZT that further reduces erythropoiesis that could compensate for the acute RBVinduced hemolysis. [bib_ref] Treatment of chronic hepatitis C in HIV/HCV-coinfection with interferon a-2b+ full-course vs...., Bräu [/bib_ref] HIV patients with decompensated cirrhosis should be assessed for liver transplantation if no contraindication exists. ## Recommendations 1. Treatment regimen is the same in HIV co-infected and non-HIV infected patients but the dose of ribavirin should always be weight-based (Grade B). 2. Treating HCV in co-HIV infected patients may require longer treatment duration (72 weeks for genotype 1 and 48 weeks for genotypes 2 and 3) (Grade B). 3. Before using RBV, the physician should make sure that patients are not on AZT, or ddI (Grade C). ## Hbv co-infection In HBV endemic areas, co-infection with HBV and HCV can be seen in people who have a high risk of parenteral infections, such as injection drug users, [bib_ref] Coinfections by HIV, hepatitis B and hepatitis C in imprisoned injecting drug..., Pallas [/bib_ref] patients on hemodialysis, [bib_ref] Prevalence of HBV and HCV dual infection in patients on hemodialysis, Reddy [/bib_ref] patients undergoing organ transplantation [bib_ref] Natural history of hepatitis B and C in renal allograft recipients, Aroldi [/bib_ref] and HIVpositive individuals. [bib_ref] TREAT Asia HIV Observational Database. Hepatitis B and C virus coinfection in..., Zhou [/bib_ref] In patients with HCV-HBV coinfection, HCV is usually the main driver of chronic hepatitis activity. Although it may fluctuate, the HBV DNA level is often low or undetectable. Due to the variety of virological profiles in HBV/HCV co-infection, it is important to assess the dominant virus prior to initiating therapy, and after hepatitis delta virus infection has been excluded. The HCV dominant virus should be treated with peg-IFN-a and RBV following the same rules as mono-infected patients. The SVR rates in this group are broadly comparable or even higher than those in HCV mono-infected patients. [bib_ref] Treatment of HBV/HCV coinfection, Potthoff [/bib_ref] [bib_ref] The HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the..., Potthoff [/bib_ref] There is a potential risk of HBV reactivation during or after HCV clearance. [bib_ref] Late hepatitis B virus relapse in patients co-infected with hepatitis B virus..., Potthoff [/bib_ref] In that case, or if HBV replication is detectable at a significant level, concurrent HBV nucleoside/nucleotide analogue therapy may be indicated. ## Recommendations 1. Treatment regimen is the same as for mono-infected patients (Grade B). 2. Concurrent HBV nucleoside/nucleotide analogue therapy is indicated if there is a significant HBV replication at any stage, pre-, peri-and post-HCV clearance (Grade C). ## Treatment of patients with renal disease Chronic renal disease represents a global health problem. Chronic HCV infection is prevalent in patients with endstage renal disease (ESRD) on hemodialysis (HD), and in renal transplant recipients, with significant impact on morbidity and mortality. The prevalence rates reported in HD patients in Middle Eastern countries are 68% in Saudi Arabia with a range of 14.5% to 94.7%, 26% in Oman, and 80% in Egypt. [bib_ref] Effect of antiretroviral therapy on liver-related mortality in patients with HIV and..., Qurishi [/bib_ref] Patients with HCV infection and chronic renal disease are prone to develop diabetes mellitus [bib_ref] Diabetes mellitus after kidney transplantation: A French multicentre observational study, Kamar [/bib_ref] and denovo glomerulonephritis post-transplantation. Additionally, HCVinfected subjects have a shorter graft survival after renal transplantation, due to increased risk of severe infection and liver disease deterioration. [bib_ref] Recurrent glomerulonephritis after kidney transplantation, Choy [/bib_ref] Accordingly, there is a general belief that these patients should be treated before transplantation. [bib_ref] National Kidney Foundation. National kidney foundation practice guidelines for chronic kidney disease:..., Levey [/bib_ref] Treatment with current standard combination therapy is challenging in patients with ESRD, due to its tolerability. Liver biopsy may be needed before treating those patients, because of the discrepancy between the level of the ALT and the extent of histologic damage that is noted in such patients. [bib_ref] End-stage renal disease and hepatitis C infection: Comparison of alanine aminotransferase levels..., Contreras [/bib_ref] At present, therapy for hepatitis C in patients with ESRD is controversial, and should be considered only in patients waiting for renal transplantation, those with significant liver disease, and minimal comorbid conditions that may affect survival, and in patients with acute hepatitis C. The therapeutic regimen varies with the severity of the kidney disease. Persons with creatinine clearance of more than 60 ml/minute can be treated like those patients without kidney disease. RBV is cleared by the kidneys; therefore hemodialysis patients have been treated with peg-IFN-a monotherapy. [bib_ref] Low-dose peginterferon alfa-2a (40KD) is safe and produces a SVR in patients..., Peck-Radosavljevic [/bib_ref] Since peg-IFN-a 2a is cleared through the liver and peg-IFN-a2b primarily through the kidneys, [bib_ref] Pharmacokinetics of alphaIFN-2b in chronic hepatitis C virus patients undergoing chronic hemodialysis..., Rostaing [/bib_ref] there could be a theoretical accumulation of peg-IFN-a 2b when used in hemodialysis, although hemodialysis does not appear to affect clearance. [bib_ref] Pegylated interferon-alpha2b: Pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention..., Glue [/bib_ref] [bib_ref] Combined antiviral therapy of hepatitis C virus in dialysis patients: Meta-analysis of..., Fabrizi [/bib_ref] Even though this has not been formally compared, no obvious differences are observed clinically. Most experts support the cautious use of peg-IFN-a, adjusting the dose to the level of renal dysfunction. Although the current practice is to administer the full dose of peg-IFN-a, the recommended starting doses for this group are peg-IFN-a 2b, at 1 µg /kg subcutaneously once weekly or peg-IFN-a 2a, 135 µg subcutaneously once weekly. In the absence of RBV, SVR rates are substantially lower, and careful patient selection and side effect management are important. Most studies used a 6-month post therapy SVR as the end point for successful therapy. Overall, 40% of HCV treated patients had an SVR, including 31% for genotype 1, a rate greater than that reported for IFN monotherapy. [bib_ref] Sustained virological response in a predominantly hepatitis C virus genotype 4 infected..., Dahlan [/bib_ref] In a single-center study of Saudi hemodialysis patients, peg-IFN-a 2a was found to be well tolerated, and hematological disturbances appeared to be the most important adverse effects. [bib_ref] Pegylated interferon alpha-2a for treatment of chronic HCV infection in hemodialysis patients:..., Alsaran [/bib_ref] At the end of therapy, a response rate of up to 76%, with 69% sustained response was obtained with Peg-IFN-a 2a therapy. In an earlier study by Huraib et al., HCV RNA became negative in 76% of patients after 12 weeks of treatment, in 88% after 12 months of treatment, and in 71% of the patients, 6 months after completion of therapy. Of 13 patients who underwent liver biopsies after 6 months of therapy, 11 patients (85%) showed histological improvement. [bib_ref] Interferon-alpha in chronic hepatitis C infection in dialysis patients, Huraib [/bib_ref] However, the use of peg-IFN and RBV in dialysis patients is hampered by fairly common side effects. Combination treatment with peg-IFN-a and RBV might be considered by experienced physicians and used with caution in those with creatinine clearance below 50 ml/minutes, [bib_ref] Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients, Bruchfeld [/bib_ref] with individualized RBV dosing of 200-800 mg/day, and titrating the dose based on creatinine clearance and hemoglobin level decline during the first few weeks of therapy. These patients may need substantial hematopoietic support, as suggested by few preliminary studies. ## Hcv post renal transplantation HCV has been recognized as one of the major causes of morbidity and mortality, and indicates a poor prognosis for patient and graft survival in renal transplantation. It is also associated with an increased risk of cirrhosis and its complications. Treatment of chronic HCV infection with peg-IFN-a and RBV in renal transplant recipients is associated with a risk of acute or chronic cellular rejection, resulting in graft loss and reduced patient survival. [bib_ref] Hepatitis C virus and kidney disease, Martin [/bib_ref] Accordingly, routine interferon-based antiviral treatment post-renal transplant should be considered only for selected patients, and those who develop post-transplantation fibrosing cholestatic hepatitis. [bib_ref] Hepatitis C virus-associated fibrosing cholestatic hepatitis after renal transplantation: response to interferon-alpha..., Toth [/bib_ref] Subjects being considered for renal transplantation should be treated for hepatitis C prior to transplantation. MC can be associated with systemic vasculitis, renal impairment and peripheral neuropathy. Treatment of HCV related cryoglobulinemia is challenging, and should be restricted to symptomatic patients in order to avoid unnecessary complications like exacerbation of vasculitis in patients with cryoglobulinemia-associated glomerulonephritis during treatment by interferon. [bib_ref] Interferon-alpha may exacerbate cryoblobulinemiarelated ischemic manifestations: An adverse effect potentially related to..., Cid [/bib_ref] [bib_ref] Cryoglobulinemia related to hepatitis C virus infection, Dore [/bib_ref] Improvement of clinical MC is reported in 50% to 70% of patients receiving antiviral therapy based on IFN-a and RBV, and correlates with the reduction of HCV RNA concentrations. [bib_ref] Sustained response to interferon-alpha or to interferon-alpha plus ribavirin in hepatitis C..., Calleja [/bib_ref] [bib_ref] Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinaemia with ribavirin..., Zuckerman [/bib_ref] Antiviral therapy should thus be considered as the first line therapeutic approach in HCV-infected patients with MCrelated disorders. However, with multi-organ involvement, antiviral therapy may be have to be limited due to the severity of a specific MC-related disorder, treatment failure, side effects or contraindications. In such cases, other therapeutic strategies, such as immuno-suppresion and/or plasmapheresis should be considered. Persons with progressive renal failure generally require treatment with immunosuppressive therapy, steroids and plasmapheresis. [bib_ref] Treatment of hepatitis C-virus-related glomerulonephritis, Kamar [/bib_ref] The role of IFN-based antiviral therapy can be considered for those with mild to moderate kidney disease, or after controlling the acute flare with immunosuppressive agents. [bib_ref] Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment..., Muir [/bib_ref] Most of the studies regarding the treatment of MC are small and uncontrolled, thus there is no evidence-based data on which to base firm recommendations. It is therefore suggested that persons with moderate proteinuria and slowly progressive kidney disease can be managed by means of a regimen of one year of low dosage RBV (200 mg-800 mg/d) in combination with IFN-a or peg-IFN-a, and in most cases this is well tolerated by HCV patients, and leads to SVR and significant improvement of GFR. [bib_ref] Interferon and ribavirin treatment in patients with hepatitis C-associated renal disease and..., Bruchfeld [/bib_ref] Recommendations 1. Liver biopsy should be individualized if the decision is made to treat HCV in a chronic renal disease patient (Grade C). 2. The same standard combination antiviral therapy can be used to treat persons with chronic HCV infection and mild renal disease (GFR >60 mL/minute) (Grade C). 3. Non-hemodialysis patients with severe renal disease can be treated cautiously with reduced doses of both peg-IFN (alpha-2a, 135 µg/week; alpha-2b, 1 µg/kg/week) and RBV (200-800 mg/day) (Grade C). 4. Patients on hemodialysis can safely be treated with peg-IFN-monotherapy (Grade A). 5. Combination treatment with individualized doses of RBV can be considered in selected patients (Grade C). 6. Patients on a renal transplant list should be treated prior to transplantation to avoid the risk of treatment-induced acute graft rejection post-transplantation (Grade B). 7. Treatment is recommended post-renal transplant only in selected patients and those with fibrosing cholestatic hepatitis (Grade C). 8. Patients with cryoglobulinemia and mild to moderate proteinuria or slowly progressive renal disease can be treated with either standard IFN or reduced doses of peg-IFN-a and RBV (Grade C). 9. Patients with cryoglobulinemia and marked proteinuria with evidence of progressive renal disease or an acute flare of cryoglobulinemia can be treated with rituximab, cyclophosphamide plus methylprednisolone, or plasma exchange, followed by interferon-based treatment once the acute process has subsided (Grade C). ## Alcohol and drug abuse Chronic alcohol consumption in patients with chronic hepatitis C is associated with an accelerated fibrosis progression, cirrhosis, and an increased risk of HCC. [bib_ref] VA-HCV-001 Study Group. Alcohol use and treatment of hepatitis C virus: Results..., Anand [/bib_ref] SVR rates are lower in patients with alcohol abuse. [bib_ref] VA-HCV-001 Study Group. Alcohol use and treatment of hepatitis C virus: Results..., Anand [/bib_ref] Patients regularly consuming alcohol should not be excluded from treatment, but should receive counseling to stop their consumption, and additional support to improve regimen-adherence during therapy. Illicit injection drug use is the predominant mode of HCV transmission and little data are available on the treatment of active drug users. Patients should be drug-free for at least 6 months before treatment, and close monitoring by an experienced multidisciplinary team of hepatologists and addictologists to be sure that they will adhere to treatment and regular follow-up visits is necessary. [bib_ref] Prevention and treatment of hepatitis C in injection drug users, Edlin [/bib_ref] Recommendations 1. Alcohol consumption should be strongly discouraged (Grade A). 2. Patients on stable maintenance substitution can be treated for HCV in an interdisciplinary team who need to also consider their slightly reduced SVR-rates when compared to conventional HCV patients, as the treatment should be individualized (Grade B). 3. Illicit drug users should continue receiving support and counseling parallel to HCV treatment (Grade C). ## Treatment of persons with psychiatric illnesses The increasing use of IFN for treating patients with hepatitis C has resulted in recognition of and increasing concern about the psychiatric side effects that can result from treatment. These effects can occur either shortly after beginning IFN therapy, or later, as a result of continued treatment. Patients may report some psychiatric illness during the course of their treatment, such as depression, anxiety, and occasional suicidal ideation, and a high percentage of previous drinkers and drug users tend to relapse. A combination of some or all of these factors would lead to an argument against treating this population. Significant depressive symptoms occur in 21% to 58% of IFN-treated patients. Case studies have demonstrated that pharmacologic interventions are beneficial in reducing iatrogenic psychiatric symptoms, while allowing patients to maintain IFN therapy. [bib_ref] Psychiatric side effects of interferon therapy: Prevalence, proposed mechanisms, and future directions, Trask [/bib_ref] Former or current drug abuse and mental disorders are considered risk factors. In addition, reports of suicide attempts during IFN-a therapy and the risk of reinfection has led to the opinion that the use of IFN-a is contraindicated for patients with a preexisting mental disorder, ongoing opiate abuse, or methadone substitution. As a consequence, most of these patients remain untreated, despite fulfilling the medical criteria for antiviral treatment of chronic hepatitis C. However, a recent prospective controlled trial [bib_ref] Hepatitis C treatment in "difficult-to-treat" psychiatric patients with pegylated interferon-alpha and ribavirin:..., Schaefer [/bib_ref] provided evidence that treatment of chronic hepatitis C infection with peg-IFN-a and RBV is possible in different subgroups of "difficult-to-treat" psychiatric patients, and treating them in interdisciplinary treatment units in order to optimize adherence and response rates and to manage side effects is recommended. Most psychotropic agents are thought to be safe. However, consideration should be given to drug interactions and dose modification in patients with advanced liver disease. ## Recommendations ## Patients with hcv infection and concomitant mental and psychiatric disorders can be considered for treatment using the currently approved regimens (Grade C). ## Treatment of hepatitis c infection in patients with psychiatric disorders should be undertaken only with the support of a multi-disciplinary team that should include psychiatric counseling services prior to therapy (Grade C). ## Hemoglobinopathies Thalassemia major, which requires frequent blood transfusions, and sickle cell disease are among the common hemoglobinopathies that challenge the physician. These patients have higher incidence of anemia and iron accumulation when treated with standard combination Hepatitis C therapy. They can however, be treated with standard combination therapy, but these complications should be carefully managed with growth factors, blood transfusions, and iron chelation therapy when needed. [bib_ref] Thalassemia Clinical Research Network. Safety and efficacy of pegylated interferon alpha-2a and..., Harmatz [/bib_ref] Chronic HCV infection is frequent in individuals with sickle cell anemia (SCA). They have life-long anemia, chronic hemolysis, and at times also have hematological crises, which can worsen the anemia and require chronic transfusions. The HCV antibody positivity is directly related to the number of transfusions given, and on average the prevalence rate in transfused patients is more than 10%. It is known that the combination of iron overload and HCV can lead to a more rapidly progressive liver disease. The treatment of HCV in sickle cell patients poses a challenge to clinicians. A novel approach described by some is the pretreatment of these patients with hydroxyurea to increase fetal hemoglobin, therefore decreasing the severity of RBV-related hemolysis. Individual cases have been successfully treated with a combination of peg-IFN-a and RBV. In one study in Saudi Arabia, fifty-two patients with SCA and HCV were treated over a period of 7 years. All were treated with peg-IFN and a standard dose of RBV for 24 weeks for those with genotype 2 and 3 infections, and for 48 weeks for those with genotype 1 and 4 infections. Only 8 were receiving hydroxyurea at the time of treatment. All tolerated the treatment well and none experienced a decrease in their Hb, which required blood transfusion before, during or after therapy. There were no hematological side effects attributable to RBV at the usual recommended dose. Thirty-seven (71.2%) achieved SVR. The authors showed that patients with SCA and HCV can be treated with peg-IFN and RBV at the usual recommended dose, including those who are not receiving hydroxyurea. The conclusion from this study was that treating HCV infection in SCA patients is considered to be safe and effective, and the response rates in these patients are comparable to those of patients without SCA. [bib_ref] Safety of pegylated interferon and ribavirin therapy for chronic hepatitis C in..., Issa [/bib_ref] In addition, a case series from the western province of Saudi Arabia enrolled 8 patients with chronic HCV infection and SCA, who were treated with peg-IFN-a-2a and RBV for one year. All 8 patients had a cEVR. Seven out of the 8 patients had an ETR of whom, 5 achieved SVR. Hemoglobin concentrations measured at 1, 3, 6, 9, and 12 month intervals during their treatment showed no significant changes from those measured at baseline. The study was able to conclude that treatment of chronic HCV hepatitis in patients with SCA with peg-IFN-a-2a and RBV seems safe and effective. [bib_ref] Successful treatment of chronic hepatitis C virus infection with peginterferon alpha-2a and..., Ayyub [/bib_ref] Recommendations [bib_ref] Hepatitis C virus infection: The new global epidemic, Butt [/bib_ref]. Patients with hemoglobinopathies can be treated with combination therapy, but need careful monitoring for hematologic side effects (Grade C). # Conclusions The SASLT guideline for HCV provides a concise, updated, evidence-based review of the diagnosis and management of chronic HCV infection in Saudi Arabia. This may help to initiate plans to prevent HCV infection in the population, to bring about early and accurate diagnosis of patients, and to facilitate appropriate and timely referrals between primary, secondary, and tertiary care providers. This guideline also aims to help identify gaps in the knowledge and understanding of the incidence of HCV in Saudi Arabia requiring further research. As noted above there is a large population of patients with few therapeutic options, and DAA therapy has become the focus of investigations and once additional information is available, this guideline needs to be updated. # Disclosures Dr. [table] Table 1: Qualitative assays for detection of HCV RNA [/table] [table] Table 2: summarizes the various definitions of virological responses obtained during dual antiviral therapy with peg-IFN and RBV. [/table] [table] Table 3: Summary of management of other adverse effects of Peginterferon/RibavirinSource: CCO Hepatology in practice. Management of Hepatitis C Infection (Feld JJ, Shah H).available at www.inPractice.com. Reproduced with permission [/table]	None	None	This guideline has been approved by the Saudi Association for the Study of Liver diseases and Transplantation and represents the position of the Association. These practice guidelines have been written to assist physicians and other health care providers to aid in the recognition, diagnosis, and management of chronically infected hepatitis C virus (HCV) patients. They are based on a formal review and analysis of published literature on the topic that impact the management of chronic HCV infection, and the experience of the authors in hepatitis C. In addition, various international practice guidelines and consensus documents on management of chronic hepatitis C were considered in the development of these guidelines. The recommendations contained herein suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care related to the disease. Our understanding of the natural history of HCV infection and the potential for therapy of the resultant disease is continuously improving. However, despite the increasing knowledge, areas of uncertainty still exist and therefore clinicians, patients, and public health authorities must continue to make choices on the basis of the evolving evidence. Therefore, these guidelines are intended to be flexible and may be updated periodically as new information becomes available.
11853c345b21160bcc90f51e60fb54014ea360ef	pubmed	The 10 fundamental principles of lay resuscitation	The 10 fundamental principles of lay resuscitation The 10 fundamental principles of lay resuscitation Recommendations by the German Resuscitation CouncilThe 10 fundamental principles of lay resuscitation Recommendations by the German Resuscitation Council EDITORIAL Sudden cardiac death due to out-of-hospital cardiac arrest is the third leading cause of mortality in industrialised nations. [bib_ref] Executive summary: heart disease and stroke statistics -2016 update: a report from..., Mozaffarian [/bib_ref] [bib_ref] KIDS SAVE LIVES: school children education in resuscitation for Europe and the..., B€ Ottiger [/bib_ref] In Europe and in the USA, 800 000 people die every year despite the fact that the emergency medical services initially resuscitate them. The main problem is that emergency medical services take an average of 8 min -and often much more -before they arrive at the scene. The brain tissue, however, commences to die after 3 to 5 min. Therefore, resuscitation procedures initiated by emergency medical services will start too late in the vast majority of cases, and this is the time interval in which lay resuscitation is mandatory. [bib_ref] Effect of bystander cardiopulmonary resuscitation in out-of-hospital cardiac arrest patients in Sweden, Holmberg [/bib_ref] [bib_ref] Bystander efforts and 1-year outcomes in out-of-hospital cardiac arrest, Kragholm [/bib_ref] [bib_ref] Return to work in out-ofhospital cardiac arrest survivors: a nationwide register-based follow-up..., Kragholm [/bib_ref] [bib_ref] Association of national initiatives to improve cardiac arrest management with rates of..., Wissenberg [/bib_ref] Lay people witness an outof-hospital cardiac arrest in more than 60% of incidents, and most of them occur at home. [bib_ref] Establishing the Aus-ROC Australian and New Zealand out-of-hospital cardiac arrest Epistry, Beck [/bib_ref] [bib_ref] Regional variation in out-ofhospital cardiac arrest survival in the United States, Girotra [/bib_ref] [bib_ref] EuReCa ONE-27 Nations, ONE Europe, ONE Registry: a prospective one month analysis..., Grä Sner [/bib_ref] [bib_ref] Outcomes for out-ofhospital cardiac arrests across 7 countries in Asia: the Pan..., Ong [/bib_ref] When lay people start chest compressions and other resuscitation procedures, survival is tripled or quadrupled, and also the probability of good neurological outcome will increase. [bib_ref] Effect of bystander cardiopulmonary resuscitation in out-of-hospital cardiac arrest patients in Sweden, Holmberg [/bib_ref] [bib_ref] Bystander efforts and 1-year outcomes in out-of-hospital cardiac arrest, Kragholm [/bib_ref] [bib_ref] Return to work in out-ofhospital cardiac arrest survivors: a nationwide register-based follow-up..., Kragholm [/bib_ref] [bib_ref] Association of national initiatives to improve cardiac arrest management with rates of..., Wissenberg [/bib_ref] Nevertheless in many countries, the lay resuscitation rate is below 30%, whereas in some countries, the rate is 50, 60 or 80%. [bib_ref] Establishing the Aus-ROC Australian and New Zealand out-of-hospital cardiac arrest Epistry, Beck [/bib_ref] [bib_ref] Regional variation in out-ofhospital cardiac arrest survival in the United States, Girotra [/bib_ref] [bib_ref] EuReCa ONE-27 Nations, ONE Europe, ONE Registry: a prospective one month analysis..., Grä Sner [/bib_ref] [bib_ref] Outcomes for out-ofhospital cardiac arrests across 7 countries in Asia: the Pan..., Ong [/bib_ref] If all countries could achieve these high lay resuscitation rates, we would be able to save several hundred thousands of patients every year worldwide. Using an interdisciplinary and interprofessional Delphi approach, the German Resuscitation Council recommends 10 fundamental principles of resuscitation for lay people. They focus on the most important and most effective issues of lay resuscitation and help in understanding and executing them. These 10 easy and precise principles will help the facilitation of achieving lay resuscitation rates of 50% or more all over the world. They should be distributed as widely as possible. (1) If lay people/bystanders start resuscitation procedures immediately in sudden out-of-hospital cardiac arrest before emergency medical services arrive, this is associated with a three-fold to fourfold increase in probability of a survival in good condition. 4-7 (2) The first measure is CHECK: if someone collapses, you must immediately check whether the person responds to loud speech or shaking of the shoulders and whether the person is breathing normally. If there is no reaction and the person is not breathing at all or is not breathing normally (gasping is not normal breathing!), resuscitation procedures should be started immediately. [bib_ref] Adult basic life support and automated external defibrillation section Collaborators. European Resuscitation..., Perkins [/bib_ref] (3) The second measure is CALL: activate emergency medical services via emergency number [112 in all countries of the European Union and other European countries respectively, 911 in the USA (where 112 is forwarded to 911)]. At best, emergency medical services should be activated by another bystander, to start uninterrupted chest compressions immediately. 12 (4) The third measure is COMPRESS: most important are hard chest compressions. It works like this: the patient is lying on the back, the rescuer kneels down beside the patient's thorax, opens the shirt and puts the heels of his hands, one on the other, in the middle of the bare thorax between the nipples. Now the breastbone is pushed downwards by at least 5 cm and at maximum 6 cm in adults with straight arms and shoulders vertical above the compression point. Immediately after a compression, the pressure to the breastbone must be released completely. Now continuously change between compression and release with a frequency of 100 to 120 hard compressions per minute, that is about two per second. 12 This is -for example -the beat of 'Stayin' alive' from the Bee Gees. Compressions must not be interrupted at all until emergency medical services take over. If possible, the rescuer should be changed every 2 min. 12 (5) CHECK-CALL-COMPRESS: this is a 'civic duty'; everyone should know how to do it, and should do it in case of cardiac arrest. During the first minutes of out-of-hospital cardiac arrest in most cases, adults still have enough oxygen in the blood, so that the interval between collapse and arrival of emergency medical services can be effectively bridged by chest compression only. [bib_ref] Effect of bystander cardiopulmonary resuscitation in out-of-hospital cardiac arrest patients in Sweden, Holmberg [/bib_ref] [bib_ref] Bystander efforts and 1-year outcomes in out-of-hospital cardiac arrest, Kragholm [/bib_ref] [bib_ref] Return to work in out-ofhospital cardiac arrest survivors: a nationwide register-based follow-up..., Kragholm [/bib_ref] [bib_ref] Association of national initiatives to improve cardiac arrest management with rates of..., Wissenberg [/bib_ref] This facilitates oxygen containing blood to flow to the brain, and therefore, will keep the brain alive. (6) Additional VENTILATION by educated laypersons should be performed, if they are able and willing to do so. [bib_ref] Adult basic life support and automated external defibrillation section Collaborators. European Resuscitation..., Perkins [/bib_ref] Ventilation may further increase the chance of survival -in particular if it takes longer until emergency medical services arrive on the scene. Ventilation is of key importance if the cause of the cardiac arrest is oxygen deficiency, which is the case in almost all newborns, infants and children or in drowning. 12 (7) About 25% of patients with an out-of-hospital cardiac arrest may benefit from an automated external defibrillator in addition. [bib_ref] Establishing the Aus-ROC Australian and New Zealand out-of-hospital cardiac arrest Epistry, Beck [/bib_ref] [bib_ref] Regional variation in out-ofhospital cardiac arrest survival in the United States, Girotra [/bib_ref] [bib_ref] EuReCa ONE-27 Nations, ONE Europe, ONE Registry: a prospective one month analysis..., Grä Sner [/bib_ref] [bib_ref] Outcomes for out-ofhospital cardiac arrests across 7 countries in Asia: the Pan..., Ong [/bib_ref] If an automated external defibrillator is available, it should be sent for. But chest compressions must never ever be interrupted to get an automated external defibrillator. [bib_ref] Adult basic life support and automated external defibrillation section Collaborators. European Resuscitation..., Perkins [/bib_ref] At least two lay rescuers must stay with the patient and provide uninterrupted chest compressions until emergency medical services arrive. (8) If a lay rescuer does not know how to perform chest compressions or if he or she is unsure, the dispatcher of the coordination centre of the emergency medical services should guide the lay rescuer to perform chest compression until emergency medical services arrive (telephone resuscitation). [bib_ref] Adult basic life support and automated external defibrillation section Collaborators. European Resuscitation..., Perkins [/bib_ref] Lay people should be able to activate the hands-free facility/loudspeaker on their phone, so that they can be guided by the dispatcher continuously. It is possible that the coordination centre activates via a smart phonebased system -simultaneously to emergency medical services -educated first responders who are nearby. [bib_ref] Adult basic life support and automated external defibrillation section Collaborators. European Resuscitation..., Perkins [/bib_ref] This can further increase the chance of survival. 13 [bib_ref] Regional variation in out-ofhospital cardiac arrest survival in the United States, Girotra [/bib_ref] The recovery position has no role in cardiac arrest. If a person is unconscious and is not breathing or is not breathing normally, he or she is in cardiac arrest and only chest compressions are helpful. [bib_ref] Adult basic life support and automated external defibrillation section Collaborators. European Resuscitation..., Perkins [/bib_ref] If an unconscious person is breathing normally, the recovery position may help to keep the airway open. In this case, normal breathing must always be rechecked carefully and continuously and, if there is any doubt, chest compressions and resuscitation procedures must start immediately. (10) CHECK-CALL-COMPRESS is a 'civic duty' which is essential for survival and must be undertaken urgently, always, and by everyone in suspected cardiac arrest. This must be taught everywhere, and this education must start in schools. [bib_ref] KIDS SAVE LIVES: school children education in resuscitation for Europe and the..., B€ Ottiger [/bib_ref] [bib_ref] Kids Save Lives -ERC position statement on school children education in CPR:..., B€ Ottiger [/bib_ref] [bib_ref] Kids save lives -training school children in cardiopulmonary resuscitation worldwide is now..., B€ Ottiger [/bib_ref] Artificial ventilation and an automated external defibrillator may also help to save lives and further increase survival rates in specific situations. Eur J Anaesthesiol 2018; 35:721-723 Acknowledgements relating to this articleAssistance with the Editorial: none.Financial support and sponsorship: none.Conflicts of interest: none.Comment from the Editor: this Editorial was checked by the editors but was not sent for external peer review. BWB is an Associate Editor of the European Journal of Anaesthesiology.Important links related to this article: www.grc-org.de; www.wiederbelebung.de; www.erc.edu; www.ilcor.org; https://kids-savelives.net/.	None	https://europepmc.org/articles/pmc6133195?pdf=render	Sudden cardiac death due to out-of-hospital cardiac arrest is the third leading cause of mortality in industrialised nations. In Europe and in the USA, 800 000 people die every year despite the fact that the emergency medical services initially resuscitate them. The main problem is that emergency medical services take an average of 8 min – and often much more – before they arrive at the scene. The brain tissue, however, commences to die after 3 to 5 min. Therefore, resuscitation procedures initiated by emergency medical services will start too late in the vast majority of cases, and this is the time interval in which lay resuscitation is mandatory. Lay people witness an outof-hospital cardiac arrest in more than 60% of incidents, and most of them occur at home. When lay people start chest compressions and other resuscitation procedures, survival is tripled or quadrupled, and also the probability of good neurological outcome will increase. Nevertheless in many countries, the lay resuscitation rate is below 30%, whereas in some countries, the rate is 50, 60 or 80%. If all countries could achieve these high lay resuscitation rates, we would be able to save several hundred thousands of patients every year worldwide.
e1dca4cc0103f3abdb2b15e99c4fa7df8d243d6b	pubmed	Antimicrobial use Guidelines for Treatment of Respiratory Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases	Antimicrobial use Guidelines for Treatment of Respiratory Tract Disease in Dogs and Cats: Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases [bib_ref] Antimicrobial drug use in veterinary medicine. ACVIM consensus statement, Morley [/bib_ref] [bib_ref] Guidelines to antimicrobial use in dogs and cats, Guardabassi [/bib_ref] [bib_ref] Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management..., Lionel [/bib_ref] [bib_ref] The management of community-acquired pneumonia in infants and children older than 3..., Bradley [/bib_ref] [bib_ref] Consensus development methods, and their use in clinical guideline development, Murphy [/bib_ref] ## Feline upper respiratory tract disease ## Definitions and causes Feline upper respiratory tract disease is a syndrome consisting of clinical signs that can include serous to mucopurulent ocular and nasal discharges, epistaxis, sneezing, and conjunctivitis. [bib_ref] Nasopharyngeal diseases in cats: A retrospective study of 53 cases (1991-1998), Allen [/bib_ref] [bib_ref] Investigation of nasal disease in the cat-a retrospective study of 77 cases, Henderson [/bib_ref] [bib_ref] Chronic nasal discharge in cats: 75 cases (1993-2004), Demko [/bib_ref] [bib_ref] Feline focus: Update on feline upper respiratory diseases: Introduction and diagnostics, Quimby [/bib_ref] Clinical signs can be acute (≤10 days) or chronic (>10 days). The term "upper respiratory infection (URI)" is reserved for cats with clinical signs of URTD that are directly associated with one or more of the known pathogenic viral, bacterial, or fungal organisms. It is believed that the majority of cats with acute clinical signs of URTD have feline herpesvirus 1 (FHV-1)or calicivirus (FCV)-associated URI. Some of the cats with viral infections can develop secondary bacterial infections. [bib_ref] Factors associated with upper respiratory tract disease caused by feline herpesvirus, feline..., Helps [/bib_ref] [bib_ref] Epidemiologic evaluation of multiple respiratory pathogens in cats in animal shelters, Bannasch [/bib_ref] [bib_ref] Etiological investigation of multiple respiratory infections in cats, Martino [/bib_ref] [bib_ref] Prevalence of selected infectious organisms and comparison of two anatomic sampling sites..., Veir [/bib_ref] Staphylococcus spp., Streptococcus spp., Pasteurella multocida, Escherichia coli, and anaerobes are organisms that are commonly cultured from the surface of the upper respiratory mucous membranes from healthy cats. [bib_ref] Assessment of infectious organisms associated with chronic rhinosinusitis in cats, Johnson [/bib_ref] [bib_ref] Update on feline upper respiratory diseases: Condition-specific recommendations, Quimby [/bib_ref] However, several bacterial species, including Chlamydia felis, Bordetella bronchiseptica, Streptococcus canis, Streptococcus equi subspp. zooepidemicus, and Mycoplasma spp., have been isolated or detected by molecular techniques such as the polymerase chain reaction (PCR) from cats with URTD without the presence of pathogenic viruses, suggesting a primary role in some cats. [bib_ref] Assessment of infectious organisms associated with chronic rhinosinusitis in cats, Johnson [/bib_ref] [bib_ref] Bordetella bronchiseptica infections in cats, Welsh [/bib_ref] [bib_ref] Prevalence and risk factors for feline Bordetella bro nchiseptica infection, Binns [/bib_ref] [bib_ref] Evaluation of pradofloxacin for the treatment of feline rhinitis, Spindel [/bib_ref] [bib_ref] Efficacy of pradofloxacin in cats with feline upper respiratory tract disease due..., Hartmann [/bib_ref] [bib_ref] Histologic and molecular correlation in shelter cats with acute upper respiratory infection, Burns [/bib_ref] The presence of purulent or mucopurulent nasal or ocular discharges might increase the suspicion that primary or secondary bacterial infection is present, but there is no definite proof of this association because viral or fungal agents can also induce mucopurulent discharges. ## Diagnosis of acute bacterial upper respiratory infection (≤10 days duration) For cats with signs of URTD of ≤10 days' duration, a thorough history should evaluate in particular the vaccination status, the presence or exposure to other cats, whether cats are allowed outdoors, contact with a shelter, kennel or veterinary hospital, health status of in-contact cats, health status of in-contact humans, exposure to dogs that might be boarded or have recently come from a shelter (possible increased risk of infection by B. bronchiseptica), likelihood of foreign body contact (including house plants), and a history of recent stress which is thought to reactivate FHV-1 infection in some cats. [bib_ref] Update on feline upper respiratory diseases: Condition-specific recommendations, Quimby [/bib_ref] Careful ocular, oral, and otic examination to evaluate for other primary problems is indicated. Thoracic auscultation should be performed to evaluate for evidence of concurrent lower respiratory disease. The Working Group recommends that all cats with suspected bacterial URI be evaluated for the presence of feline leukemia virus antigen and feline immunodeficiency virus antibodies in serum in accordance with the American Association of Feline Practitioners Retrovirus Panel Report. [bib_ref] Feline retrovirus management guidelines, Levy [/bib_ref] Although these retroviruses do not cause respiratory disease directly, both have been associated with lymphoma (which could cause URTD) and both can cause immunosuppression that could predispose to severe viral and bacterial URIs. Many diagnostic tests could be performed to assess for evidence of primary or secondary bacterial URI (See the Diagnosis of Chronic Bacterial Upper Respiratory Infection (>10 Days of Duration) section). It is the opinion of the Working Group that there is limited benefit to performing cytology of nasal discharges to diagnose bacterial infection and guide the antimicrobial choice. If nasal discharges are serous and lack a mucopurulent or purulent component, the Working Group believes that antimicrobial treatment is not recommended because of the likelihood of uncomplicated viral infection. If acute bacterial URI is suspected based on purulent or mucopurulent discharge, in the absence of evidence of the cause of URTD based on history and physical examination findings, the Working Group recommends a period of observation without immediate use of an antimicrobial drug. This might vary in duration based on other clinical findings (See the Treatment of Suspected Acute Bacterial Upper Respiratory Infection section). In humans, antimicrobial treatment is recommended only if clinical signs have not improved after 10 days or have worsened after 5-7 days. [bib_ref] Guidelines for the use of antimicrobials in acute upper respiratory tract infections, Wong [/bib_ref] A more extensive workup for an underlying cause can be postponed until after the period of observation, up to 10 days after the onset of clinical signs if the cat develops chronic URTD. Aerobic bacterial culture and antimicrobial susceptibility test results from nasal discharges are difficult to interpret because (1) some pathogenic organisms (eg, Chlamydia and Mycoplasma) cannot be cultured on standard laboratory media and (2) positive culture might not be associated with bacterial infection due to growth of commensal organisms. Thus, the Working Group recommends that aerobic bacterial culture and antimicrobial susceptibility testing not be performed on nasal secretions collected from cats with acute bacterial URI. Results from Mycoplasma spp. culture (or PCR assay), and molecular diagnostic procedures for FHV-1, FCV, and C. felis are difficult to interpret in individual cats. Mycoplasma spp., FHV-1, FCV, and C. felis can be grown or amplified by molecular assays from both healthy or diseased cats, and vaccine strains of B. bronchiseptica, FHV-1, FCV, and C. felis can be detected by molecular diagnostic assays for varying periods of time depending on the vaccine type. [bib_ref] Results of molecular diagnostic assays targeting feline herpesvirus-1 and feline calicivirus in..., Maggs [/bib_ref] When positive, molecular diagnostic tests for FCV, FHV-1, or C. felis might be useful to support a diagnosis of infection in the presence of suggestive clinical signs and the absence of a history of recent vaccination. However, if an outbreak of URI is suspected in populations of cats like those in shelters, catteries, boarding facilities, or multiple cat households, these assays also might be indicated, particularly if severe clinical disease is occurring. If possible, several affected cats should be evaluated to increase sensitivity and positive predictive value of the assay results. ## Treatment of suspected acute bacterial upper respiratory infection Some cats with mucopurulent nasal discharge maintain normal appetite and attitude and experience spontaneous resolution of illness within 10 days without antimicrobial treatment. The Working Group recommends that antimicrobial treatment be considered within the 10-day observation period only if fever, lethargy, or anorexia is present concurrently with mucopurulent nasal discharge. If antimicrobial treatment is chosen for a cat with acute bacterial URI, the optimal duration of treatment is unknown and so this recommendation is based on experiences of the Working Group members that are clinicians. The Working Group recommends empirical administration of doxycycline [fig_ref] Table 1: First-line antimicrobial options for bacterial respiratory infections in the dog and cat [/fig_ref] for 7-10 days to cats with suspected acute bacterial URI as the first-line antimicrobial option. [bib_ref] Comparison of the polymerase chain reaction and culture for the detection of..., Sykes [/bib_ref] The Working Group believes that doxycycline is a good first choice because it is well tolerated by cats; most B. bronchiseptica isolates from cats are susceptible to doxycycline in vitro (by unapproved standards for testing), despite resistance to other agents such as beta-lactams and sulfonamides, [bib_ref] Bordetella bronchiseptica infection in cats. ABCD guidelines on prevention and management, Egberink [/bib_ref] [bib_ref] Antimicrobial susceptibility of Pasteurella multocida and Bordetella bronchiseptica from dogs and cats..., Schwarz [/bib_ref] [bib_ref] Antimicrobial susceptibility of canine Bordetella bronchiseptica isolates, Speakman [/bib_ref] and doxycycline is effective in vivo for the treatment of cats with C. felis infections, [bib_ref] Comparison of the polymerase chain reaction and culture for the detection of..., Sykes [/bib_ref] [bib_ref] Controlled study of the efficacy of clavulanic acid-potentiated amoxycillin in the treatment..., Sturgess [/bib_ref] [bib_ref] Efficacy of azithromycin for the treatment of feline chlamydophilosis, Owen [/bib_ref] [bib_ref] The clinical efficacy of topical and systemic therapy for the treatment of..., Sparkes [/bib_ref] and Mycoplasma spp. infections. [bib_ref] Randomized masked controlled clinical trial to compare 7-day and 14-day course length..., Kompare [/bib_ref] Doxycycline is also effective for the treatment of a variety of chlamydial and mycoplasma infections in cats and other Minocycline has been substituted in some situations when doxycycline is unavailable or of greater expense. See [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref] for dose recommendations. b Culture and antimicrobial susceptibility testing = C&S. c For animals with clinical findings of life-threatening disease, the consensus of the Working Group was to administer dual agent treatment parenterally with the potential for de-escalation of treatment and switch to oral drugs based on clinical responses and culture and antimicrobial susceptibility testing. See [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref] for dose differences by route and the text for further recommendations for oral or parenteral administration. d Enrofloxacin is often chosen as there is a veterinary product for parenteral administration and the drug has a wide spectrum against Gram-negative organisms and Mycoplasma spp. There are other drugs with a wide spectrum against Gram-negative bacteria that can be substituted based on antimicrobial susceptibility testing or clinician preference. See [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref] for a discussion of how to administer enrofloxacin and for other drug choices. Enrofloxacin should be administered at ≤5 mg/kg/24 h in cats to lessen risk of retinal degeneration. One reviewer noted that IV ciprofloxacin could also be used; however, the other reviewers (94%) believed that enrofloxacin should be used as labeled for veterinary use. e When enrofloxacin or other drugs with Gram-negative activity are administered parenterally to animals with life-threatening disease, concurrent administration of other parenteral drugs with activity against anaerobes and Gram-positive bacteria is recommended. Common choices include ampicillin or clindamycin. Which of these drugs to choose will depend on the most likely infectious agent suspected and historical antimicrobial resistance in the geographical region. For example, Enterococcus spp. and Streptococcus spp. are more likely to be susceptible to a penicillin, and Toxoplasma gondii and Neospora caninum are more likely to be susceptible to clindamycin. Cephalosporins are generally not recommended for the treatment of anaerobic infections because of unpredictable activity and lack of evidence for their efficacy. Please see the text for further discussion of other potential drug choices or combinations. mammalian host species. It also has activity against many opportunistic bacterial pathogens that are components of the normal microbiota of the respiratory tract. Of the 17 reviewers, 16 (94%) agreed with this Working Group recommendation and 1 disagreed because there is no breakpoint data for this antimicrobial for B. bronchiseptica or other bacteria in cats and there are no pharmacokinetics, controlled clinical trials, susceptibility data, or pharmacodynamic data on which to base the recommendation. Due to delayed esophageal transit time for capsules and tablets, cats are prone to drug-induced esophagitis and resultant esophageal strictures. [bib_ref] Evaluation of esophageal transit of tablets and capsules in 30 cats, Westfall [/bib_ref] [bib_ref] A comparative study evaluating the esophageal transit time of eight healthy cats..., Bennett [/bib_ref] Although any table or capsule could cause this problem, doxycycline hyclate tablets and clindamycin hydrochloride capsules have been reported most frequently to cause problems. [bib_ref] Suspected doxycycline-induced esophagitis and esophageal stricture formation in three cats, Melendez [/bib_ref] [bib_ref] Oesophageal strictures in cats associated with doxycycline therapy, German [/bib_ref] [bib_ref] Suspected clindamycin-associated oesophageal injury in cats: 5 cases, Beatty [/bib_ref] Thus, tablets and capsules should be given coated with a lubricating substance, followed by water, administered in a pill treat, concurrently with at least 2 mL of a liquid, or followed by a small amount of food. [bib_ref] A comparative study evaluating the esophageal transit time of eight healthy cats..., Bennett [/bib_ref] Doxycycline formulated and approved for use in cats is available in some countries and should be used if available. The use of compounded suspensions of doxycycline should be avoided because marketing of such formulations is in violation with regulations in some countries, including the USA. In addition, compounded aqueous-based formulations of doxycycline are associated with a variable loss of activity beyond 7 days. [bib_ref] Doxycycline concentration over time after storage in a compounded veterinary preparation, Papich [/bib_ref] Minocycline pharmacokinetics are now available for cats and this tetracycline should be evaluated further for efficacy against infectious disease agents in cats. [bib_ref] Efficacy of amoxicillin and azithromycin for the empirical treatment of cats with..., Tynan [/bib_ref] The Working Group considers amoxicillin to be an acceptable alternate first-line option for the treatment of acute bacterial URI when C. felis and Mycoplasma are not highly suspected. This is based on evidence that cats administered amoxicillin for the treatment of suspected secondary bacterial infections in shelter cats with acute bacterial URI often have apparent clinical responses. [bib_ref] Evaluation of pradofloxacin for the treatment of feline rhinitis, Spindel [/bib_ref] Cats administered amoxicillin and clavulanate potassium (amoxicillin-clavulanate) had apparent clinical responses in 1 study of shelter cats with acute bacterial URI and so this drug also could be considered as an alternative to doxycycline in regions where a high prevalence of beta-lactamase-producing organisms has been identified (eg, based on regional antibiograms). [bib_ref] Comparison of the efficacy of amoxicillin-clavulanic acid, cefovecin, and doxycycline in the..., Litster [/bib_ref] In 1 study of shelter cats with suspected bacterial URI, the injectable cephalosporin, cefovecin was inferior to doxycycline or amoxicillin-clavulanate. [bib_ref] Comparison of the efficacy of amoxicillin-clavulanic acid, cefovecin, and doxycycline in the..., Litster [/bib_ref] One limitation of this study was the lack of a negative control group. [bib_ref] Comparison of the efficacy of amoxicillin-clavulanic acid, cefovecin, and doxycycline in the..., Litster [/bib_ref] Thus, it is the opinion of the Working Group that more evidence is needed before cefovecin can be recommended for the treatment of bacterial URI in cats [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref]. ## Monitoring treatment of suspected acute bacterial upper respiratory infection Most cats with this syndrome will rapidly improve within 10 days with or without antimicrobial administration. If an antimicrobial drug was prescribed and was ineffective and bacterial infection is still suspected after the first 7-10 days of administration, the Working Group recommends that a more extensive diagnostic workup should be offered to the owner. An alternate antimicrobial agent with a different spectrum should be considered only if the owner refuses a diagnostic workup and careful re-evaluation of the cat still supports the presence of a bacterial infection without an obvious underlying cause (see the Diagnosis of acute bacterial Upper Respiratory Infection section). Longer duration of treatment might be required to clear the carrier state of C. felis. [bib_ref] Efficacy of azithromycin for the treatment of feline chlamydophilosis, Owen [/bib_ref] [bib_ref] The clinical efficacy of topical and systemic therapy for the treatment of..., Sparkes [/bib_ref] Diagnosis of Chronic Bacterial Upper Respiratory Infection (>10 Days of Duration) A more extensive diagnostic workup should be considered for cats with URTD of >10 days of duration, particularly in the face of therapeutic failure after treatment of suspected acute bacterial URI as described. The diagnostic workup should be performed to evaluate for other causes including Cuterebra spp. and fungal diseases as well as noninfectious causes of URTD including allergic diseases, neoplasia, foreign bodies, nasopharyngeal stenosis, oronasal fistulas, nasopharyngeal polyps, and trauma. [bib_ref] Nasopharyngeal diseases in cats: A retrospective study of 53 cases (1991-1998), Allen [/bib_ref] [bib_ref] Investigation of nasal disease in the cat-a retrospective study of 77 cases, Henderson [/bib_ref] [bib_ref] Chronic nasal discharge in cats: 75 cases (1993-2004), Demko [/bib_ref] [bib_ref] Feline focus: Update on feline upper respiratory diseases: Introduction and diagnostics, Quimby [/bib_ref] Referral to a specialist is recommended if advanced imaging or rhinoscopy capabilities are not available. If other treatable causes of URTD are not identified, The Working Group recommends that nasal lavage or brushings (for cytology, aerobic bacterial culture and antimicrobial susceptibility testing, Mycoplasma spp. culture or PCR, and fungal culture) and nasal tissue biopsy for histopathological examination with or without cultures (if not evaluated by lavage) should be performed. Of the 17 reviewers, 16 (94%) agreed with the recommendation and 1 disagreed and stated that the results of nasal tissue cultures in cats with chronic URTD are always impossible to interpret. In 1 study, nasal lavage specimens gave a higher sensitivity for bacterial growth than tissue biopsy specimens. [bib_ref] Effect of sample collection methodology on nasal culture results in cats, Johnson [/bib_ref] However, as discussed previously, bacterial culture results can be difficult to impossible to interpret as bacteria can be cultured from the nasal cavity of healthy cats. For example, multidrug-resistant bacteria can colonize and be grown from the nasal passages in the absence of infection. The purpose of culture and susceptibility testing in cats with chronic bacterial URI is usually to identify the antimicrobial susceptibility of severe secondary bacterial infections that occur secondary to an untreatable underlying cause (eg, idiopathic inflammatory rhinitis). Antimicrobial treatment of these cats might provide relief from severe clinical signs, but it should be recognized that these cats will continue to be predisposed to opportunistic infections, often with antimicrobial-resistant bacteria. Therefore, use of antimicrobials should be limited to those cats with severe clinical signs. The Working Group recommends consultation with an internal medicine specialist with expertise in infectious disease, clinical pharmacologist, or clinical microbiologist before treating multidrug-resistant organisms (resistant to ≥3 drug classes) isolated from nasal lavage cultures. ## Treatment of chronic feline bacterial upper respiratory infection In cats with chronic bacterial URI, the antimicrobial agent should be selected on the basis of culture and antimicrobial susceptibility test results if available. If an organism with resistance against a previously prescribed antimicrobial agent is identified and the clinical response is poor, an alternate drug should be substituted [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref]. Pradofloxacin is a veterinary fluoroquinolone that is approved in some countries for the treatment of acute infections of the upper respiratory tract caused by susceptible strains of P. multocida, E. coli and the Staphylococcus intermedius group. [bib_ref] Pharmacokinetics, pharmacodynamics and therapeutics of pradofloxacin in the dog and cat, Lees [/bib_ref] In 1 study of shelter cats, a pradofloxacin protocol was equivalent to amoxicillin for the treatment of suspected bacterial URI. [bib_ref] Evaluation of pradofloxacin for the treatment of feline rhinitis, Spindel [/bib_ref] The other veterinary fluoroquinolones (enrofloxacin, orbifloxacin, and marbofloxacin [ [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref] have also been used by veterinarians to treat suspected feline bacterial URI. [bib_ref] Comparative field evaluation of marbofloxacin tablets in the treatment of feline upper..., Dossin [/bib_ref] In the first study, all cats were administered an antibiotic; 20 a placebo control study evaluating pradofloxacin for the treatment of bacterial URI in cats has not been published to our knowledge. Because of concerns about the emergence of, and animal and public health consequences of, resistance to fluoroquinolones and third-generation cephalosporins, the Working Group recommends that these drugs should be reserved for situations where culture and susceptibility results indicate potential efficacy and when other antimicrobial agents (eg, doxycycline, amoxicillin) are not viable options. Moreover, there is no clinical evidence indicating that fluoroquinolones and third-generation cephalosporins are superior to doxycycline and amoxicillin in the treatment of chronic bacterial URI in cats. Although azithromycin pharmacokinetics have been determined in cats, 48,49 azithromycin and amoxicillin protocols for the treatment of suspected bacterial upper respiratory tract infections in shelter cats were equivalent in 1 study where all cats were administered an antibiotic. 43 Azithromycin is also not as efficacious as doxycycline for the treatment of feline ocular chlamydiosis in a study in which all cats were administered an antibiotic. [bib_ref] Efficacy of azithromycin for the treatment of feline chlamydophilosis, Owen [/bib_ref] Thus, the Working Group recommends that azithromycin should be reserved for situations when chlamydiosis is not likely and when other antimicrobial agents (eg, doxycycline, amoxicillin) are not viable options. Of the 17 reviewers, 16 (94%) agreed with this recommendation. One reviewer commented that there is evidence that azithromycin treatment in people produces therapeutic benefits for infections of the respiratory tract via mechanisms that are not attributed to the antibacterial properties. [bib_ref] Azithromycin: Mechanisms of action and their relevance for clinical applications, Parnham [/bib_ref] However, at this time, the Working Group does not advocate for the administration of azithromycin to animals only for its disease-modifying properties or immunomodulatory effects. If Pseudomonas aeruginosa is isolated in pure or nearly pure culture and believed to be the cause of a secondary infection, extensive flushing of the nasal cavity under anesthesia should be performed to remove loculated secretions. Although use of drug combinations (such as a fluoroquinolone combined with a beta-lactam [ [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref] has been recommended to treat P. aeruginosa infections because of the tendency of this organism to rapidly develop resistance, monotherapy with a fluoroquinolone is accepted for the treatment of P. aeruginosa otitis/osteomyelitis in human patients, unless resistance is encountered. [bib_ref] Malignant external otitis. Comparison of monotherapy vs. combination therapy, Meyers [/bib_ref] [bib_ref] Predicting antimicrobial resistance in invasive pneumococcal infections, Hollis [/bib_ref] Regardless of whether monotherapy or combination treatment is chosen, the Working Group recommends that antimicrobials be selected on the basis of culture and susceptibility testing and that a clinical microbiologist, clinical pharmacologist, or internal medicine specialist with expertise in infectious disease be consulted before initiating treatment. Of the 17 reviewers, 15 (88%) agreed with this recommendation and 2 were neutral (12%). Optimal duration of the treatment of chronic bacterial URI in cats with no other underlying disease is unknown. The consensus of the Working Group was to administer the chosen antimicrobial for at least 7 days and if the drug is tolerated and showing a positive clinical effect, the drug should be continued as long as there is progressive clinical improvement and for at least 1 week past clinical resolution of nasal disease or plateau in response to treatment. However, the Working Group acknowledges that stopping treatment sooner might also be effective in some cats. If mucopurulent discharge with or without sneezing recurs after treatment in a cat that has had a thorough diagnostic evaluation, the previously effective antimicrobial agent is usually prescribed empirically again, for at least 7-10 days, to assess for the treatment response. The Working Group recommends avoidance of repeated empirical treatment on a regular basis whenever possible. However, some cats with suspected chronic bacterial URI require such an approach to lessen clinical signs of disease even though clinical cure is never achieved. The Working Group believes there is currently no known optimal protocol for repeated empirical treatment for chronic URI in cats. Evidence from the human infectious disease literature shows organisms cultured from patients within 3 months of primary treatment had a higher likelihood of resistance to the treatment drug or class used. As such, some respiratory treatment guidelines in human medicine recommend a different drug (or drug class) if used within 3 months of the initial treatment. 52 Until further data are available, the Working Group recommends use of the previously effective antimicrobial drug with switch to a different drug class or a more active drug within the class if treatment is ineffective after a minimum of 48 hours. Collection of specimens for culture and susceptibility is recommended if neither of these approaches is successful. There is no evidence to support the use of topical (intranasal) antiseptic or antimicrobial administration for the treatment of acute or chronic bacterial URI. However, topical administration of 0.9% saline solution is believed to have has a mild mucolytic effect and might be effective in clearing nasal secretions in some cats. Many cats with chronic URTD have complete diagnostic evaluations performed and the only finding is lymphocytic-plasmacytic or mixed inflammation identified on histopathological evaluation without a known underlying cause (idiopathic feline rhinosinusitis). Although chronic infection with respiratory viruses has been speculated to play a role in this disease, the true underlying etiology remains enigmatic. [bib_ref] Assessment of infectious organisms associated with chronic rhinosinusitis in cats, Johnson [/bib_ref] [bib_ref] Histologic and molecular correlation in shelter cats with acute upper respiratory infection, Burns [/bib_ref] Although there was no association among Bartonella spp. test results among cats with and without URTD in shelters in 1 study or with chronic rhinosinusitis in another study, additional research is required to ascertain the role of Bartonella spp. in feline chronic rhinosinusitis. [bib_ref] Prevalence of Bartonella spp. DNA in conjunctival cells collected from shelter cats..., Mcinnis [/bib_ref] ,54 ## Monitoring treatment of chronic bacterial upper respiratory infection Because results of bacterial culture and antimicrobial susceptibility testing from specimens collected from the nasal cavity are difficult to interpret, monitoring the efficacy of treatment of cats with suspected chronic bacterial URI is usually based on clinical signs of disease. ## Canine infectious respiratory disease complex ## Definition and causes The clinical syndrome associated with CIRDC is generally characterized by an acute onset of cough with or without sneezing. Nasal and ocular discharges can also occur depending on the infectious agent that is involved. Fever is uncommon but might be present. The viruses that have been implicated include canine adenovirus 2, canine distemper virus, canine respiratory coronavirus, canine influenza viruses, canine herpesvirus, canine pneumovirus, and canine parainfluenza virus. [bib_ref] Etiologic study of upper respiratory infections of household dogs, Mochizuki [/bib_ref] [bib_ref] Detection of coronavirus in cases of tracheobronchitis in dogs: A retrospective study..., Ellis [/bib_ref] [bib_ref] Canine respiratory coronavirus: An emerging pathogen in the canine infectious respiratory disease..., Erles [/bib_ref] [bib_ref] New and emerging pathogens in canine infectious respiratory disease, Priestnall [/bib_ref] Bacteria implicated as primary pathogens in this complex include B. bronchiseptica, S. equi subspecies zooepidemicus, and Mycoplasma spp. [bib_ref] Etiologic study of upper respiratory infections of household dogs, Mochizuki [/bib_ref] [bib_ref] New and emerging pathogens in canine infectious respiratory disease, Priestnall [/bib_ref] [bib_ref] Role of Bordetella bronchiseptica in infectious tracheobronchitis in dogs, Keil [/bib_ref] [bib_ref] The association of Streptococcus equi subsp. zooepidemicus with canine infectious respiratory disease, Chalker [/bib_ref] [bib_ref] Mycoplasmas associated with canine infectious respiratory disease, Chalker [/bib_ref] [bib_ref] Streptococcus zooepidemicus: An emerging canine pathogen, Priestnall [/bib_ref] Dogs with canine distemper virus infection often have diarrhea and can have mucopurulent ocular and nasal discharge that might be confused with mucopurulent discharges caused by primary bacterial pathogens. Because of its significance to the health of other dogs and for prognosis, the possibility of underlying distemper virus infection should always be considered in young dogs with mucopurulent ocular and nasal discharges, even when other signs of distemper are absent. Infection with S. equi subspecies zooepidemicus should be suspected if cases of acute hemorrhagic pneumonia or sudden death are reported. [bib_ref] A clonal outbreak of acute fatal hemorrhagic pneumonia in intensively housed (shelter)..., Pesavento [/bib_ref] Co-infections with multiple respiratory pathogens are common in dogs with CIRDC and each of the agents can be harbored by dogs with no clinical signs. Vaccines are available for some of the causes of CIRDC in some countries and include canine parainfluenza virus, canine adenovirus 2, canine distemper virus, H3N8 canine influenza virus, H3N2 influenza virus, and B. bronchiseptica. With the exception of canine distemper virus, the immunity induced by vaccination does not prevent colonization and shedding of the organisms and clinical signs of disease can develop in vaccinated dogs (2011 AAHA Canine Vaccination Guidelines; www.aahanet. org). However, morbidity is generally decreased in vaccinates compared with dogs that are not vaccinated when exposed to the pathogens. ## Diagnosis of bacterial causes of cirdc A thorough history and physical examination should be performed on all dogs with suspected CIRDC. Many diagnostic tests could be performed to assess for evidence of primary or secondary bacterial CIRDC. It is the opinion of the Working Group that there is limited benefit to performing cytology of nasal discharges to diagnose bacterial infection and guide the antimicrobial choice. Aerobic bacterial culture and antimicrobial susceptibility testing, Mycoplasma spp. culture (or PCR assay), and molecular diagnostic procedures for canine parainfluenza virus, canine adenovirus 2, canine distemper virus, canine respiratory coronavirus, canine influenza viruses, canine herpesvirus, pneumovirus, B. bronchiseptica, and Mycoplasma spp. (or M. cynos alone) can be performed. However, each of these organisms can be grown or detected by molecular methods from healthy and diseased dogs and vaccine strains of the organisms can be amplified by molecular diagnostic assays. [bib_ref] Adenovirus 2, Bordetella bronchiseptica, and parainfluenza molecular diagnostic assay results in puppies..., Ruch-Galle [/bib_ref] Molecular assays might also be of limited sensitivity by the time dogs are presented for examination because viral shedding rates tend to peak very early in disease. Thus, these tests are generally not recommended by the Working Group for single cases with typical clinical presentations, no evidence of pneumonia, and when high-risk populations (eg, breeding kennels) are not involved. If an outbreak of CIRDC is suspected in populations of dogs like those in shelters, breeding kennels, boarding facilities, or multiple dog households, molecular assays might be indicated, along with bacterial culture and serological testing for viral pathogens, particularly if poor response to treatment or severe clinical disease is occurring. If possible, specimens from respiratory discharges should be collected from several affected dogs and assayed individually to increase sensitivity and positive predictive value and necropsy should be performed if there are fatalities. If clinical signs consistent with pneumonia develop, a more extensive diagnostic evaluation is indicated (See the Pneumonia in Dogs and Cats section). ## Treatment of suspected bacterial canine infectious respiratory disease complex The majority of cases of CIRDC are currently believed to be viral in etiology and so antimicrobial administration is often not indicated. Most dogs with clinical signs of CIRDC including mucopurulent nasal discharge maintain normal appetite and attitude and might resolve spontaneously within 10 days without antimicrobial treatment. The Working Group recommends that antimicrobial treatment be considered within the 10-day observation period only if fever, lethargy, or inappetence is present together with mucopurulent discharges. If bacterial CIRDC is suspected in dogs with mucopurulent nasal discharge, fever, lethargy, or inappetence but no clinical evidence of pneumonia (eg, crackles or wheezes on thoracic auscultation), the Working Group recommends administration of doxycycline empirically for 7-10 days as the first-line antimicrobial option [fig_ref] Table 1: First-line antimicrobial options for bacterial respiratory infections in the dog and cat [/fig_ref]. Doxycycline is believed to have clinical activity against Mycoplasma. As in cats, doxycycline is well tolerated by dogs and isolates of B. bronchiseptica from dogs are typically susceptible in vitro to doxycycline. [bib_ref] Role of Bordetella bronchiseptica in infectious tracheobronchitis in dogs, Keil [/bib_ref] However, the susceptibility testing studies used an unapproved standard. Optimal duration of treatment for dogs with bacterial causes of CIRDC is unknown and the 7-10-day recommendation was based on the clinical experiences of the Working Group. Of the 17 reviewers, 15 (88%) agreed with this recommendation and 2 disagreed. One reviewer stated that if there is no evidence of pneumonia and the case is not at high risk of pneumonia (brachycephalic, collapsing airways; immunosuppressed), antimicrobial treatment is not indicated at all. The other dissenting reviewer disagreed with the recommendation because there is no breakpoint data for doxycycline for B. bronchiseptica or Mycoplasma spp. in dogs and so whether the agents are truly susceptible to the drug is unknown. Additional antimicrobial susceptibility data for secondary bacterial agents like Pasteurella spp., Streptococcus spp., Staphylococcus spp., and anaerobes are needed. For Pasteurella spp. and Streptococcus spp., amoxicillin is usually adequate, whereas strains of Staphylococcus spp. are usually susceptible in vitro to amoxicillin-clavulanic acid. Thus, these antimicrobials are considered by the Working Group to be alternate first-line antimicrobials for the treatment of secondary bacterial infections in this syndrome if treatment with doxycycline fails or is not possible (eg, it is not well tolerated). However, it should also be recognized that some B. bronchiseptica isolates and all mycoplasmas are resistant to amoxicillin-clavulanate. Of the 17 reviewers, 13 (77%) agreed, 3 reviewers (18%) disagreed, and 1 reviewer was neutral (6%). Reviewers that provided negative comments were concerned that because the concentrations of beta-lactams in bronchial secretions are unknown for dogs and cats, the use of these drugs could be ineffective if tracheobronchitis without pneumonia was present. Another concern was that use of amoxicillin-clavulanate more likely selects for resistance phenotypes of clinical concern (eg, methicillin resistance in staphylococci). Inhalational aminoglycoside treatment has been anecdotally mentioned as beneficial for the management of dogs with B. bronchiseptica-associated CIRDC. However, in the absence of controlled studies for safety or efficacy, the Working Group does not recommend this treatment protocol for dogs with suspected bacterial CIRDC. ## Monitoring treatment of bacterial canine infectious respiratory disease complex This disease syndrome is usually self-limited or responds quickly to antimicrobial treatment. Thus, primary or repeated diagnostic tests are rarely needed unless pneumonia is suspected. Bacterial culture is not recommended after successful treatment. Canine infectious respiratory disease complex has not been associated with chronic upper respiratory disease in the dogs. Most dogs with bacterial CIRDC have clinical signs that resolve quickly and so if the first drug chosen is ineffective and bacterial disease is still suspected after the first 7 days, the Working Group recommends that a more extensive diagnostic workup should be considered before considering use of other drug classes like fluoroquinolones or azithromycin. ## Bacterial bronchitis in dogs and cats ## Definition and causes Inflammation of the bronchi in dogs and cats is associated with many different conditions including inhaled irritants; infections by bacteria, viruses, Dirofilaria immitis, respiratory parasites (tissue migration of Toxocara canis); pharyngeal or esophageal dysfunction; and allergies. [bib_ref] Canine chronic bronchitis, Rozanski [/bib_ref] Acute inflammation of the bronchi can occur secondary to the primary infectious disease agents discussed in the acute and chronic URI in cats section and in CIRDC section. In general, the clinical manifestations, diagnostic plan, and treatment plan are as described in those sections. However, some dogs and cats infected with the primary bacterial pathogens B. bronchiseptica and Mycoplasma spp. can develop chronic bronchitis or bronchopneumonia. [bib_ref] Mycoplasmal respiratory infections in small animals: 17 cases (1988-1999), Chandler [/bib_ref] In addition, dogs and cats with other inflammatory diseases of the bronchi or anatomic defects of the larynx and trachea (eg, laryngeal paralysis, collapsing airways) might develop secondary bacterial bronchitis. The source of those bacteria is thought to be the natural oral microbiota. Thus, the same bacteria described for secondary bacterial URI in cats and secondary bacterial CIRDC in dogs might be associated with bronchitis. However, many dogs with chronic bronchitis do not have large numbers of bacteria cultured after bronchoalveolar lavage and so the syndrome is not always associated with bacterial infection. [bib_ref] Quantitative bacterial cultures and cytological examination of bronchoalveolar lavage specimens in dogs, Peeters [/bib_ref] ## Diagnosis of suspected bacterial bronchitis The primary clinical manifestation of bacterial bronchitis in dogs and cats is cough, with or without signs of respiratory distress. Dogs or cats with chronic cough, with or without prior evidence of URI or CIRDC should have a full physical examination performed, which should include thorough tracheal and thoracic auscultation. Thoracic radiographs should be made on full inspiration to evaluate for pulmonary and cardiac changes that could be associated with cough. In dogs, radiographs should include the cervical and intrathoracic trachea and both inspiratory and expiratory radiographs can be performed to identify collapsing airways. Alternately, fluoroscopy is available in some veterinary clinics for diagnosis of collapsing airways. Some dogs and cats with bacterial bronchitis have radiographic evidence of thickened bronchi, but others have normal radiographs even though inflammation exists on cytology of airway washings. Computed tomography can also be used to determine the extent of disease. Other causes of bronchial inflammation should be explored (D. immitis serology, fecal flotation, fecal sedimentation, Baermann test, laryngeal function evaluation) as indicated by the history. If radiographic evidence of bronchial disease is present or suspected based on clinical findings, airway washings for cytological examination are indicated to determine the type of inflammation that is present and to obtain materials for Mycoplasma spp. culture and aerobic bacterial culture and antimicrobial susceptibility testing. Mycoplasma PCR assay results do not always correlate with those of culture and might reflect oral contamination. [bib_ref] A comparison of routine culture with polymerase chain reaction technology for the..., Johnson [/bib_ref] Specimens obtained by bronchoscopy are most accurate for diagnosis, but collection of specimens by other methods like tracheal washing is acceptable if diffuse disease is present and bronchoscopy is not available, not affordable or of too great a risk to the animal. The results of analysis of bronchoalveolar lavage and brush specimens are not always in agreement. [bib_ref] Antimicrobial susceptibility of Bordetella bronchiseptica isolates from cats and a comparison of..., Zhu [/bib_ref] The presence of neutrophilic inflammation, intracellular bacteria, and positive bacterial culture with characteristic radiographic findings suggests primary or secondary bacterial bronchitis. However, the trachea is not sterile in normal dogs and low numbers of bacteria cultured in the absence of cytological evidence of intracellular bacteria might not imply bacterial infection. ## Treatment of suspected bacterial bronchitis While waiting for results of culture and antimicrobial susceptibility testing, the Working Group recommends either no antimicrobial treatment or, if the clinical disease is severe, empirical administration of doxycycline for 7-10 days . The use of doxycycline is recommended based on its in vitro activity against B. bronchiseptica isolates from dogs and cats, [bib_ref] Antimicrobial susceptibility of canine Bordetella bronchiseptica isolates, Speakman [/bib_ref] reports of positive clinical responses to doxycycline in cats with respiratory Mycoplasma infections, and a low rate of adverse effects. [bib_ref] Atypical pneumonia associated with a Mycoplasma isolate in a kitten, Bongrand [/bib_ref] [bib_ref] Primary mycoplasma pneumonia associated with reversible respiratory failure in a cat, Trow [/bib_ref] Of the 17 reviewers, 16 (94%) agreed with this Working Group recommendation and 1 disagreed because there is no breakpoint data for this antimicrobial drug for these bacteria in dogs. Depending on the clinical and laboratory testing results, antimicrobial treatment is continued, initiated, or modified based on antimicrobial susceptibility testing with the drug that is selected being one believed to penetrate the blood bronchus barrier based on data from other species. If a positive response is obtained in the first 7-10 days, treatment should be continued to 1 week past resolution of clinical signs of disease. Optimal duration of treatment for this syndrome is unknown and so this recommendation was based on the experiences of the clinicians on the Working Group. Dogs that fail to respond to antimicrobial treatment are likely to have primary chronic (noninfectious) bronchitis. Most veterinary microbiology laboratories do not report antimicrobial susceptibility results for Mycoplasma spp. and this genus can be difficult to culture. Thus, the antimicrobial choices for dogs with suspected or proven Mycoplasma-associated bronchitis are often made empirically. Doxycycline or minocycline is commonly used by veterinarians for this syndrome and is likely to have a therapeutic effect for pets with suspected Mycoplasma spp. bronchitis. [bib_ref] Mycoplasmal respiratory infections in small animals: 17 cases (1988-1999), Chandler [/bib_ref] [bib_ref] Antimicrobials for community-acquired lower respiratory tract infections secondary to Mycoplasma pneumoniae in..., Mulholland [/bib_ref] Veterinary fluoroquinolones and azithromycin are other drugs that might be effective for the treatment of Mycoplasma spp. infections. ## Monitoring treatment of bacterial bronchitis If bronchitis is associated with Mycoplasma spp. or B. bronchiseptica, clinical resolution might be obtained with 1 course of antimicrobial treatment. In some cases, prolonged antimicrobial treatment might be needed. In the event that another primary cause of inflammation such as allergic bronchitis exists and secondary bacterial infections are occurring, recurrent treatment might be required. Controlling inflammation associated with the primary disease syndrome might also lessen recurrence of secondary bacterial bronchitis. [bib_ref] Management of 13 cases of canine respiratory disease using inhaled corticosteroids, Bexfield [/bib_ref] Repeated thoracic radiographs can be taken to follow bronchial changes, but this is of limited sensitivity. In some cases, repeated cytology and culture might be indicated. ## Pneumonia in dogs and cats ## Definition and causes Inflammation of the lungs (pneumonia) can occur after a variety of insults. In dogs and cats, although uncommon, primary bacterial pneumonia can occur after infection with B. bronchiseptica, Mycoplasma spp., S. equi zooepidemicus, S. canis, and Yersinia pestis. [bib_ref] The association of Streptococcus equi subsp. zooepidemicus with canine infectious respiratory disease, Chalker [/bib_ref] [bib_ref] Mycoplasmas associated with canine infectious respiratory disease, Chalker [/bib_ref] [bib_ref] Streptococcus zooepidemicus: An emerging canine pathogen, Priestnall [/bib_ref] [bib_ref] A clonal outbreak of acute fatal hemorrhagic pneumonia in intensively housed (shelter)..., Pesavento [/bib_ref] [bib_ref] Mycoplasmal respiratory infections in small animals: 17 cases (1988-1999), Chandler [/bib_ref] [bib_ref] Clones of Streptococcus zooepidemicus from outbreaks of hemorrhagic canine pneumonia and associated..., Velineni [/bib_ref] Of 65 puppies <1 year of age with "community acquired" pneumonia in the United States, 49% were infected with B. bronchiseptica.Dogs with B. bronchiseptica infection were younger and had more severe disease than dogs from which other bacteria were cultured. Most cases of bacterial pneumonia in dogs and cats are secondary to other primary inflammatory events like viral infections or aspiration of oral, esophageal, or gastric contents during vomiting or regurgitation (commonly associated with megaesophagus), after aspiration because of pharyngeal or laryngeal function abnormalities, during anesthesia recovery, and after inhalation of foreign bodies. [bib_ref] Potential risks, prognostic indicators, and diagnostic and treatment modalities affecting survival in..., Kogan [/bib_ref] [bib_ref] Rajam€ aki MM. Co-infections with respiratory viruses in dogs with bacterial pneumonia, Viitanen [/bib_ref] In addition, bacterial pneumonia can develop in the presence of immunodeficiency syndromes. Secondary bacterial pneumonia potentially could develop as a result of other pulmonary or airway diseases like neoplasia, ciliary dyskinesia, bronchiectasis, and collapsing airways. Common organisms isolated from dogs and cats with lower respiratory disease include E. coli, Pasteurella spp., Streptococcus spp, B. bronchiseptica, Enterococcus spp., Mycoplasma spp., S. pseudintermedius and other coagulase-positive Staphylococcus spp., and Pseudomonas spp. [bib_ref] Clones of Streptococcus zooepidemicus from outbreaks of hemorrhagic canine pneumonia and associated..., Velineni [/bib_ref] [bib_ref] Microbiological study of transtracheal aspirates from dogs with suspected lower respiratory tract..., Angus [/bib_ref] [bib_ref] In vitro bacterial isolate susceptibility to empirically selected antimicrobials in 111 dogs..., Proulx [/bib_ref] [bib_ref] Bacterial pneumonia in dogs and cats, Dear [/bib_ref] [bib_ref] Antimicrobial susceptibility of bacterial isolates from 502 dogs with respiratory signs, Rheinwald [/bib_ref] ## Diagnosis of bacterial pneumonia Dogs and cats that develop cough that is associated with fever, lethargy, inappetence, or tachypnea should be evaluated for the presence of pneumonia by a full physical examination, complete blood cell count, and thoracic radiographs. If clinicopathologic findings and thoracic radiological findings (alveolar lung disease) support a diagnosis of bacterial pneumonia, collection of a transtracheal, endotracheal, or a bronchoalveolar lavage specimen for cytologic examination, aerobic bacterial culture, and antimicrobial susceptibility and Mycoplasma spp. culture is recommended. Culture and susceptibility testing should be recommended to the client and performed before starting antimicrobial drug treatment, provided that the animal is sufficiently stable; however, antimicrobial treatment should not be unduly delayed. Although no controlled data are available for dogs and cats, the clinical opinion of the Working Group is that antimicrobial treatment should be initiated as soon as possible and within 1-2 hours if clinical signs of sepsis exist. In addition, not all cases of aspiration pneumonia require antimicrobial treatment, because clinical disease might be primarily or solely chemical pneumonitis from aspirated materials. Anaerobic bacteria are sometimes associated with pneumonia, particularly if there is a history of aspiration, or grass awn foreign bodies are present. However, some commercial laboratories have difficulty culturing these agents and most do not provide antimicrobial susceptibility data; thus, antimicrobial agents with an anaerobic spectrum are often included for the treatment of bacterial pneumonia in dogs and cats when anaerobic culture is not available or likely to be reliable. In cases with probable aspiration pneumonia, multiple bacteria are often cultured making it difficult to determine which is involved with continued inflammation. Care should also be exercised when interpreting the significance of few or rare organisms, mixed culture, or presence of possible airway contaminants such as coagulase-negative staphylococci or Bacillus spp. If an endoscope is used to collect a lavage specimen, the possibility of endoscope-related contamination should also be considered, particularly when unusual species such as Serratia or Stenotrophomonas are isolated. [bib_ref] Association between Mycoplasma-specific polymerase chain reaction assay results and oral bacterial contamination..., Chan [/bib_ref] The Working Group recommends consulting with a clinical microbiologist or specialist with expertise with infectious diseases or pulmonology for interpretation of culture and antimicrobial susceptibility results from endotracheal or bronchoalveolar lavage specimens. Fifteen reviewers (88%) agreed, 1 disagreed (6%), and 1 (6%) was neutral to this Working Group recommendation. The person that disagreed believes that a consultation is only needed for difficult cases. Because bacterial pneumonia is often associated with an underlying disease process, attempts to identify and manage current problems should be made. In cats and dogs that have life-threatening bacterial pneumonia or are oxygen dependent, airway sampling might not be feasible. Although more data are required to clarify the usefulness of blood cultures (aerobic and anaerobic) in animals with severe pneumonia, it is the consensus opinion of the Working Group to consider blood cultures in these animals before starting empirical antimicrobial drug treatment as an alternative way to obtain isolates for targeted antimicrobial susceptibility to guide long-term management. Empirical antimicrobial treatment should not be delayed in an effort to stabilize affected animals and obtain a pre-antimicrobial airway sample. Thirteen reviewers (82%) agreed, 3 were neutral (18%), and 1 (6%) disagreed with this Working Group recommendation. The primary comment was that blood culture for this purpose in children is known to be insensitive and false-positive results can be obtained. [bib_ref] Blood culture in evaluation of pediatric community-acquired pneumonia: A systematic review and..., Bernstein [/bib_ref] ## Treatment of suspected bacterial pneumonia The Working Group discussed whether antimicrobial treatment should be delayed while waiting until the results of culture and antimicrobial susceptibility testing are available. However, as not all clients can afford the diagnostic procedures and pneumonia can be a lifethreatening disease, the consensus opinion was to provide empirical antimicrobial treatment while waiting for test results with potential for de-escalation of treatment based on antimicrobial susceptibility testing. While hospitalized, parenteral antimicrobial treatment is generally recommended by the Working Group for the treatment of animals with pneumonia, regardless of the severity of disease. Once the animal is discharged, treatment can be continued by means of the oral route. It is the opinion of the Working Group that doxycycline is a reasonable empiric choice for dogs or cats with mild pneumonia that is suspected to be from infection with B. bronchiseptica or Mycoplasma spp. (eg, the animal is from a shelter or boarding environment) and no other systemic signs of disease like fever, dehydration, lethargy, or respiratory distress are present. This is based on the known susceptibility of these organisms to doxycycline (see Section on Canine Infectious Respiratory Disease Complex) and published case reports of successful treatment with doxycycline [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref]. [bib_ref] Atypical pneumonia associated with a Mycoplasma isolate in a kitten, Bongrand [/bib_ref] [bib_ref] Primary mycoplasma pneumonia associated with reversible respiratory failure in a cat, Trow [/bib_ref] Fifteen reviewers (88%) agreed and 2 (12%) disagreed with this Working Group recommendation. One reviewer stated that they doubted that pneumonia would be present without fever and if pneumonia exists, it should be treated with bactericidal drugs. The other dissenting reviewer commented on the lack of breakpoint data for doxycycline and the bacteria from dogs and cats as well as the concern that doxycycline might not penetrate into the extracellular fluids of the lungs. Azithromycin is used by some veterinarians empirically in dogs with uncomplicated pneumonia, but the Working Group believes that data supporting this recommendation are lacking. Streptococcus equi subspecies zooepidemicus strains isolated from dogs are susceptible to penicillin, amoxicillin, and ampicillin. Administration of amoxicillinclavulanate is unnecessary if this organism is suspected because streptococci are not known to produce beta-lactamases. [bib_ref] Three decades of beta-lactamase inhibitors, Drawz [/bib_ref] Not all dogs or cats with acute aspiration pneumonia have a bacterial infection. However, aspirated bacteria can cause infection secondary to the chemical inflammation associated with aspiration. If the dog or cat is acutely affected and has no evidence of systemic sepsis, the Working Group believes that either no treatment or parenteral administration of a beta-lactam antimicrobial like ampicillin, ampicillin-sulbactam, or the first-generation cephalosporin cefazolin might be sufficient [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref]. Thirteen reviewers (82%) agreed, 3 were neutral (18%), and 1 (6%) disagreed with this Working Group recommendation. The primary comments were that the risk of not treating a case was greater than the perceived benefit of withholding treatment or that oral medications could be adequate for this syndrome. However, if megaesophagus or other esophageal motility disorders exist, parenteral administration of the antimicrobial drug is indicated. If clinical findings in dogs or cats with pneumonia suggest the existence of sepsis (eg, injected mucous membranes, hypoglycemia), the Working Group recommends concurrent parenteral administration of either enrofloxacin or marbofloxacin (available in injectable form in some countries) combined with a drug with Gram-positive and anaerobic spectra until bacterial culture and antimicrobial susceptibility testing results return. In 1 study, most bacteria from the lower airways of dogs with respiratory disease were susceptible to enrofloxacin. [bib_ref] Antimicrobial susceptibility of bacterial isolates from 502 dogs with respiratory signs, Rheinwald [/bib_ref] Other drugs for parenteral use with a Gram-negative spectrum might be indicated in lieu of enrofloxacin based on culture and antimicrobial susceptibility testing [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref]. The Working Group states that common options for Gram-positive and anaerobic bacteria include ampicillin or clindamycin administered parenterally [fig_ref] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat [/fig_ref]. Which of these drugs to choose while waiting on antimicrobial susceptibility test results will depend on the most likely infectious agent suspected, previously prescribed antimicrobials (if any), and historical antimicrobial resistance in the geographical region. Fourteen reviewers (82%) agreed and 3 (18%) disagreed with this Working Group recommendation. The primary comment was that if Bacteroides spp. were present, clindamycin could be ineffective and that metronidazole could be considered another option. Drugs that could be administered PO for outpatient treatment of bacterial pneumonia should be selected on the basis of culture and antimicrobial susceptibility results for organisms isolated from the lower airways, de-escalating whenever possible. If culture and antimicrobial susceptibility testing was not performed, the antimicrobial drug class or classes that were initially prescribed and associated with clinical response is/are chosen for continued oral treatment. Inflammatory responses to bacterial pneumonia increase pulmonary pathology. Thus, glucocorticoids are used concurrently in some human patients with bacterial pneumonia. However, it was the consensus opinion of the Working Group that further data are needed from dogs and cats before a definitive recommendation can be made in regard to the use of systemic or inhaled glucocorticoids, which have the potential to contribute to adverse outcomes due to immunosuppression. ## Monitoring treatment of bacterial pneumonia The current recommendation in most veterinary textbooks is to treat bacterial pneumonia for 4-6 weeks, but evidence to support this duration of treatment in either cats or dogs is lacking. Although such lengthy courses of antimicrobial treatment might be necessary for some animals with severe pulmonary involvement or those with immunodeficiency syndromes, it is the consensus opinion of the Working Group that shorter courses of appropriate treatment, such as those used to treat pneumonia in humans, might be effective in some situations. In the face of insufficient data supporting a shorter course of treatment, the Working Group recommends re-evaluation of animals with pneumonia no later than 10-14 days after starting treatment. At that point, decisions to extend treatment should be based on clinical, hematological, and radiographic findings. Additional studies evaluating durations of treatment that are shorter than 4-6 weeks are required. ## Pyothorax in dogs and cats ## Definition and causes In cats with pyothorax, the bacteria isolated from thoracic fluid are most commonly a mixture of oropharyngeal anaerobes including Fusobacterium, Prevotella, Porphyromonas, Bacteroides, Peptostreptococcus, Clostridium, Actinomyces, and Filifactor villosus. Pasteurella spp, Streptococcus spp., and Mycoplasma spp. have also been isolated. [bib_ref] Bacteria associated with pyothorax of dogs and cats: 98 cases (1989-1998), Walker [/bib_ref] [bib_ref] Canine and feline pyothorax: A retrospective study of 50 cases in the..., Demetriou [/bib_ref] [bib_ref] Feline pyothorax: A retrospective study of 27 cases in Australia, Barrs [/bib_ref] Less commonly, Staphylococcus spp., Gram-negative bacteria other than Pasteurella, and organisms such as Nocardia spp. and Rhodococcus equi have been isolated. Wounds resulting from cat fights and URI are risk factors for pyothorax in cats. [bib_ref] Feline pyothorax: A retrospective study of 27 cases in Australia, Barrs [/bib_ref] Bacteria isolated from dogs with pyothorax are most commonly mixed anaerobes (Prevotella spp., Peptostreptococcus spp., Propionibacterium acnes, Clostridium spp., Bacteroides spp., Fusobacterium spp.) and Enterobacteriaceae, especially E. coli and Klebsiella pneumoniae. 94,98-100 Streptococcus canis, Staphylococcus spp, Enterococcus spp., Corynebacterium spp., Bacillus spp., Trueperella (formerly Arcanobacterium) pyogenes, Pasteurella, Acinetobacter, Capnocytophaga spp., Enterobacter spp., Stenotrophomonas maltophila, Aeromonas hydrophila, Achromobacter xylosoxidans, Serratia marcescens and Pseudomonas spp. Actinomyces spp. and to a lesser extent Nocardia spp. and Streptomyces spp. have been implicated in canine pyothorax. [bib_ref] Successful medical treatment of 15 dogs with pyothorax, Johnson [/bib_ref] Pyothorax in dogs commonly results from migrating plant foreign bodies or trauma but can also result from bite wound inoculation. [bib_ref] Bacteria associated with pyothorax of dogs and cats: 98 cases (1989-1998), Walker [/bib_ref] [bib_ref] Medical and surgical treatment of pyothorax in dogs: 26 cases, Rooney [/bib_ref] [bib_ref] Successful medical treatment of 15 dogs with pyothorax, Johnson [/bib_ref] [bib_ref] Surgical or medical management of pyothorax in dogs?, Lee [/bib_ref] [bib_ref] A clinical review of the pathophysiology, diagnosis, and treatment of pyothorax in..., Stillion [/bib_ref] ## Diagnosis of pyothorax in dogs and cats Thoracic radiographs should be made to evaluate for the presence of lung consolidation in the dog or cat after therapeutic thoracocentesis. A pleural fluid specimen should be submitted for cytologic analysis, aerobic bacterial culture, and antimicrobial susceptibility testing, as well as culture for anaerobic bacteria and Mycoplasma spp. (cats) if available. Performance of Gram stain and acid-fast stains might provide addition information. Detection of actinomycetes and Mycoplasma spp. requires specialized growth conditions and prolonged incubation, and so the laboratory should be informed that Actinomyces spp., Nocardia spp., or Mycoplasma spp. are differential diagnoses. ## Treatment of pyothorax in dogs and cats The Working Group recommends that treatment of pyothorax include IV fluid administration and critically, drainage of pus after placement of chest tubes with intermittent or preferably continuous suction with or without lavage. [bib_ref] Feline pyothorax: A retrospective study of 27 cases in Australia, Barrs [/bib_ref] [bib_ref] Medical and surgical treatment of pyothorax in dogs: 26 cases, Rooney [/bib_ref] [bib_ref] Successful medical treatment of 15 dogs with pyothorax, Johnson [/bib_ref] [bib_ref] Surgical or medical management of pyothorax in dogs?, Lee [/bib_ref] [bib_ref] A clinical review of the pathophysiology, diagnosis, and treatment of pyothorax in..., Stillion [/bib_ref] Surgical debridement might be required in some cases. Sixteen reviewers (94%) agreed, and 1 (6%) disagreed with this Working Group recommendation. The primary comment was that evidence supporting the definitive need for thoracic lavage was lacking. However, based on lack of data supporting its use, the Working Group does not recommend administration of antimicrobial drugs into the pleural space. The Working Group recommends the combination of parenteral administration of enrofloxacin or marbofloxacin (when available in parenteral form) with a penicillin or clindamycin combined with therapeutic drainage of the pleural space with or without lavage for the initial treatment or canine and feline pyothorax pending the results of culture and antimicrobial susceptibility testing. Sixteen reviewers (94%) agreed and 1 (6%) disagreed with this Working Group recommendation. The primary comment was that pradofloxacin administered PO as a single drug could be effective if available. Treatment with an antimicrobial drug with activity against anaerobes should be continued regardless of culture results because fastidious anaerobic bacteria could be present. If combination treatment was initiated and the bacterial isolates are susceptible to both drugs in the initial treatment regime, then either of the treatment drugs could be discontinued. If organisms are grown that are resistant to one of the drugs and clinical improvement is not noted, that antimicrobial agent should be discontinued. A second drug to which the isolate is susceptible should be substituted if the animal has not responded sufficiently. If organisms are grown that are resistant to both antimicrobials or clinical evidence of improvement is not evident, antimicrobial treatment should be changed to a drug to which the organisms are susceptible in vitro. Fifteen reviewers (88%) agreed, 1 was neutral (6%), and 1 (6%) disagreed with this Working Group recommendation. The dissenting reviewer stated that mixed culture results can be difficult to interpret and so if the animal's clinical condition improves on the first therapeutic regimen, changes should not be made. Consultation with a specialist is recommended when multidrug-resistant organisms are isolated. In all situations, the clinical condition must be considered when interpreting culture results, and continuing apparently effective treatment despite in vitro resistance is recommended because of the potential that the offending organism was not isolated. ## Monitoring treatment of pyothorax It has been recommended that cats with pyothorax be treated for a minimum of 3 weeks and ideally 4-6 weeks. [bib_ref] Feline pyothorax: A retrospective study of 27 cases in Australia, Barrs [/bib_ref] Additional research is required to determine whether shorter periods of antimicrobial drug treatment might be adequate. Serial thoracic radiography might be useful to determine whether antimicrobial treatment needs to be continued, although further study is also required to determine whether persistent radiographic abnormalities correlate with the need for additional antimicrobial drug treatment. At a minimum, follow-up radiography should be performed for 10-14 days after starting treatment and at completion of treatment. If the pyothorax persists or reoccurs after cessation of antimicrobials, repeated thoracocentesis should be performed for cytological assessment and for culture and antimicrobial susceptibility testing. # Conclusions The Working Group emphasizes the need for additional prospective studies to evaluate different treatments and treatment durations in dogs and cats with bacterial respiratory diseases so that more accurate recommendations can be made. For the same purpose, research is needed to develop standard practices for collection of clinical specimens and interpretation of culture results. # Acknowledgments The Working Group thanks the following individuals for a prepublication review of the document and for providing votes to be used with the panel recommenda- Grant support: The work was supported by the International Society for Companion Animal Infectious Diseases (ISCAID; www.iscaid.org). Conflict of Interest Declaration: Jane Sykes serves as Associate Editor for the Journal of Veterinary Internal Medicine. She was not involved in review of this manuscript. M.G. Papich has received consulting fees, research support, and gifts from Bayer and Zoetis, who are sponsors of some of the antibiotics recommended in this manuscript. He receives royalties from a book (published by Elsevier) that was the source of dosages listed in this paper. Off-label Antimicrobial Declaration: This document describes off-label antimicrobial use in multiple sections. [table] Table 1: First-line antimicrobial options for bacterial respiratory infections in the dog and cat. [/table] [table] Table 2: Antimicrobial treatment options for respiratory tract infections in the dog and cat. [/table]	None	None	Respiratory tract disease can be associated with primary or secondary bacterial infections in dogs and cats and is a common reason for use and potential misuse, improper use, and overuse of antimicrobials. There is a lack of comprehensive treatment guidelines such as those that are available for human medicine. Accordingly, the International Society for Companion Animal Infectious Diseases convened a Working Group of clinical microbiologists, pharmacologists, and internists to share experiences, examine scientific data, review clinical trials, and develop these guidelines to assist veterinarians in making antimicrobial treatment choices for use in the management of bacterial respiratory diseases in dogs and cats.
7b264de7c0e3c49565891cd5f677dc55cf9ab007	pubmed	The Use of Bronchoscopy During the Coronavirus Disease 2019 Pandemic	The Use of Bronchoscopy During the Coronavirus Disease 2019 Pandemic BACKGROUND: The coronavirus disease 2019 has swept the globe and is causing significant morbidity and mortality. Given that the virus is transmitted via droplets, open airway procedures such as bronchoscopy pose a significant risk to health-care workers (HCWs). The goal of this guideline was to examine the current evidence on the role of bronchoscopy during the COVID-19 pandemic and the optimal protection of patients and HCWs.STUDY DESIGN AND METHODS: A group of approved panelists developed key clinical questions by using the Population, Intervention, Comparator, and Outcome (PICO) format that addressed specific topics on bronchoscopy related to COVID-19 infection and transmission. MEDLINE (via PubMed) was systematically searched for relevant literature and references were screened for inclusion. Validated evaluation tools were used to assess the quality of studies and to grade the level of evidence to support each recommendation. When evidence did not exist, suggestions were developed based on consensus using the modified Delphi process.RESULTS:The systematic review and critical analysis of the literature based on six PICO questions resulted in six statements: one evidence-based graded recommendation and 5 ungraded consensus-based statements.INTERPRETATION:The evidence on the role of bronchoscopy during the COVID-19 pandemic is sparse. To maximize protection of patients and HCWs, bronchoscopy should be used sparingly in the evaluation and management of patients with suspected or confirmed COVID-19 infections. In an area where community transmission of COVID-19 infection is present, bronchoscopy should be deferred for nonurgent indications, and if necessary to perform, HCWs should wear personal protective equipment while performing the procedure even on asymptomatic patients. CHEST 2020; 158(3):1268-1281 KEY WORDS: bronchoscopy; COVID-19; personal protective equipment ABBREVIATIONS: AABIP = American Association for Bronchology and Interventional Pulmonology; AGP = aerosol generating procedure; CDC = Centers for Disease Control and Prevention; CHEST = American College of Chest Physicians; COVID-19 = coronavirus disease 2019; GRADE = Grading of Recommendations, Assessment, Development and Evaluations; HCW = health-care worker; PAPR = powered air purifying respirator; PICO = Population, Intervention, Comparator, and Outcome; PPE = personal protective equipment;rRT-PCR = real-time reverse transcription-polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2 ## Summary of recommendations 1. When patients with suspected or confirmed COVID-19 infection are undergoing bronchoscopy, we suggest that health care workers in the procedure and recovery rooms use either an N-95 respirator or a powered air purifying respirator (Ungraded Consensus-Based Statement). ## Remarks: In addition, health care workers should wear personal protection equipment including face shield, gown and gloves. N-95 respirators should be discarded after bronchoscopy. 2. In patients suspected of having COVID-19 infection, we suggest that a nasopharyngeal specimen be obtained first. In the setting of severe or progressive disease requiring intubation, if additional specimen is needed to establish a diagnosis of COVID-19 or other diagnosis that will change clinical management, lower respiratory specimens from endotracheal aspirate or bronchoscopy with BAL can be performed (Ungraded Consensus-Based Statement). Remarks: More research is needed to further compare diagnostic sensitivity for COVID-19 infection utilizing other less invasive lower respiratory specimen collection techniques such as blinded bronchial sampling, blinded protected brush and nonbronchoscopic mini-BAL. 3. When asymptomatic patients present for bronchoscopy in an area where community spread of COVID-19 is present, we suggest that health care workers in the procedure room wear N-95 respirators or powered air-purifying respirators as opposed to surgical masks (Ungraded Consensus-Based Statement). Remarks: In addition, health care workers should wear personal protection equipment including face shield, gown and gloves. 4. Prior to performing bronchoscopy in asymptomatic patients in an area where community transmission of COVID-19 infection is present, we suggest testing for COVID-19 infection (Ungraded Consensus-Based Statement). ## Remarks: This strategy is contingent on the availability of testing in the local setting. In all patients with negative results, we suggest that the procedure is performed using personal protection equipment including face shield, gown, gloves and N-95 respirators or powered air purifying respirators (PAPR). When test results are positive prior to bronchoscopy, we suggest postponing all non-emergent bronchoscopies. In patients who require emergent bronchoscopy who have positive SARS-CoV-2 test results, we suggest using personal protection equipment including face shield, gown, gloves and N-95 respirators or powered air purifying respirators (PAPR) in pre, intra, and post bronchoscopy settings as would be with every SARS-Cov-2 positive patient. 5. When bronchoscopy is indicated to diagnose, stage, or characterize a known or suspected lung cancer in an area where community transmission of COVID-19 is present, we suggest that bronchoscopy be performed in a timely and safe manner (Grade 2C). ## Remarks: Strategies to perform bronchoscopy in a timely manner should be developed locally, taking into account local resource availability including availability of personal protective equipment, availability of COVID-19 testing and availability ofdownstream resourcesrequired fortreatment (eg, surgery requires ICU beds and ventilators). Regional availability of diagnostic and therapeutic interventions for cancer patients should be considered. In particularly resource-depleted hospitals, COVID-19 negative cancer patients should be referred to other centers, preserving resources for COVID-19 patients and facilitating safe, timely, and effective care for the cancer patient as well. Although efforts should be made to provide timely care, these should be balanced by the need to attend to other dimensions of quality, including safety, effectiveness, and consistency with patient values and preferences. 6. In patients with confirmed COVID-19 infection who recover and need a routine bronchoscopy, we suggest that the timing of the procedure be customized based on the indication for the procedure, the severity of the COVID-19 infection and time from symptom resolution (Ungraded Consensus-Based Statement). ## Remarks: The exact time to perform bronchoscopy is still unknown. It would be reasonable to wait at least 30 days from resolution of symptoms with negative SARS-CoV-2 RNA tests from at least two consecutive nasopharyngeal swab specimens collected $24 hours apart. Further research is needed to better understand optimal timing of bronchoscopy performance relative to symptom resolution. # Background The coronavirus disease 2019 (COVID-19) pandemic has manifested primarily as a severe lower respiratory tract illness with significant associated morbidity and mortality throughout the globe. 1 Transmission is generally via respiratory droplets, but airborne transmission may be possible with aerosol generating procedures (AGPs) such as bronchoscopy.Therefore, bronchoscopy and other AGPs put health-care workers (HCWs) at particularly high risk of exposure and infection. Under these trying circumstances, the medical community has three overarching imperatives. The first is to ensure the protection and welfare of all patients, irrespective of their COVID-19 status. The second is to preserve the health-care workforce to sustainably meet the first responsibility, and finally, the third is to promote the health of the community at large. Although specific data on the risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during bronchoscopy are not available, the US Centers for Disease Control and Prevention (CDC) recommends performing these AGPs in an airborne infection isolation room with an N95 respirator or higher-level respirator, eye protection, gloves, and gown.These considerations and the often overwhelming demand on available human and material resources during a pandemic necessitates thoughtful and deliberate balancing of the tradeoffs that may be required to optimally fulfil the primary responsibilities of the health-care system. In an effort to provide interim guidance to health-care practitioners, various specialty societies have issued statements germane to their particular specialties. The American Association for Bronchology and Interventional Pulmonology (AABIP) 4 recently issued a statement on the use of bronchoscopy in COVID-19. Most of these statements have relied primarily on the available CDC guidance and the consensus opinions of single specialty experts. This report provides an indepth, multidimensional, and multidisciplinary review of the available scientific evidence and puts forward suggestions for key clinical scenarios that many practitioners are likely to face. In such a kinetic milieu, these can be expected to evolve based on an expanding evidence base, the public health burden of disease, and the availability of trained personnel or medical infrastructure. These suggestions are therefore best envisioned as a decision-making framework that continually strives for optimality among possibly competing mandates. # Methods The primary aim of this collaborative effort between the American College of Chest Physicians (CHEST) and AABIP was to create a list of clinically relevant recommendations and suggestions for HCWs who perform bronchoscopy during the COVID-19 pandemic. We chose to base recommendations on the assumption that resources are abundant. These recommendations can then be adapted by local decision-makers based on resource availability. Using the assumption that resources (for prevention, diagnosis, and treatment) are plentiful, we aimed to answer some of the most common and important questions related to bronchoscopy during the COVID-19 pandemic. ## Panelist and content expert selection CHEST and AABIP participated in the selection of panelists. Two cochairs were assigned to lead this endeavor (M. M. W. appointed by AABIP and R. A. appointed by CHEST). Cochairs in conjunction with CHEST and AABIP leadership nominated two methodologists (S. S. and D. O.) and core panelists (G. E., C. R. L., F. M., D. O., and S. S.) based on their clinical expertise in bronchoscopy and interventional pulmonology. Advisory panel members consisted of infectious disease experts (M. P. S. and D. A. C.), critical care medicine experts (D. R. O. and C. L.), an interventional pulmonology trainee (K. G.), a pulmonary and critical care trainee (K. P.), and a respiratory therapist (D. D. G.) nominated and selected by both organizations. All panel members received individual education regarding the process and schedule, followed by conflict of interest disclosure and evaluation by cochairs. Guideline creation schedule was developed by cochairs. Given the timesensitive nature of the topic amid on-going COVID-19 pandemic, the schedule spanned over a period of 3 weeks and included 10 conference calls including topic and question development, literature search, literature evaluation using Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology, discussion, modified Delphi surveys, and statement development. ## Question development and systematic search Cochairs and core panelists discussed and developed the primary questions in the Population, Intervention, Comparator, and Outcome (PICO) format during the first conference call. Six PICO questions were developed and assigned to each core panelist for literature review [fig_ref] TABLE 1 ]: PICO Questions [/fig_ref]. To identify relevant evidence, the panel members conducted a comprehensive search using MEDLINE via PubMed followed by manual search related to each a priori developed PICO question. Search strategy, evidence table, and details of search results depicted in a Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram for each PICO question are available in e-Appendix 1. Studies were excluded if they were not available in English or if they were single case reports. Expert reviews, opinions, and statements were not included, but their references were reviewed to search for additional evidence. ## Study selection and evidence assessment Each panel member screened their respective search results to exclude duplicates, followed by title and abstract screen, excluding literature based on a priori established exclusion criteria. All remaining text was reviewed and direct and indirect evidence was selected and presented in evidence tables for final review and core panel discussion. With the exception of one single-center retrospective observational study related to PICO question 2, 5 and 13 studies related to PICO question 5, 6-18 no other direct evidence was identified. Evidence was graded by the methodology team using the standard GRADE quality assessment tool categorized as high, moderate, low, or very low. [bib_ref] Use of GRADE grid to reach decisions on clinical practice guidelines when..., Jaeschke [/bib_ref] [bib_ref] Methodologies for the development of CHEST guidelines and expert panel reports, Lewis [/bib_ref] With exception of PICO question 5, none of the available direct and indirect literature provided sufficient evidence for the development of recommendations. Expert opinion instead was sought to answer these PICO questions in form of suggestions in place of recommendations. Suggestions were developed based on the use of a modified Delphi process. ## Method for achieving consensus Search results were shared and discussed among members during a conference call with 100% participation. Evidence graded by the methodology team and summary of evidence and suggestions written by respective panel members for each PICO question were disclosed to all panel members including the advisory panel. During the conference call, suggestions were reviewed and rewritten in real time per adjustment and suggestions from the panel. This was followed by another conference call with 100% participation, soliciting additional comments and input from the advisory panel. All panel members participated in the development of suggestions to be incorporated in the initial round of the modified Delphi survey. The modified Delphi technique is a widely accepted method for the development of consensus among experts. [bib_ref] Evidence vs consensus in clinical practice guidelines, Djulbegovic [/bib_ref] [bib_ref] Consensus methods: characteristics and guidelines for use, Fink [/bib_ref] [bib_ref] Development of evidence-based recommendations: implications for preparing expert consensus statements, Kwong [/bib_ref] To achieve consensus, a priori decision was made to conduct up to three rounds of anonymous voting or until consensus was achieved (defined a priori as consensus agreement at $ 80% with a minimal response rate of 80%) for each PICO question, whichever came first. To maintain complete transparency and limit bias from interaction among members, additional discussions outside of the scheduled meetings before voting were discouraged. The survey incorporated the suggestions made by all panelists and was developed and reviewed by chairs and methodologists and sent to all panel members by a CHEST-designated project coordinator. The project coordinator tallied and reported the results of the survey to the group, and all votes were anonymous. The results of the survey were discussed with all panel members including the advisory panel on the same day during a group discussion. There was 100% survey participation from the members and consensus was achieved on four PICO questions. After discussion and revision of statements, a second round of surveys was distributed, including three questions (two questions did not achieve consensus and one question required rewriting based on panel recommendation). There was 100% survey participation and agreement on all three PICO questions from the second survey. # Results 1. When patients with suspected or confirmed COVID-19 infection are undergoing bronchoscopy, we suggest that health care workers in the procedure and recovery rooms use either an N-95 respirator or a powered air purifying respirator (Ungraded Consensus-Based Statement). ## Remarks: In addition, health care workers should wear personal protection equipment including face shield, gown and gloves. N-95 respirators should be discarded after bronchoscopy. COVID-19 is caused by SARS-CoV-2 and currently understood to be transmitted from person-to-person via droplets, contact, and fomites, largely based on prior epidemiologic data from the previous coronavirus outbreaks. [bib_ref] Another decade, another coronavirus, Perlman [/bib_ref] Accordingly, the World Health Organization and the CDC have made recommendations for HCWs and individuals to maintain a 1-m (3-ft) or 2-m (6-ft) distance, respectively, from patients suspected of being infected.Routinely performed AGPs such as bronchoscopy have however been associated with infection of HCWs despite droplet and contact precautions, prompting the CDC and many scientific societies to recommend airborne precautions in these circumstances. [bib_ref] American Association for Bronchology and Interventional Pulmonology (AABIP) statement on the use..., Wahidi [/bib_ref] Although data specific to SARS-CoV-2 are lacking, a systematic review reported ORs for transmission of SARS-CoV-2 to HCWs of 6.6 (95% CI, 2.3-18.9), 4.2 (95% CI, 1.5-11.5), and 1.9 (95% CI, 0.2-14.2) for endotracheal intubation, tracheostomy, and bronchoscopy, respectively; however, the association with bronchoscopy did not reach statistical significance. [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] One study demonstrated that SARS-CoV-2 could remain aerosolized for up to 3 h in experimental conditions. [bib_ref] Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1, Van Doremalen [/bib_ref] The CDC currently recommends the use of either powered air purifying respirators (PAPRs) with contact precautions or N95 respirators based enhanced respiratory and contact precautions (including eye protection) as comparable strategies for protection of HCWs during AGPs such as bronchoscopy.Our systematic review did not identify any study directly comparing these two interventions, either in the context of SARS-CoV-2 or other pathogens associated with a risk of aerosolization during bronchoscopy. A theoretical benefit of PAPRs over N95 respirators is a higher assigned protection factor, as defined by the minimum factor by which exposure is reduced, which ranges from 25 to 1,000 for PAPRs vs 10 for N95 respirators (higher number representing higher filtration efficiency).Accordingly, during the 2009 influenza pandemic, the CDC, Occupational Safety and Health Administration, and Institute of Medicine suggested the use of PAPRs over other precautions during AGPs. [bib_ref] Special article: personal protective equipment for care of pandemic influenza patients: a..., Tompkins [/bib_ref] In addition, PAPRs do not require prior fit testing (which even when performed appropriately does not guarantee consistent face seal), are more comfortable, are reusable (a potential benefit in times of scarce resources), and do not require an additional face shield. 32 N95 respirators, conversely, do not afford protection unless a tight seal is maintained throughout the procedure and may be uncomfortable because of resistance of airflow and CO 2 rebreathing. [bib_ref] Respirator-fit testing: does it ensure the protection of healthcare workers against respirable..., Lee [/bib_ref] [bib_ref] Effects of wearing N95 and surgical facemasks on heart rate, thermal stress..., Li [/bib_ref] The reusability of PAPRs may however carry significant risks of contamination if donning and doffing and decontamination procedures are not strictly followed. Errors in don and doff procedures may be more common with PAPRs, exposing HCWs and patients to possible contamination. [bib_ref] Contamination: a comparison of 2 personal protective systems, Zamora [/bib_ref] Other potential downsides of PAPRs include availability, upfront investment, storage issues, maintenance (high-efficiency particulate filter and battery), training issues, and possibly movement limitations which may interfere with highly technical procedures. [bib_ref] Special article: personal protective equipment for care of pandemic influenza patients: a..., Tompkins [/bib_ref] Although the higher assigned protection factor of PAPRs provides increased protections, these practical considerations do not allow firm conclusions favoring one intervention over the other. One major characteristic of the COVID-19 pandemic has been the shortage of personal protective equipment (PPE) for HCWs, specifically regarding face masks and N95 respirators. The CDC suggested that the extended N95 respirator use (same N95 respirator used for consecutive patients) and reuse (N95 respirator donned and doffed multiple times) for 8 h (continuous or intermittent) may be acceptable under specific conditions provided (1) the respirator is not damaged, hard to breathe through, or contaminated; (2) the respirator is discarded after close interaction with patients under contact precautions or after AGPs; and (3) appropriate handwashing is performed before and after touching or adjusting the respirator. We agree with these recommendations and suggest that N95 respirator be discarded after bronchoscopy. 2. In patients suspected of having COVID-19 infection, we suggest that a nasopharyngeal specimen be obtained first. In the setting of severe or progressive disease requiring intubation, if additional specimen is needed to establish a diagnosis of COVID-19 or other diagnoses that will change clinical management, lower respiratory specimens from endotracheal aspirate or bronchoscopy with BAL can be performed (Ungraded Consensus-Based Statement). Remarks: More research is needed to further compare diagnostic sensitivity for COVID-19 infection utilizing other less invasive lower respiratory specimen collection techniques such as blinded bronchial sampling, blinded protected brush and non-bronchoscopic mini-BAL. The optimal test to detect COVID-19 infection centers around a balance of the availability of the test, timeliness of result, diagnostic yield, and invasiveness of sampling, while minimizing the risk of disease transmission to HCWs. To generate guidance for best practice in the diagnostic assessment for COVID-19 infection, it is reasonable to use available data from prior recommendations on similar infections such as Middle East respiratory syndrome coronavirus and influenza A (H1N1) coupled with known assessment of the risk of AGPs. [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] [bib_ref] Airborne transmission and precautions: facts and myths, Seto [/bib_ref] Data was published on 1,070 specimens from 205 patients with COVID-19 infections, described as having a spectrum of severity of symptoms from mild fever, dry cough, and fatigue to more severe respiratory symptoms, who underwent a variety of specimen collections from different sites; however, the severity of illness was not distinguished relative to the sites sampled and the number of some sampled sites was small. The specimen sites were described and confirmed with [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref] Given sample size, the true sensitivity for each site is not fully known in this setting. [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref] The World Health Organization 37 online guidelines for COVID-19 suggest that endotracheal aspirate or bronchoscopy with BAL be considered if a single upper respiratory specimen is negative and there is clinical concern because of severe or progressive disease. When reviewing the literature for comparisons of various techniques for respiratory specimens and distinguishing upper and lower respiratory tract specimens, there are limited data assessing diagnostic yield in bacterial pathogens and none specifically for viruses or SAR-CoV-2. The literature on ventilatorassociated pneumonia described multiple sampling methods to detect pathogens including endotracheal aspirate, blinded bronchial sampling, blinded protected brush, nonbronchoscopic mini-BAL, and bronchoscopic BAL. [bib_ref] Evaluation of early minibronchoalveolar lavage in the diagnosis of health care-associated pneumonia:..., Lacroix [/bib_ref] [bib_ref] Diagnosis of ventilator-associated pneumonia: focus on nonbronchoscopic techniques (nonbronchoscopic bronchoalveolar lavage, including..., Fujitani [/bib_ref] [bib_ref] Comparison of bronchoalveolar lavage and minibronchoalveolar lavage in the diagnosis of pneumonia..., Tasbakan [/bib_ref] When these particular sampling modalities were reviewed and compared with endotracheal aspirates in that setting, the data did not suggest superiority of a specific technique performed nonbronchoscopically and cited high variability and inconsistency in standardization of technique. Beyond actual specimen collection, it will be important to follow safety procedures for transport and processing of the specimens in the laboratory setting. Lower respiratory specimen testing and handling for COVID-19 is different than upper respiratory specimen testing and may require expert laboratory facilities and therefore longer turnaround times. [bib_ref] Potential preanalytical and analytical vulnerabilities in the laboratory diagnosis of coronavirus disease..., Lippi [/bib_ref] We determined that because bronchoscopy is an AGP, minimizing risk of transmission of infection to HCWs should be considered and less invasive modalities of establishing the diagnosis of COVID-19 should be used first. The role of lower respiratory specimens via endotracheal aspirate or bronchoscopy can be considered in the setting of severe progressive disease after negative upper respiratory specimens or when considering an alternative diagnosis which may lead to a change in clinical management. chestjournal.org 3. When asymptomatic patients present for bronchoscopy in an area where community spread of COVID-19 is present, we suggest that health care workers in the procedure room wear N-95 respirators or powered air-purifying respirators (PAPR) as opposed to surgical masks (Ungraded Consensus-Based Statement). Remarks: In addition, health care workers should wear personal protection equipment including face shield, gown and gloves. In a major pandemic like the one we are experiencing with COVID-19, a guiding principle of health-care delivery is full protection of HCWs to preserve the workforce able to care for sick patients. The SARS-CoV-2 virus presents a major challenge because people can carry the virus but remain asymptomatic, and therefore, can transmit the infection to fellow humans and HCWs while seemingly appearing healthy. [bib_ref] Presumed asymptomatic carrier transmission of COVID-19, Bai [/bib_ref] [bib_ref] A familial cluster of infection associated with the 2019 novel coronavirus indicating..., Yu [/bib_ref] A mathematical model, that simulated the spatiotemporal dynamics of COVID-19 infections among 375 Chinese cities prior to travel restrictions, showed that undocumented infections were the infection source for 79% of documented infections. [bib_ref] Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2), Li [/bib_ref] A small study of 24 asymptomatic infected patients from China found that the median communicable period, defined as the interval from the first day of positive nucleic acid tests to the first day of continuous negative tests, was 9.5 days (up to 21 days). [bib_ref] Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts..., Hu [/bib_ref] Another study evaluated 468 COVID-19 transmission events that were reported in mainland China outside of Hubei Province and estimated presymptomatic transmission of the infection at 12.6%. [bib_ref] Serial interval of COVID-19 among publicly reported confirmed cases, Du [/bib_ref] Asymptomatic communication of infection becomes a major concern when community transmission is confirmed in a geographic area. This is particularly concerning to HCWs performing open airway procedure such as bronchoscopy in such a community. We sought to determine whether HCWs should don N95 respirators or surgical masks during bronchoscopy performed on asymptomatic patients and found only one study related to COVID-19 infections. Wang et al [bib_ref] Association between 2019-nCoV transmission and N95 respirator use, Wang [/bib_ref] retrospectively evaluated the infection rate among HCWs in a Chinese hospital in two different groups: the first group was comprised of staff at high-risk units (respiratory, infectious disease, and ICU wards) who wore N95 respirators and cleaned hands frequently, whereas the second group included staff in other less-risky wards who did not wear surgical masks and washed their hands occasionally. Despite a higher exposure to patients with COVID-19 infection, none of the 278 staff (56 doctors and 222 nurses) in the N95 respirator group became infected, whereas 10 of 213 staff (77 doctors and 136 nurses) from the no-mask group were confirmed as infected. The study did not speculate as to whether the protection of HCWs in the N95 respirator group was solely because of wearing the mask or aided by the frequent handwashing strategy. A meta-analysis conducted in 2020 showed that the use of N95 respirators compared with surgical masks was not associated with a lower rate of transmission of influenza. [bib_ref] Effectiveness of N95 respirators versus surgical masks against influenza: a systematic review..., Long [/bib_ref] Another recent systematic review and metaanalysis found low certainty evidence suggesting that surgical masks and N95 respirators offer similar protection against viral respiratory infection during nonaerosol generating care. However, the study recommended use of N95 respirators for high-risk AGPs such as bronchoscopy.The panel reached consensus favoring wearing N95 respirators vs surgical masks based on the weak evidence that originated from China supporting the superior protection of N95 respirators over surgical masks against COVID-19 infections and the serious consequences of exposing HCWs to asymptomatic patients carrying the COVID-19 infection. ## Prior to performing bronchoscopy in asymptomatic patients in an area where community transmission of covid-19 infection is present, we suggest testing for covid-19 infection (ungraded consensus-based statement). ## Remarks: This strategy is contingent on the availability of testing in the local setting. In all patient with negative results, we suggest that the procedure be performed using personal protection equipment including face shield, gown, gloves and N-95 respirators or powered air purifying respirators (PAPR). When test results are positive prior to bronchoscopy, we suggest postponing all non-emergent bronchoscopies. In patients who require emergent bronchoscopy with either a known positive SARS-CoV-2 test results or unknown infection status due to inability to test emergently, we suggest using personal protection equipment including face shield, gown, gloves and N-95 respirators or powered air purifying respirators (PAPR) in pre, intra, and post bronchoscopy settings as would be with every SARS-CoV-2 positive patient. Our comprehensive literature search showed no direct evidence comparing COVID-19 testing vs no testing prior to bronchoscopy in any population, including asymptomatic patients. Examination of the existing indirect evidence shows that effect estimates of asymptomatic disease proportion in the population and infection transmission rates are limited by population heterogeneity, small sample size, selection bias because most asymptomatic patients may never seek medical attention to undergo testing, and lack of adjustment for other covariates; all of this results in significant imprecision in effect estimates. The diagnosis of SARS-CoV-2 is based on viral RNA detection using rRT-PCR tests. Multiple molecular assays are available and new assays are being developed around the world. [bib_ref] Molecular diagnosis of a novel coronavirus (2019-nCoV) causing an outbreak of pneumonia, Chu [/bib_ref] [bib_ref] Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR, Corman [/bib_ref] Debates about the efficiency, sensitivity, and availability of the tests have been ongoing, both within and outside the United States. The Food and Drug Administration has granted emergency use authorization to > 20 commercial COVID-19 diagnostic tests and assays. Different rRT-PCR tests' sensitivities are reported in the literature ranging from 59% to 97%. [bib_ref] Chest CT for typical 2019-nCoV pneumonia: relationship to negative RT-PCR testing, Xie [/bib_ref] [bib_ref] Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19)..., Ai [/bib_ref] Interpretation of negative test results becomes even harder in an asymptomatic patient without suspicion of disease. Numerous potential preanalytical and analytical deficiencies exist in the diagnosis of COVID-19 infection ranging from inadequate procedures for specimen collection and handling, sample contamination, inadequately validated assays, and misinterpretation of expression profiles as noted by Lippi et al. [bib_ref] Potential preanalytical and analytical vulnerabilities in the laboratory diagnosis of coronavirus disease..., Lippi [/bib_ref] Ongoing refinement of molecular targets and validation of rRT-PCR assays are underway. Although direct evidence regarding the utility of COVID-19 testing prior to bronchoscopy does not exist, review of the existing literature supports the presence of patients with asymptomatic COVID-19 in the community. Some but not all asymptomatic patients may be identified through testing. However, a proportion of these asymptomatic patients may have false-negative results. During a pandemic crisis and when dealing with highly contagious infections, there are numerous factors that play a role in every response. The decision to use a test relies on more than just test sensitivity and specificity. Some of the other factors that play a significant role are the magnitude of harm that comes from lack of infection detection, potential actionable items once infection is identified, and overall loss and cost to the public at large, should an infected individual go unrecognized. In the case of COVID-19 infection, a major consideration is the prevalence of asymptomatic disease. When asymptomatic disease is rare, the need for extensive workup and testing may be unnecessary, and harm may outweigh the benefit. If a patient with asymptomatic COVID-19 who is in need of urgent bronchoscopy is tested positive, postponing the bronchoscopy may protect HCWs who would have come in contact with the patient. This in turn can reduce the chance of infection transmission to vulnerable patients by asymptomatic HCWs during the incubation period. Additionally, patients who would come in contact with a patient with asymptomatic COVID-19 during the postbronchoscopy recovery period are spared. Inevitably, some asymptomatic patients may be missed on a false-negative test and undergo bronchoscopy. However, given all elective and semielective bronchoscopies are avoided, and some asymptomatic patients are detected on testing, the number of infected individuals who would not be detected can be significantly diminished, decreasing the frequency of harm. This highlights the importance of testing as a tool for risk reduction and not risk elimination. Assuming an ideal scenario with abundant availability of resources, performing tests prior to every bronchoscopy in an asymptomatic patient in the era of COVID-19 pandemic mitigates risks to HCWs and patients. We fully realize that test availability may be limited even for symptomatic patients and therefore this strategy may not be feasible in highly endemic areas. An equally important approach in these settings is to limit the number of bronchoscopy procedures performed and postpone most of them unless absolutely necessary. [fig_ref] TABLE 2 ]: Urgency of Bronchoscopy Procedures [/fig_ref] provides general guidance to bronchoscopists on procedure urgency. Acknowledging the possibility of false negative results, necessary respiratory protection and appropriate PPE should be used to prevent transmission of disease during bronchoscopy, on asymptomatic patients who were not detected on testing. 5. When bronchoscopy is indicated to diagnose, stage, or characterize a known or suspected lung cancer in an area where community transmission of COVID-19 is present, we suggest that bronchoscopy be performed in a timely and safe manner (Grade 2C). ## Chestjournal.org Remarks: Strategies to perform bronchoscopy in timely manner should be developed locally, taking into account local resource availability, including availability of personal protective equipment, availability of COVID-19 testing, and availability of downstream resources required for treatment (eg, surgery requires ICU beds and ventilators). Regional availability of diagnostic and therapeutic interventions for cancer patients should be considered. In particularly resource-depleted hospitals, COVID-19 negative cancer patients should be referred to other centers, preserving resources for COVID-19 patients and facilitating safe, timely, and effective care for the cancer patient as well. Although efforts should be made to provide timely care, these should be balanced by the need to attend to other dimensions of quality, including safety, effectiveness, and consistency with patient values and preferences. The Institute of Medicine has identified timeliness as one of the six dimensions of health-care quality. For lung cancer, delays in care may lead to missed opportunities for cure or palliation and emotional distress. The CHEST Evidence-Based Guidelines and the British Thoracic Society and the National Cancer Network all address timeliness of care to varying degrees, but they vary somewhat in the details and definitions of what constitutes timely care. Bronchoscopy is an integral part of lung cancer care because it is often required for diagnosis and staging, which in turn determines treatment. Timeliness of bronchoscopic diagnosis impacts everything that occurs downstream from it. Indeed, guideline consistent care with bronchoscopic endobronchial ultrasound for staging and diagnosis as the first test in patients with T1-3, N1-3, M0 disease has been shown to decreases complications, decrease number of tests required, and decrease time to treatment. [bib_ref] Quality gaps and comparative effectiveness in lung cancer staging and diagnosis, Ost [/bib_ref] However, in the context of the COVID-19 epidemic, there is a compelling need to consider the efficient allocation of constrained resources. Balancing the need to deliver high-quality cancer care and the public health and resource allocation needs associated with the COVID-19 pandemic requires careful consideration of where resources can be deployed for the most benefit. In the context of the COVID-19 pandemic, the question is whether it is reasonable to forego or delay bronchoscopy of patients with known or suspected lung cancer, and if so for how long? The answer to this question is highly context dependent and will of course vary depending on the presentation of the patient. In addition, optimal diagnostic and staging strategies are contingent on the benefits and harms of the available treatments. [bib_ref] Decision making in patients with pulmonary nodules, Ost [/bib_ref] The availability of different A complete quantitative analysis of every possible scenario according to resources availability and stage of disease is beyond the scope of this guideline. We instead focus on a more general question: What is the impact of delays in care on lung cancer survival? The goal is to summarize the available evidence to arrive at a more nuanced understanding of how timeliness of care impacts lung cancer outcomes. This information can in turn be used to inform decision-making at the local level as to how best to allocate available health-care resources. To summarize the evidence of the impact of timeliness of care on lung cancer outcomes, we used the third edition of the CHEST evidence-based lung cancer guidelines. [bib_ref] Clinical and organizational factors in the initial evaluation of patients with lung..., Ost [/bib_ref] A supplemental literature review identified 13 additional references. [bib_ref] Interaction between treatment delivery delay and stage on the mortality from non-small..., Abrao [/bib_ref] [bib_ref] Association of diagnostic delays to survival in lung cancer: single center experience, Alanen [/bib_ref] [bib_ref] Time to treatment as a quality metric in lung cancer: staging studies,..., Gomez [/bib_ref] [bib_ref] Timeliness of care and prognosis in patients with lung cancer, Gonzalez-Barcala [/bib_ref] [bib_ref] Survival after community diagnosis of early-stage non-small cell lung cancer, Kanarek [/bib_ref] [bib_ref] Time to initial cancer treatment in the United States and association with..., Khorana [/bib_ref] [bib_ref] Guideline-concordant timely lung cancer care and prognosis among elderly patients in the..., Nadpara [/bib_ref] [bib_ref] Disparities in lung cancer care and outcomes among elderly in a medically..., Nadpara [/bib_ref] [bib_ref] Influence of delays in diagnosis and treatment on survival in small cell..., Radzikowska [/bib_ref] [bib_ref] Effects of delayed surgical resection on short-term and long-term outcomes in clinical..., Samson [/bib_ref] [bib_ref] Impact of timing of lobectomy on survival for clinical stage IA lung..., Yang [/bib_ref] [bib_ref] Effect of delays on survival in patients with lung carcinoma in Montenegro, Zivkovi C [/bib_ref] The methodology of the studies, the definitions used, and the evidence quality precluded arriving at a point estimate of the effect of time delay on outcomes. Issues included varying definitions of when cancer was first identified (eg, symptoms vs imaging vs tissue diagnosis), which interval was relevant (eg, symptoms to treatment vs diagnosis to treatment), heterogeneity in populations (eg, surgically treated vs all patients with lung cancer), differences in histology (eg, all types vs non-small cell lung cancer), intractable problems because of residual confounding within groups, confounding by indication (eg, sicker patients seen more rapidly), selection bias, and failure to adjust for lead time bias (eg, measuring survival from time of treatment rather than time of presentation). We therefore have provided evidence tables with the new studies identified, with additional methodology comments (e-Appendix 2, 3). [bib_ref] Interaction between treatment delivery delay and stage on the mortality from non-small..., Abrao [/bib_ref] [bib_ref] Association of diagnostic delays to survival in lung cancer: single center experience, Alanen [/bib_ref] [bib_ref] Time to treatment as a quality metric in lung cancer: staging studies,..., Gomez [/bib_ref] [bib_ref] Timeliness of care and prognosis in patients with lung cancer, Gonzalez-Barcala [/bib_ref] [bib_ref] Survival after community diagnosis of early-stage non-small cell lung cancer, Kanarek [/bib_ref] [bib_ref] Time to initial cancer treatment in the United States and association with..., Khorana [/bib_ref] [bib_ref] Guideline-concordant timely lung cancer care and prognosis among elderly patients in the..., Nadpara [/bib_ref] [bib_ref] Disparities in lung cancer care and outcomes among elderly in a medically..., Nadpara [/bib_ref] [bib_ref] Influence of delays in diagnosis and treatment on survival in small cell..., Radzikowska [/bib_ref] [bib_ref] Effects of delayed surgical resection on short-term and long-term outcomes in clinical..., Samson [/bib_ref] [bib_ref] Impact of timing of lobectomy on survival for clinical stage IA lung..., Yang [/bib_ref] [bib_ref] Effect of delays on survival in patients with lung carcinoma in Montenegro, Zivkovi C [/bib_ref] [bib_ref] Reasons for delay in diagnosis and treatment of lung cancer among patients..., Sawicki [/bib_ref] [bib_ref] Delays for diagnosis and treatment of lung cancers: a systematic review, Vinas [/bib_ref] [bib_ref] Socio-economic inequalities in stage at diagnosis, and in time intervals on the..., Forrest [/bib_ref] [bib_ref] Timeliness of care and lung cancer tumor-stage progression: How long can we..., Maiga [/bib_ref] [bib_ref] How long is too long? A scoping review of health system delays..., Malalasekera [/bib_ref] The available evidence is often conflicting regarding the relationship between timeliness of care and outcome. [bib_ref] Association of diagnostic delays to survival in lung cancer: single center experience, Alanen [/bib_ref] [bib_ref] Disparities in lung cancer care and outcomes among elderly in a medically..., Nadpara [/bib_ref] [bib_ref] Impact of timing of lobectomy on survival for clinical stage IA lung..., Yang [/bib_ref] Paradoxically, multiple studies reported that more timely care was associated with worse outcomes. [bib_ref] Interaction between treatment delivery delay and stage on the mortality from non-small..., Abrao [/bib_ref] [bib_ref] Association of diagnostic delays to survival in lung cancer: single center experience, Alanen [/bib_ref] [bib_ref] Timeliness of care and prognosis in patients with lung cancer, Gonzalez-Barcala [/bib_ref] [bib_ref] Guideline-concordant timely lung cancer care and prognosis among elderly patients in the..., Nadpara [/bib_ref] [bib_ref] Disparities in lung cancer care and outcomes among elderly in a medically..., Nadpara [/bib_ref] Two studies found evidence that the impact of timeliness of care on survival varies based on lung cancer stage. [bib_ref] Interaction between treatment delivery delay and stage on the mortality from non-small..., Abrao [/bib_ref] [bib_ref] Time to treatment as a quality metric in lung cancer: staging studies,..., Gomez [/bib_ref] Timely care was associated with improved survival in local and stage II disease. Conversely, in patients with metastatic disease, timely care was associated with decreased survival. These findings explain the paradoxical and contradictory results of earlier studies. In early stage disease, medical emergencies are less common, and there is likely to be less confounding by indication. In late stage disease, confounding by indication plays a role (e-Appendix 2). On balance, the available data suggest that although we cannot precisely quantify the impact of delays in care, it is probable that delays have a greater impact early in the disease process. [bib_ref] Interaction between treatment delivery delay and stage on the mortality from non-small..., Abrao [/bib_ref] [bib_ref] Guideline-concordant timely lung cancer care and prognosis among elderly patients in the..., Nadpara [/bib_ref] [bib_ref] Impact of timing of lobectomy on survival for clinical stage IA lung..., Yang [/bib_ref] More timely care is likely to have the greatest benefit in patients with stage IA2, IA3, IB, IIA, and IIB disease. When resources for cancer care are constrained because of COVID-19, the first step is to take an inventory of what treatments and diagnostic modalities are available for cancer care. In hospitals most burdened by COVID-19, surgery will not be an option; therefore, collaboration with outside centers and referral may be best. Inventory should not be just at the local hospital level, but rather hospitals should share information regarding availability of resources regionally, such as ICU beds, ventilators, and types of services still available for cancer care. If there is no availability because of the absence of resources at one hospital, then referral to outside centers is warranted. In areas with the highest rates of COVID-19, referral of COVID-19-negative patients with cancer to other centers will be a good strategy. This requires coordination between centers, hence the emphasis on taking inventory at both the hospital and regional level. Cancer centers that are physically separate from general hospitals with separate teams would be able to serve this purpose well. This has some appeal because it would keep vulnerable patients with cancer out of hospitals with a high rate of COVID-19, freeing up resources for patients with COVID-19. It would also create a sort of reverse quarantine, where care for COVID-19-negative patients with cancer would be delivered. Finally, although there is limited evidence of the benefit of timeliness of care, there is evidence that guideline consistent care leads to better outcomes. [bib_ref] Disparities in lung cancer care and outcomes among elderly in a medically..., Nadpara [/bib_ref] [bib_ref] Quality gaps and comparative effectiveness in lung cancer staging and diagnosis, Ost [/bib_ref] [bib_ref] Quality gaps and comparative effectiveness in lung cancer staging and diagnosis, Ost [/bib_ref] In a study of 1,924 elderly patients, Nadpara et al 13 found no association between survival outcomes and timeliness of care but did find an association with guideline consistent care. Hence, the emphasis should still be on appropriate evidence-based guideline consistent care. Regional information sharing and collaboration between centers with appropriate referral to optimize resource utilization is probably the single most important intervention that can help minimize delays in cancer care while optimizing resource allocation. This will help to protect COVID-19-negative patients with cancer from becoming infected and will maximize resources for patients with COVID-19. chestjournal.org 6. In patients with confirmed COVID-19 infection who recover and need a routine bronchoscopy, we suggest the timing of the procedure is customized based on the indication for the procedure, the severity of the COVID-19 infection and time from symptom resolution (Ungraded Consensus-Based Statement). ## Remarks: The exact time to perform bronchoscopy is still unknown. It would be reasonable to wait at least 30 days from resolution of symptoms with negative SARS-CoV-2 RNA tests from at least two consecutive nasopharyngeal swab specimens collected $24 hours apart. Further research is needed to better understand optimal timing of bronchoscopy performance relative to symptom resolution. Other studies on patients with COVID-19 infections noted that rRT-PCR was positive from the respiratory tract up to 37 days from onset of symptoms and for an even longer duration in stool samples than throat swabs. [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation..., Ling [/bib_ref] In a study comparing sputum samples with pharyngeal swabs, sputum rRT-PCR reported positive up to 39 days after pharyngeal swabs turned negative in patients with COVID-19; the duration was longer in patients who received steroids. [bib_ref] SARS-CoV-2-positive sputum and feces after conversion of pharyngeal samples in patients with..., Chen [/bib_ref] Complicating the extended viral shedding is the performance of the rRT-PCR test because it has been shown to be false negative both in the early part of the infection and after resolution of symptoms when viral shedding may be below the threshold of detection for the test. [bib_ref] Potential preanalytical and analytical vulnerabilities in the laboratory diagnosis of coronavirus disease..., Lippi [/bib_ref] The CDC 68 has guidance on discontinuation of transmission-based precautions using both a test-based and a non-test-based strategy. This guidance does not extend to procedure timing, but it does favor a testbased strategy in patients with severe illness, immunocompromised state, and those being transferred to long-term or assisted living facilities. This panel reached a consensus that the timing of nonurgent bronchoscopy in patients who have recovered from COVID-19 infection will need to be individualized based on disease severity, duration of illness, and a negative SARS-CoV-2 RNA test from at least two consecutive nasopharyngeal swab specimens collected $ 24 h apart (total of two negative specimens). The exact time to perform bronchoscopy is still unknown, but it would be reasonable to wait at least 30 days from resolution of symptoms. Further research is needed to validate this suggested waiting period. # Discussion and summary The recommendation and suggestions outlined in this document were specifically created to address what were thought to be clinically common and urgent questions that frontline physicians are likely to face. We focused mainly on questions related to bronchoscopy as an AGP, but it is important to note that the primary mode of transmission for COVID-19 infection is droplets. Therefore, contact precautions (face shield, mask, gown, and gloves) are the integral components of PPE strategy to prevent the transmission of this disease, and N-95 respirators or PAPRs represent additional precautions during AGPs such as bronchoscopy. We would like to stress that these protective strategies can be rendered completely ineffective if proper training on donning and doffing is not provided to HCWs. Proper personnel instruction and practice for wearing PPE should receive as much attention by health facilities as the chosen strategy for protection. There are three important limitations that need to be kept in mind. The first is the overall paucity of robust and direct evidence to inform the guidance. Although this is not entirely surprising for a disease process that is brand new to humanity, it underscores the importance of multiinstitutional and multinational collaboration in collating and rapidly disseminating clinical experiences and outcomes data under these unique circumstances. Specialty societies can play an enormously helpful role in such efforts and may be able to leverage their various networks for this, and future, novel pandemics. Second, because of the urgency of the situation, there may have been important questions that were unavoidably omitted in this particular statement. Information needs to be available at the speed of relevance and sometimes this results in a less comprehensive package. Finally, although all direct and indirect evidence was discussed with all panelists, literature search for every PICO question was performed by one panelist without an independent parallel search by a second panel member. This was unavoidable because of the limited time allotted for this effort and the desire to rapidly disseminate useful information to frontline physicians. The strengths of this document are the multidisciplinary panel that was composed of experienced bronchoscopists and interventional pulmonologists, infectious disease specialists, intensivists, respiratory therapists, and trainees and the robust methodology to formulate specific questions, evaluate the literature with validated tools, and seek consensus while minimizing groupthink. Physicians searching for evidence on bronchoscopy during this challenging time of the COVID-19 pandemic should use this document as general guidance and adapt it to their local situation. This statement should be envisioned as a living document that should be updated in the future as new evidence undoubtedly comes to light. [table] TABLE 1 ]: PICO Questions [/table] [table] TABLE 2 ]: Urgency of Bronchoscopy Procedures [/table]	None	http://journal.chestnet.org/article/S0012369220308503/pdf	None
6f7ada14ea1be1e69bb7af2cc9efb64fcc57a69f	pubmed	Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015) – short version	Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 (DAS-Guideline 2015) – short version # Methods This guideline has the highest development credentials, S3, indicating that it is both evidence-and consensus based. The guideline task-force consisted of 49 voting members nominated by 17 participating national societies. These members formed work groups that identified main clinical issues and framed key-questions to be addressed. Should previous versions of the guideline not /no longer provide satisfactory resolutions to the selected topics, search strategies were developed to address the subject. The resulting recommendations were then collected in an early version and further discussed within the groups. The members interacted with each other via consensus-conferences, email, fax, or mail. Communication was managed by a coordinating group consisting of 4 members, as well as the chairing societies. A systematic literature search was performed by a special team under the supervision of an epidemiologist. Finally, the evalu-ation process was done by the individual working groups, which also set the level-of-evidence (LoE). All searches were performed between April and May of 2014. When necessary, new evidence was integrated manually. The LoE was determined, as in the previous version of the guideline, using the Oxford System [1]. The overview tables allow to identification the evidence for each individual manuscript. Literature was accessible for all taskforce members. The specific search strategies, searched terms, inclusion and exclusion criteria, as well as exact time frames, are all detailed in the methodological report. Sources were electronic databases (Medline ® ), guideline networks, and (manually) abstracts and congress-publications. In order to identify "grey literature", all task-force members were asked to search for publications outside Medline and Embase and include relevant entries to the literature-data-base. Systematic guideline searches were conducted within the AWMF-registry (http://www.awmf. org/leitlinien.html) and the Guidelines International Network (G-I-N) (http://www.g-i-n.net). In line with the AWMFguideline developer manual, a consensus-based decision was used to assess whether recommendations from other guidelines could be adapted. Cultural adaptions were adopted in accordance with recommendations from the ADAPTE-Collaboration. Voting only took place following a full disclosure of potential conflicts of interest by the task-force members. The conflict of interest forms were stored centrally, and all task-force members declaring a conflict of interest were required to abstain from voting in the corresponding issues. This was consented in the task-force before the voting process. The voting-process itself was conducted during consensus-conferences, under the supervision of an independent observer from the AWMF. Alternatively, members could vote using an online DELPHI, as published and recommended in the AWMF-guideline developer manual. The used grades of recommendation (GoR) were A = strong recommendation (we recommend/one shall), B = recommendation (we suggest/one should), and O = open recommendation (one might consider) for or against any specific intervention. Significant deviations between LoE and GoR were generally possible if a member of the group requested upgrading or downgrading of a recommendation (e.g. due to ethical relevance or lack of research-possibilities). Expert opinions and consensusbased decisions were only allowed when the resolutions were highly relevant for clinical routine and there was lack of available evidence. The guideline was reviewed and approved by 17 scientific societies. Reviewers were all independent peers. All procedures are in adherence to the actualization protocol. The next regular update of the guideline is scheduled for 2018, although earlier modifications are permitted should significant new evidence arise. ## Management of delirium, analgesia, and sedation in adult intensive care Risk and prevention of ICU related delirium Pain, stress, anxiety, and a disrupted sleep-wake cycle are common symptoms that occur in critically ill patients that increase the risk for ICU related delirium [bib_ref] Investigators; Canadian Critical Care Trials Group. Prevalence, risk factors, and outcomes of..., Mehta [/bib_ref]. Delirium is one of the most common manifestations of cerebral dysfunction in critically ill patients, which affects not only short-term recovery (in terms of prolonged ventilation and length of stay, as well as increased mortality) [bib_ref] Delirium as a predictor of mortality in mechanically ventilated patients in the..., Ely [/bib_ref] , [bib_ref] Incidence, risk factors and consequences of ICU delirium, Ouimet [/bib_ref] , [bib_ref] Impact of delirium on clinical outcome in critically ill patients: a meta-analysis, Zhang [/bib_ref] , but also leads to cognitive long-term impairment, posttraumatic stress disorders (PTSD), and reduced quality of life [bib_ref] BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness, Pandharipande [/bib_ref]. These entities are part of the Post Intensive Care Unit Syndrome (PICS) that has been recently described in ICU survivors. Aside from managing the risk factors, several effective pharmacological and non-pharmacological prevention strategies can be used to prevent or treat ICU delirium. In addition to baseline factors, the risk for delirium also comprises treatment associated factors, as well as psychological, social, and iatrogenic aspects [bib_ref] Risk factors for incident delirium among older people in acute hospital medical..., Ahmed [/bib_ref]. The presence or development of risk factors for delirium shall be closely evaluated in order to ensure the prompt introduction of preventive measures. The non-pharmacological measures were shown to be particularly effective in the prevention of delirium, and shall therefore be implemented for all critically ill patients. The excessive use of sedation shall be avoided, since a deep sedation were shown to deteriorate the clinical outcome. A pharmacological prevention is to be reserved only for patients at high risk for delirium, and is not generally recommended [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. [All the tables are displayed following the (English) version of the article.] Monitoring of analgesia, sedation, delirium, anxiety, stress, and sleep A basic concept of patient-oriented therapy in intensivecare is the definition of a patient-specific treatment goal, and the frequent assessment of the current status in order to promptly introduce or adjust interventions (Goal Directed Therapy). The definition and monitoring of treatment goals must be symptom-oriented, using validated scores and instruments. The use of such validated methods has a major impact on treatment: the systematic evaluation of pain, sedation, and delirium can significantly improve treatment of pain, reduce nosocomial infections, decrease duration of mechanical ventilation and hospitalization, as well as reduce mortality [bib_ref] Impact of systematic evaluation of pain and agitation in an intensive care..., Chanques [/bib_ref] , [bib_ref] Key performance indicators in intensive care medicine. A retrospective matched cohort study, Kastrup [/bib_ref]. Therefore, it should be a standard in all ICUs to define goals, measure, and document the current state of analgesia, sedation, and delirium once per shift (usually every The evaluation of anxiety with a validated scale is desirable, since anxiety is often not properly estimated, and thus not properly treated. There are short versions of standard psychological measurement instruments available (State-Trait Anxiety Inventory, state subscale [STAI-s], Brief Symptom Inventory Anxiety, subscale [BSI-A]) that allow a valid and reliable assessment of anxiety. From pain assessment, we know that one-dimensional selfassessment scales have proven to be especially practical to measure therapeutic needs and therapeutic response. From pain assessment studies, it is clear that the use one-dimensional self-assessment scales are particularly useful in evaluating the therapeutic needs and therapeutic response. Studies on anxiety show that similar scales (for example linear Visual Analogue Scale and the Faces Anxiety Scale) are also suitable to measure anxiety with good diagnostic validity . Further studies are needed to clarify whether the controllability of anxiolysis can also be monitored with these scales. Stress and disturbances of the sleep-wake cycle are further syndromes in ICU-patients that not only negatively affect recovery, but also constitute risk factors for serious complications. Nevertheless, there are currently no validated routine instrument for measuring stress and sleep, and the sole subjective assessment of vital signs by the ICU personnel is not suitable to monitor stress in critically ill patients [bib_ref] A systematic review of measurements of physical function in critically ill adults, Tipping [/bib_ref]. Regarding the sleep-wake cycle of ICU patients, not only is there a lack of suitable monitoring procedures that can be routinely used, but also no valid evaluation of sleep stages in critically ill subjects [bib_ref] Diurnal sedative changes during intensive care: impact on liberation from mechanical ventilation..., Seymour [/bib_ref] [fig_ref] Table 4: Monitoring -general aspects [/fig_ref]. ## Treatment concepts See . ## Non-pharmacological concepts See [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. Analgesia ICU-patients require an individualized pain management. Pain exerts considerable negative effects on recovery and is one of the most commonly reported stressors for ICU-patients. Therefore, a sufficient analgesia in all ICU patients -regardless of indication of sedation -should be ensured, and potentially painful procedures should be met with a preventive analgesic approach. In the ICU, the analgesia regimen is usually opioid based, [bib_ref] Short term analgesia based sedation in the Intensive Care Unit: morphine vs..., Carrer [/bib_ref] , [bib_ref] Remifentanil for tracheal tube tolerance: a case control study, Machata [/bib_ref] , [bib_ref] Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse..., Memis [/bib_ref] , as the risk-benefit profile of non-opioid analgesics is still a matter of scientific discussion (low analgesic potential, but considerable side effects). A combination with regional analgesia can be used [bib_ref] Protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic..., Pöpping [/bib_ref] , and a patient-controlled analgesia is recommended as soon as the patient is sufficiently awake (RASS 0/-1 and no delirium) [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## Sedation The current evidence reveals that a measurable sedation should always be avoided, as long as there is no mandatory clinical indication for sedation [bib_ref] Efficacy and safety of a paired sedation and ventilator weaning protocol for..., Girard [/bib_ref] , [bib_ref] Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation, Kress [/bib_ref]. A deep sedation, also within the first 48 hours, is associated with increased mortality, prolonged mechanical ventilation, prolonged ICU-LOS, and hospitalization, [bib_ref] SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Delirium..., Shehabi [/bib_ref] , [bib_ref] Early deep sedation is associated with decreased in-hospital and two-year follow-up survival, Balzer [/bib_ref] , [bib_ref] Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials..., Shehabi [/bib_ref]. Aside from specific indications (e.g. surgical indications, signs of increased intracranial pressure with impending herniation, or reduction of oxygen consumption in case of imminent hypoxia), the treatment goal should be an alert, cooperative patient who can tolerate the required interventions (RASS 0/-1). It is fundamental to achieve an adequate analgesia, which is accompanied by a specific treatment of possible symptoms, such as hallucinations, stress, and anxiety [bib_ref] Management of sedation in mechanically ventilated patients, Hogarth [/bib_ref] , [bib_ref] Sedation in the intensive care unit, Young [/bib_ref] , [bib_ref] A protocol of no sedation for critically ill patients receiving mechanical ventilation:..., Strom [/bib_ref]. A recent systematic review revealed a decreased importance of daily sedation interruptions (DSIs), which is no longer considered superior to protocol-driven management of sedation. The goal for light sedation should be set as early as possible, as the first 48 hours of sedation predict long-term outcome. Sedation should follow the principles of an "early goal directed therapy" with target-RASS 0/-1 [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## Moderate or deep sedation If the indication for a deep sedation is provided, the target RASS and the time of the next re-evaluation must be defined. Sedation should be performed with a combination of hypnotic and analgesic agents, whereas the choice of hypnotic agent should be appropriate to level of sedation and controllability desired. Aside from propofol and benzodiazepines, volatile anesthetics are also feasible options. In the absence of contraindications, DSI protocol (e.g., Spontaneous Awakening Trial, SAT) and Spontaneous Breathing Trials (SBT) should be carried out daily in patients with RASS ≤-2 [bib_ref] Canadian Critical Care Trials Group. Daily sedation interruption in mechanically ventilated critically..., Mehta [/bib_ref] [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## Symptom oriented sedative therapy Aside from pain, the most common symptoms of critically ill patients are stress, anxiety, agitation, psychotic symptoms, and sleep disturbances, all of which require a targeted, symptom-oriented therapy. In addition to nonpharmacological strategies and a causal treatment, a pharmacological therapy may be necessary to control the symptoms. Alpha-2-agonists are available for stress-reduction and treatment of vegetative symptoms, and benzodiazepines can be used for anxiolysis [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## Pharmacological therapy of delirium Preventive measures for delirium are both safe and effective [bib_ref] Pharmacological treatments of non-substance-withdrawal delirium: a systematic review of prospective trials, Friedman [/bib_ref]. If delirium does occur, it should be treated promptly and symptomatically. The treatment of psychotic symptoms (with or without delirium) may include low-dose neuroleptics [bib_ref] Atypical antipsychotics in the treatment of delirium, Wang [/bib_ref]. In addition, the use of alpha-2 : Symptom-based therapy and reduction of delirium, anxiety, stress, and protocol-based analgesia, sedation, and sleep-management in intensive care medicine Algorithm that focuses on a possible holistic management for adult critically ill patients. RASS: Richmond Agitation-Sedation Scale. Other scores (delirium, analgesia: observational/self-assessment), please, s.f. addendum at http://www.awmf.org/leitlinien/detail/ll/001-012.html. agonists is also suitable for a symptom-orientated therapy of delirium, [bib_ref] MIND Trial Investigators. Feasibility, efficacy, and safety of antipsychotics for intensive care..., Girard [/bib_ref]. A special situation is the alcohol withdrawal delirium in the ICU, for which long-acting benzodiazepines should be considered [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## Weaning from mechanical ventilation The new German S2k-Guidelines on "Prolonged Weaning" AWMF (020/015) provides recommendations regarding weaning from mechanical ventilation. The management of analgesia, sedation, and delirium influence the weaning process significantly [bib_ref] Weaning from mechanical ventilation and sedation, Luetz [/bib_ref]. In order to start weaning as early as possible, it is useful to combine sedation and weaning protocols [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## Treatment with neuromuscular blocking agents (nmba) There is no indication for a general use of a neuromuscular blockade during intensive care treatment. During neuromuscular blockade, patients cannot be awake, actively participate in their recovery, nor benefit from physiotherapy. When there is a specific indication for NMBAs, adequate analgesia and sedation should be provided . Furthermore, the depth of blockade should be monitored [bib_ref] Pharmacodynamics of cisatracurium in the intensive care unit: an observational study, Dieye [/bib_ref] , and the duration should be kept as short as possible [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## Intra-and inter-hospital transports Especially during intra-and inter-hospital transports, movements or changes in the position of the patient are potentially painful events. Therefore, a symptomatic therapy should be continued and possibly adjusted during a transport [bib_ref] Bispectral index monitoring in helicopter emergency medical services patients, Heegaard [/bib_ref]. An inadequate sedation (over-and undersedation) should be avoided at all times, as this can lead to an acute deterioration of neurological and cardiovascular parameters [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. Analgesia, sedation, and delirium management in special patients ## Pregnant and breastfeeding women in the icu The pharmacotherapy of pregnant and breastfeeding patients in the ICU is particularly challenging, as it must account for the effects of the drugs on the unborn or breast-fed child. Due to the lack of randomized-controlled trials, there is little evidence for pharmacotherapy of pregnant or breastfeeding women. Should there be an indication for opioids or sedatives during these periods, an adequate monitoring of the child is obligatory [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## End-of-life care Impending death is a period that can be severely influenced by anxiety, stress, and pain. Dying patients require the same patient-centred care as other ICU patients. Frequent monitoring and sufficient pharmacotherapy should ensure the patient is free of discomfort, even if this leads to a acceleration of the dying process [bib_ref] Challenges in end-of-life care in the ICU, Carlet [/bib_ref]. This guideline should be used and evaluated in the light and in-line with the "guideline of limitations to intensive care treatment"and the "basic principles for medical palliative care", published by the German Medical Association [fig_ref] Table 2: Prevention and risk reduction [/fig_ref]. ## Patients with severe burn injury Severe burn injuries lead to strong pain, possible hyperalgesia, as well as a prolonged hospitalization. Aside from an adequate basic level of analgesia, additional analgesics (local and systemic) and/or procedural sedation may be necessary when performing various procedures (e.g. dressing changes). There are multimodal concepts for the use of analgesics, adjuvants, and non-pharmacological strategies regarding pain management in patients with severe burns [bib_ref] The management of pain in the burns unit, Richardson [/bib_ref]. Especially for analgesia and sedation of burn-injured children, the use of standardized protocols and training programs should be used [bib_ref] Analgesia and sedation for children undergoing burn wound care, Bayat [/bib_ref] [fig_ref] Table 1: Risk factors for ICU-delirium [/fig_ref]. ## Multiple trauma patients The German AWMF-guideline registered under 012/019 provides recommendations regarding patients with multiple trauma . There is no evidence for a clear superiority of a particular drug for analgesia in severely injured patients. Opioids (morphine, fentanyl, sufentanil, alfentanil, remifentanil), ketamine [bib_ref] Ketamine for continuous sedation of mechanically ventilated patients, Umunna [/bib_ref] (s-enantiomer, racemate), and adjuvant alpha-2-agonists (clonidine) are used routinely in the clinic. Due to an increased risk for adrenal insufficiency and numerous alternatives, etomidate should no longer be used for procedural sedation, and is no longer recommended in trauma patients. Nevertheless, there is no evidence that the administration of etomidate has long-term effects on outcome [47], [fig_ref] Table 2: Prevention and risk reduction [/fig_ref]. ## Patients with intracranial hypertension A main focus of the intensive care management of patients with severe traumatic brain injury is the reduction of secondary damage. Although there is little evidence that sedation directly lowers intra-cranial-pressure (ICP), the acute treatment of patients with elevated ICP starts with a deep sedation (RASS-5). There are no validated monitoring systems for this patient subgroup, so the general scores and monitoring instruments are used [bib_ref] Neurological examination of critically ill patients: a pragmatic approach, Sharshar [/bib_ref]. A frequent neurological examination is obligatory. The choice of sedatives should be in-line with recommendations made in the general part. An ideal analgesic/ [fig_ref] Table 2: Prevention and risk reduction [/fig_ref] properties, and should allow short wake-up times for the assessment of patients after a brief infusion interruption [bib_ref] Sedation in neurointensive care: advances in understanding and practice, Citerio [/bib_ref] [fig_ref] Table 2: Prevention and risk reduction [/fig_ref]. ## Cardiac surgery Fast-track concepts include a 2-hour sedation phase after uncomplicated cardiac surgery. In this setting, numerous analgesia and sedation protocols have proven to be advantageous [bib_ref] A greater analgesia, sedation, delirium order set quality score is associated with..., Dale [/bib_ref] , and fast-track strategies seem to reduce the incidence of postoperative delirium [bib_ref] Meta-analysis of factors which influence delirium following cardiac surgery, Lin [/bib_ref]. Delirium in cardiac surgical patients is associated with a higher mortality [bib_ref] Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and..., Witlox [/bib_ref] , so that a delirium screening with a validated tool -as generally recommended -is especially important [bib_ref] Postoperative delirium in a substudy of cardiothoracic surgical patients in the BAG-RECALL..., Whitlock [/bib_ref] , [bib_ref] Pregabalin has an opioidsparing effect in elderly patients after cardiac surgery: a..., Pesonen [/bib_ref] [fig_ref] Table 2: Prevention and risk reduction [/fig_ref]. ## Patients on extracorporeal life support systems (ecls) There is a grey area regarding the level of sedation for patients on ECLS, where safety-aspects and the ability to positively influence recovery must be balanced. Patients on ECLS have numerous delirium risk-factors. Hyperactive delirium or agitation can be life-threatening for these patients, so that a consequent monitoring and a symptomatic therapy of stress, anxiety, delirium, pain, and insomnia is essential to safely achieve a target RASS of 0 [bib_ref] Extracorporeal Co2 removal in hypercapnic patients at risk of noninvasive ventilation failure:..., Sorbo [/bib_ref] , [bib_ref] Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation, Fuehner [/bib_ref] , [bib_ref] Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide removal in patients failing..., Kluge [/bib_ref] , [bib_ref] Extracorporeal CO2 removal as bridge to lung transplantation in life-threatening hypercapnia, Schellongowski [/bib_ref] , [fig_ref] Table 2: Prevention and risk reduction [/fig_ref]. ## Special positioning of patients Positioning therapy is used for prophylaxis and treatment of respiratory dysfunctions , and requires an individual sedation target. Changes of the position frequently represent a challenge for the symptomatic treatment of anxiety, stress, and pain. Therefore, a symptom-orientated therapy should be adapted for changing demands during positioning therapy. Though a deep sedation may be indicated for patient repositioning, , , an excessive sedation should be avoided. ## Analgesia, sedation, and delirium management in children monitoring For the monitoring of analgesia, sedation, and delirium in children, there are validated monitoring scales are that take developmental stage into account . Also in the pediatric intensive care, adequate monitoring and individual therapy goals are essential for successful patientoriented care [fig_ref] Table 2: Prevention and risk reduction [/fig_ref]. Generally, children aged ≥3 years are able to evaluate pain-levels. Even in children, a self-assessment of pain is superior to observational scales , and the Faces Pain Scale-revised has been well-established as a valid monitoring tool . If children are unable to assess their pain, there are several age-appropriate observational pain assessment scales. However, both in very premature infants as well as in children and adolescents with neurocognitive impairment, those instruments have a limited value and tend to systematically underestimate pain [bib_ref] Judgments of pain in the neonatal intensive care setting: a survey of..., Breau [/bib_ref] , , . Combined pain and distress sedation scales have been validated for the monitoring of sedation in children. For premature and full-term neonates, the Neonatal Pain, Agitation and Sedation Scale (N-PASS) is available. For infants and toddlers, the COMFORTneo Scale and the Comfort-B Scale are available. Additionally, there are special scales for assessing opioid or sedative withdrawal following a continuous therapy. Children can also suffer from delirium, and their symptoms are often misinterpreted. The pediatric critical care community has a need for a systematic delirium screening with validated tools , , , . ## Treatment strategies in children Critically ill children -like adults -require an individual pain therapy adapted to their current situation. This includes multimodal therapy strategies for opioids, nonopioids, and regional analgesia, as well as for local anesthetics, co-analgesics and non-pharmacological procedures [fig_ref] Table 3: Long-term consequences [/fig_ref]. When regarding analgesia in children, it is important to consider that pharmacokinetics and pharmacodynamics differ with age. Additional and supportive procedures for analgesia are also recommended for children. There are different non-pharmacological procedures available that can be used for co-analgesia, per example the administration of oral glucose, non-nutritive suction for neonates, or virtual reality for pediatric burn patients. Children require sedation, sometimes continuously, in order to undergo certain diagnostic and therapeutic procedures. For sedation in children, special personnel and structural prerequisites are required. Oversedation should be avoided as always, and careful titration is required to keep dosages as low as possible. There is still a high demand for research regarding pediatric delirium. In principle, it is essential to detect delirious symptoms as early as possible and identify and neutralize potential causes. Current evidence revealed a combination of psychological, social (presence of family, toys, pictures of home, normal day-night rhythm, etc.), and pharmacological interventions to be effective . Analgesia, sedation, and delirium management in elderly patients The "clinical age" is determined by the biological age, frailty, comorbidities, long-term medication, and external influences. The ageing of the cardiovascular, respiratory, renal, and nervous-systems lead to changes in pharmacodynamics and kinetics. The inherent age cannot be based on a chronological age alone [fig_ref] Table 3: Long-term consequences [/fig_ref]. Elderly patients lack the resources to compensate for delirium-associated complications, thus a frequent and active screening for delirium is paramount. In principle, all monitoring instruments used for the adult patients may be used for elderly patients. To evaluate pain in patients with cognitive impairment or dementia, tools such as Faces Pain Scale, PAINAD-scale as well as the BESDscale (German scale) are available. Preventive measures such as reorientation, visual and hearing aids are especially indicated for elderly patients . Regarding the treatment of delirium, a symptomatic treatment should consider the delirogenic effects of longacting benzodiazepines , the cardiac side effects of neuroleptics, and the use of appropriately cautious dosages , , . For the treatment of delirium, melatonin or melatonin-analogues should be considered at night to reduce the incidence and duration of delirium . Economy, quality assurance and implementation of the guideline In terms of quality assurance, management of analgesia, sedation and delirium in the ICU should be conducted according to guidelines and subject to a continuous quality verification [bib_ref] American College of Critical Care Medicine. Clinical practice guidelines for the management..., Barr [/bib_ref]. This includes the regular training of personnel in the implementation of the guidelines [bib_ref] Large-scale implementation of sedation and delirium monitoring in the intensive care unit:..., Pun [/bib_ref]. Special consideration for regional characteristics and internal Standard Operating Procedures improved the integration of guideline recommendations [bib_ref] Large-scale implementation of sedation and delirium monitoring in the intensive care unit:..., Pun [/bib_ref]. As a follow-up to the surveys of 2002 and 2006, a current survey on the current implementation of the S3-guideline in clinical routine is being carried out and will be published. Before the next guideline update process, an additional survey will assess the level of implementation [fig_ref] Table 3: Long-term consequences [/fig_ref]. ## Notes Extended version of the guideline We recommend the use of validated scales for the therapy control of analgesia, sedation, anxiety, and delirium (10). [10] 1b A The suitability and significance of diagnostic devices are still unclear. However, we recommend the use of such devices, in a supporting role, on patients who are deeply sedated (RASS -4/-5) or under neuromuscular blockade, so as to promptly identify under or oversedation [bib_ref] Monitoring sedation in critically ill patients: bispectral index, Ramsay and observer scales, Hernández-Gancedo [/bib_ref] [bib_ref] Continuous nervous system monitoring, EEG, the bispectral index, and neuromuscular transmission, Arbour [/bib_ref] [bib_ref] Role of the bispectral index in sedation monitoring in the ICU, Leblanc [/bib_ref]. Upgrading: relevance [bib_ref] Monitoring sedation in critically ill patients: bispectral index, Ramsay and observer scales, Hernández-Gancedo [/bib_ref] 2b [bib_ref] Continuous nervous system monitoring, EEG, the bispectral index, and neuromuscular transmission, Arbour [/bib_ref] 3b [bib_ref] Role of the bispectral index in sedation monitoring in the ICU, Leblanc [/bib_ref] 2a A 4. [bib_ref] Impact of systematic evaluation of pain and agitation in an intensive care..., Chanques [/bib_ref] We recommend the use of EEG monitoring in order to identify non-convulsive seizure activity in patients with reduces level of consciousness (e.g., hypoactive delirium, which does not respond to a pharmacological therapy) [bib_ref] Baseline EEG pattern on continuous ICU EEG monitoring and incidence of seizures, Swisher [/bib_ref]. Upgrading: clinical relevance / frequency [bib_ref] Baseline EEG pattern on continuous ICU EEG monitoring and incidence of seizures, Swisher [/bib_ref] 2b A According to the pain level and potential side effects, non-opioids and/or co-analgesics may be considered as alternative or adjunctive medication. ## Downgrading: individual indication [129] 1a 0 ## 5.b.4 A patient-controlled analgesia may be considered dependent on the patient's condition (RASS 0/-1, no delirium). ## Downgrading: feasibility [20] 1a 0 [formula] 5.b.5 [/formula] If the patient is awake and cooperative, patient-controlled analgesia (PCA) should be preferred over conventional application methods, as improved pain control and patient satisfaction are achieved. ## Downgrading: feasibility [20] 1a B 5.b. [bib_ref] Impact of delirium on clinical outcome in critically ill patients: a meta-analysis, Zhang [/bib_ref] The possibility of a combination with regional analgesia (in particular epidural analgesia) should be considered [bib_ref] Protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic..., Pöpping [/bib_ref]. The placement of regional catheters and initiation of therapy should take place as early as possible before surgery. ## Downgrading: feasibility, individual indication [formula] [19] 1a B 5.b.7 [/formula] Potentially painful interventions shall only be performed under adequate analgesia (local, regional, general anaesthesia, or sedation). Upgrading: ethics 5 A ## Regional analgesia loe gor 6.1 Before employing regional anesthesia, an individual risk-benefit assessment should take place, and this assessment should be re-evaluated on a daily basis. Upgrading: safety 5 B ## 6.2 In accordance with the indication and risk-benefit assessment, we recommend the preferred use of epidural catheters with local-anesthetics, as this has been shown to improve results on perioperative analgesia [bib_ref] Epidural anaesthesia and survival after intermediate-to-high risk non-cardiac surgery: a population-based cohort..., Wijeysundera [/bib_ref] , reduce pulmonary complications, improve intestinal motility and mobilization, as well as reduce ICU length of stay [bib_ref] The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses..., Ballantyne [/bib_ref] when compared to intravenous opioid-treatment. [130] 1a [bib_ref] Epidural anaesthesia and survival after intermediate-to-high risk non-cardiac surgery: a population-based cohort..., Wijeysundera [/bib_ref] 1b [bib_ref] The comparative effects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses..., Ballantyne [/bib_ref] 1a A 6. [bib_ref] Investigators; Canadian Critical Care Trials Group. Prevalence, risk factors, and outcomes of..., Mehta [/bib_ref] We suggest the use of an epidural catheter analgesia with either local anesthetics or in combination with an opioid, as these have been shown to be more effective than a sole epidural opioid administration in the treatment of pain [bib_ref] Epidural local anaesthetics versus opioid-based analgesic regimens on postoperative gastrointestinal paralysis, PONV..., Jorgensen [/bib_ref]. [133] 1a B 6.4 Neuraxial regional analgesia procedures should be atraumatic. If this is not possible, the procedure should be aborted and the patient should be closely monitored for possible complications. Upgrading: relevance, safety We suggest the development of local standards for the use of regional analgesic techniques in the ICU, so as to improve patient safety and facilitate the decision making process [bib_ref] University of Virginia Long Term Mechanical Ventilation Team. Implementation of an institutional..., Burns [/bib_ref]. ## Upgrading: relevance, safety [138] 4 B In adult burn patients, the use of co-analgesics, such as gabapentin, may be considered adjunctively to opioids [bib_ref] Effects of gabapentin on morphine consumption and pain in severely burned patients, Cuignet [/bib_ref]. [184] 3b 0 B3. [bib_ref] Delirium as a predictor of mortality in mechanically ventilated patients in the..., Ely [/bib_ref] We suggest the use of ketamine to reduce secondary hyperalgesia [bib_ref] Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burninduced..., Warncke [/bib_ref] [bib_ref] Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia..., Ilkjaer [/bib_ref] , and the opioid demand (187) of burn patients. [185] 1b [bib_ref] Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia..., Ilkjaer [/bib_ref] 1b [bib_ref] Ketamine for long-term sedation and analgesia of a burn patient, Edrich [/bib_ref] 4 B B3. [bib_ref] Incidence, risk factors and consequences of ICU delirium, Ouimet [/bib_ref] We suggest the use of alpha-2 agonists for sedation, as they have been shown to be more effective on burn patients as other drugs (e.g. benzodiazepines) [bib_ref] A meta-analysis of analgesic and sedative effects of dexmedetomidine in burn patients, Asmussen [/bib_ref]. Downgrading: individual indication [bib_ref] A meta-analysis of analgesic and sedative effects of dexmedetomidine in burn patients, Asmussen [/bib_ref] 1a B B3. [bib_ref] Impact of delirium on clinical outcome in critically ill patients: a meta-analysis, Zhang [/bib_ref] The topical application of lidocaine may be considered during dressing changes, as it alleviates pain during the procedure [bib_ref] Effectiveness of a topical local anaesthetic spray as analgesia for dressing changes:..., Desai [/bib_ref]. ## Downgrading: individual indication [189] 1b 0 B3. [bib_ref] BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness, Pandharipande [/bib_ref] We suggest using virtual reality (VR) as a non-pharmacological intervention, in additional to the pharmacological therapy of pain and anxiety [bib_ref] Grimmer-Somers K. The effectiveness of virtual reality on reducing pain and anxiety..., Morris [/bib_ref]. Downgrading: availability [bib_ref] Grimmer-Somers K. The effectiveness of virtual reality on reducing pain and anxiety..., Morris [/bib_ref] 1a B ## Burn-injured children loe gor B3a.1 We recommend using standardized protocols and training programs for analgesia and sedation during dressing changes in burned children [bib_ref] Analgesia and sedation for children undergoing burn wound care, Bayat [/bib_ref]. ## Upgrading: relevance [formula] [46] 5 A B3a.2 [/formula] For the of procedural pain, we suggest the use of ketamine over opioids [bib_ref] Superiority of oral ketamine as an analgesic and sedative for wound care..., Humphries [/bib_ref]. [bib_ref] Superiority of oral ketamine as an analgesic and sedative for wound care..., Humphries [/bib_ref] 2b B B3a.The combination of non-pharmacological procedures (massage in non-burned areas, hypnosis, and virtual reality) with opioids is more effective at alleviating pain than a single opioid analgesia. Therefore, we suggest using non-pharmacological procedures in combination with opioids in burn-injured children [bib_ref] Burn injuries benefit from massage therapy, Field [/bib_ref] , [bib_ref] Childrens' distress during burn treatment is reduced by massage therapy, Hernandez-Reif [/bib_ref] , [bib_ref] Psychological approaches during dressing changes of burned patients: a prospective randomised study..., Frenay [/bib_ref]. Downgrading: availability [bib_ref] Burn injuries benefit from massage therapy, Field [/bib_ref] 1b [bib_ref] Childrens' distress during burn treatment is reduced by massage therapy, Hernandez-Reif [/bib_ref] 1b [bib_ref] Psychological approaches during dressing changes of burned patients: a prospective randomised study..., Frenay [/bib_ref] 1b B B3a.3 For procedural sedation during dressing changes in burned children, the use of dexmedetomidine may be considered [bib_ref] A comparison of dexmedetomidine and midazolam for sedation in severe pediatric burn..., Fagin [/bib_ref]. Downgrading: off-label-use [bib_ref] A comparison of dexmedetomidine and midazolam for sedation in severe pediatric burn..., Fagin [/bib_ref] 1b 0 We suggest no longer the use of etomidate for procedural sedation on critically ill trauma patients [bib_ref] Increased risk of adrenal insufficiency following etomidate exposure in critically injured patients, Cotton [/bib_ref] [bib_ref] Adrenal suppression following a single dose of etomidate for rapid sequence induction:..., Hildreth [/bib_ref] [bib_ref] Single-dose etomidate for rapid sequence intubation may impact outcome after severe injury, Warner [/bib_ref]. Downgrading: inconsistent evidence1a [bib_ref] Increased risk of adrenal insufficiency following etomidate exposure in critically injured patients, Cotton [/bib_ref] 3b [bib_ref] Adrenal suppression following a single dose of etomidate for rapid sequence induction:..., Hildreth [/bib_ref] 1b [bib_ref] Single-dose etomidate for rapid sequence intubation may impact outcome after severe injury, Warner [/bib_ref] 2b1a B ## Patients with intracranial hypertension loe gor B5.1 According to current evidence, there is no evidence for the use of a specific monitoring tool able to assess analgesia or sedation of ICU patients with with severe traumatic brain injury or intracranial hypertension. We recommend frequent neurological examinations in these patients [bib_ref] Neurological examination of critically ill patients: a pragmatic approach, Sharshar [/bib_ref]. [50] 1a A B5.2 In patients with severe traumatic brain injury or intracranial hypertension, we recommend an adequate analgesia and sedation with a well-defined sedation targets (in terms of target RASS) [bib_ref] Guidelines for the management of severe traumatic brain injury. XI. Anesthetics, analgesics,..., Bratton [/bib_ref]. [bib_ref] Guidelines for the management of severe traumatic brain injury. XI. Anesthetics, analgesics,..., Bratton [/bib_ref] 1a A B5. [bib_ref] Investigators; Canadian Critical Care Trials Group. Prevalence, risk factors, and outcomes of..., Mehta [/bib_ref] We suggest the use of ketamine racemate during mechanical ventilation (constant paCO2) and additive sedation with GABAA-receptor-agonists (suppression of excitation) in patients with severe traumatic brain injury and intracranial hypertension [bib_ref] Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized..., Wang [/bib_ref]. Downgrading: off-label-use1a [bib_ref] Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized..., Wang [/bib_ref] 1a B B5. [bib_ref] Delirium as a predictor of mortality in mechanically ventilated patients in the..., Ely [/bib_ref] We suggest the use of a ketamine-racemate / midazolam-based or an opioid / midazolambased sedation regimen in mechanically ventilated patients with severe traumatic brain injury and intracranial hypertension [bib_ref] Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized..., Wang [/bib_ref]. ## Downgrading: off-label-use, individual indication [201] 1a [bib_ref] Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized..., Wang [/bib_ref] 1a B B5.5 A S(+)-ketamine / methohexital-based or a fentanyl / methohexital-based sedation strategy may be considered in mechanically ventilated patients with severe traumatic brain injury and intracranial hypertension [bib_ref] Ketamine for analgosedative therapy in intensive care treatment of headinjured patients, Kolenda [/bib_ref] [bib_ref] Safety of sedation with ketamine in severe head injury patients: comparison with..., Bourgoin [/bib_ref]. ## Downgrading: individual indication [203] 2b [bib_ref] Safety of sedation with ketamine in severe head injury patients: comparison with..., Bourgoin [/bib_ref] 2b 0 B5. [bib_ref] Impact of delirium on clinical outcome in critically ill patients: a meta-analysis, Zhang [/bib_ref] We suggest the monitoring the mean arterial pressure during continuous application of opioids (remifentanil, sufentanil, fentanyl, morphine) in patients with intracranial hypertension [bib_ref] Ketamine for analgosedative therapy in intensive care treatment of headinjured patients, Kolenda [/bib_ref] [bib_ref] Safety of sedation with ketamine in severe head injury patients: comparison with..., Bourgoin [/bib_ref] [bib_ref] Opioid sedation does not alter intracranial pressure in head injured patients, Lauer [/bib_ref]. [bib_ref] Ketamine for analgosedative therapy in intensive care treatment of headinjured patients, Kolenda [/bib_ref] [bib_ref] Safety of sedation with ketamine in severe head injury patients: comparison with..., Bourgoin [/bib_ref] [bib_ref] Opioid sedation does not alter intracranial pressure in head injured patients, Lauer [/bib_ref] 2b B B5. [bib_ref] BRAIN-ICU Study Investigators. Long-term cognitive impairment after critical illness, Pandharipande [/bib_ref] The favourable pharmacokinetics of remifentanil allows for a rapid neurological assessment. Therefore, we suggest the preferential use of remifentanil over other opioids for analgesia in NICU-patients, as long as the duration of sedation is expected to last less than 72 hours [bib_ref] Sedation in neurointensive care: advances in understanding and practice, Citerio [/bib_ref] [bib_ref] Critical care sedation for neuroscience patients, Mirski [/bib_ref]. [206] 2b [bib_ref] Critical care sedation for neuroscience patients, Mirski [/bib_ref] 2a [bib_ref] Sedation in neurointensive care: advances in understanding and practice, Citerio [/bib_ref] 2a2a2b B B5. [bib_ref] Risk factors for incident delirium among older people in acute hospital medical..., Ahmed [/bib_ref] We suggest avoiding bolus administration of opioids whenever possible. In the exceptional cases where it is necessary, MAP and ICP should be monitored [bib_ref] Sedation for critically ill adults with severe traumatic brain injury: a systematic..., Roberts [/bib_ref]. Downgrading: problem of steerability [bib_ref] Sedation for critically ill adults with severe traumatic brain injury: a systematic..., Roberts [/bib_ref] 1a B B5.9 For traumatic brain injury patients, the propofol-based and midazolam-based sedation regimens are similarly safe. We suggest the preferential use of propofol if rapid neurological assessments are necessary [bib_ref] Sedation for critically ill adults with severe traumatic brain injury: a systematic..., Roberts [/bib_ref]. ## Downgrading: individual medical situation/indication [formula] [210] 1a B [/formula] B5. [bib_ref] Impact of systematic evaluation of pain and agitation in an intensive care..., Chanques [/bib_ref] We do not recommend a high-dose barbiturate as prophylaxis for intracranial hypertension in patients with severe traumatic brain injury [bib_ref] Guidelines for the management of severe traumatic brain injury. XI. Anesthetics, analgesics,..., Bratton [/bib_ref] [bib_ref] The University of Toronto head injury treatment study: a prospective, randomized comparison..., Schwartz [/bib_ref] [bib_ref] Failure of prophylactic barbiturate coma in the treatment of severe head injury, Ward [/bib_ref] ## Monitoring of sedation in children loe gor [formula] C.1.b.1 [/formula] The Neonatal Pain, Agitation and Sedation Scale (N-PASS) and the COMFORTneo scale may be considered for the depth of sedation assessment in premature and full-term infants [bib_ref] The Neonatal Pain, Agitation and Sedation Scale and the bedside nurse's assessment..., Hillman [/bib_ref] [bib_ref] Successful implementation of a neonatal pain and sedation protocol at 2 NICUs, Deindl [/bib_ref] [bib_ref] The Neonatal Pain, Agitation and Sedation Scale reliably detected oversedation but failed..., Giordano [/bib_ref] [bib_ref] Clinical reliability and validity of the N-PASS: neonatal pain, agitation and sedation..., Hummel [/bib_ref] [bib_ref] The COMFORT behavioural scale and the modified FLACC scale in paediatric intensive..., Johansson [/bib_ref] [bib_ref] COMFORT scale: a reliable and valid method to measure the amount of..., Wielenga [/bib_ref]. [228] 2b [bib_ref] Successful implementation of a neonatal pain and sedation protocol at 2 NICUs, Deindl [/bib_ref] 1b [bib_ref] The Neonatal Pain, Agitation and Sedation Scale reliably detected oversedation but failed..., Giordano [/bib_ref] 1b [bib_ref] Clinical reliability and validity of the N-PASS: neonatal pain, agitation and sedation..., Hummel [/bib_ref] 1b2b [bib_ref] The COMFORT behavioural scale and the modified FLACC scale in paediatric intensive..., Johansson [/bib_ref] 2b [bib_ref] COMFORT scale: a reliable and valid method to measure the amount of..., Wielenga [/bib_ref] 2b [formula] 0 C.1.b.2 [/formula] As an observational scale, we recommend using the Comfort-B Scale to assess the depth of sedation in neonates and children (238). [238] 1b A [formula] C.1.b.3 [/formula] Following a continuous sedative therapy, we suggest considering the possibility of a sedative withdrawal (especially as seizure). The Finnegan-Score Monitoring tool is available to assess sedative-withdrawal in neonates, whereas the SOS and the WAT-1 scores are available for children and adolescents [bib_ref] Review of the assessment and management of neonatal abstinence syndrome, Bagley [/bib_ref] [bib_ref] Construction of the Sophia Observation withdrawal Symptomsscale (SOS) for critically ill children, Ista [/bib_ref] [bib_ref] The Withdrawal Assessment Tool-1 (WAT-1): an assessment instrument for monitoring opioid and..., Franck [/bib_ref]. [229] 1a [bib_ref] Construction of the Sophia Observation withdrawal Symptomsscale (SOS) for critically ill children, Ista [/bib_ref] 2b [bib_ref] The Withdrawal Assessment Tool-1 (WAT-1): an assessment instrument for monitoring opioid and..., Franck [/bib_ref] 1b B ## Non-pharmacological procedures in children loe gor ## C.2.b.1 We suggest regarding every corrigible environmental factor, and a attentive treatment should be ensured [bib_ref] Double-blind, placebo-controlled analgesic study of ibuprofen or rofecoxib in combination with paracetamol..., Pickering [/bib_ref]. Upgrading: relevance [formula] [250] 4 B C.2.b.2 [/formula] We suggest supporting a normal sleep pattern, particularly an adequate light and noise reduction, and the sleep-wake cycle of the patient should be considered. Upgrading: relevance In older, critically ill children, we suggest the use of enteral sedatives as early as possible [bib_ref] A randomized controlled trial of sedation in the critically ill, Parkinson [/bib_ref]. [formula] [239] 5 B [/formula] ## Downgrading: individual indication [260] 1b B C.2.c. [bib_ref] Impact of delirium on clinical outcome in critically ill patients: a meta-analysis, Zhang [/bib_ref] We recommend that the long-term sedation of neonates be undertaken only after critical risk-benefit analysis, and in very exceptional cases, such as life-threatening, otherwise uncontrollable agitation [bib_ref] Intravenous midazolam infusion for sedation of infants in the neonatal intensive care..., Ng [/bib_ref]. [formula] [261] 1a A C.2.c.7 [/formula] In the rare cases when neonate sedation is required, we suggest the preferential use of morphine over midazolam. In order to avoid sedative withdrawal, one may consider gradually tapering-off these drugs following a continuous therapy. In patients with advanced dementia, the "PAINAD Scale" (pain assessment in advanced dementia) may be considered for pain assessment [bib_ref] Development and psychometric evaluation of the Pain Assessment in Advanced Dementia (PAINAD)..., Warden [/bib_ref]. ## Downgrading: insufficient evidence at this point of the review ## 0 ## Downgrading: individual indication ## Economy, quality assurance, and implementation of the guideline loe gor ## E.1 We recommend that the management of analgesia, sedation and delirium in the ICU be compliant to the guidelines, and subject to a continuous quality review [bib_ref] American College of Critical Care Medicine. Clinical practice guidelines for the management..., Barr [/bib_ref]. [bib_ref] American College of Critical Care Medicine. Clinical practice guidelines for the management..., Barr [/bib_ref] 1a A E.2 Provided that the ICU nursing staff shows specific and qualified knowledge, experience, and skill, they may control the management of analgesia and sedation (using a syringe pump) according to predetermined protocols and doctor's orders [bib_ref] Effect of a nurse-implemented sedation protocol on the incidence of ventilator-associated pneumonia, Quenot [/bib_ref] [bib_ref] Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation, Brook [/bib_ref] [bib_ref] Effect of a scoring system and protocol for sedation on duration of..., Brattebo [/bib_ref]. Downgrading: individual clinical setting [bib_ref] Effect of a nurse-implemented sedation protocol on the incidence of ventilator-associated pneumonia, Quenot [/bib_ref] 1b [bib_ref] Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation, Brook [/bib_ref] 1b [bib_ref] Effect of a scoring system and protocol for sedation on duration of..., Brattebo [/bib_ref] 3b 0 E.3 In order to increase therapeutic safety and to facilitate decision-making, we recommend the implementation of internal standards for analgesia, sedation and treatment of delirium (including the use of sedation protocols) [bib_ref] Efficacy and safety of a paired sedation and ventilator weaning protocol for..., Girard [/bib_ref] [bib_ref] Protocol-driven ventilator weaning: reviewing the evidence, Girard [/bib_ref]. [formula] [21] 1b [281] 2b A E.4 [/formula] For the consistent implementation of guidelines and standards, we recommend the regular training of personnel in their application [bib_ref] Large-scale implementation of sedation and delirium monitoring in the intensive care unit:..., Pun [/bib_ref] [bib_ref] How to implement monitoring tools for sedation, pain and delirium in the..., Radtke [/bib_ref] [bib_ref] A systematic review of implementation strategies for assessment, prevention, and management of..., Trogrlic [/bib_ref]. [83] 2b [bib_ref] How to implement monitoring tools for sedation, pain and delirium in the..., Radtke [/bib_ref] 1b [bib_ref] A systematic review of implementation strategies for assessment, prevention, and management of..., Trogrlic [/bib_ref] 1a A [bib_ref] A systematic review of measurements of physical function in critically ill adults, Tipping [/bib_ref]. Zum Monitoring von Schlaf fehlt es an einer validen Beurteilung von Schlafstadien bei intensivmedizinischen Patienten, zum anderen an praktisch durchführbaren Monitoringverfahren, die sich in die Routine eingliedern lassen [bib_ref] Diurnal sedative changes during intensive care: impact on liberation from mechanical ventilation..., Seymour [/bib_ref] (Tabelle 4-9). ## Therapeutische konzepte Siehe Abbildung 2. ## Nicht-pharmakologische konzepte Siehe Tabelle 10. ## Analgesie Intensivmedizinisch-behandelte Patienten bedürfen einer individuell angepassten Schmerztherapie. Schmerzen haben deutlich negative Auswirkungen auf den Genesungsprozess und sind die häufigsten subjektiv empfundenen Stressoren bei Intensivpatienten. Daher muss eine suffiziente Analgesie bei allen Intensivpatienten -unab-hängig von der Indikation einer Sedierung-durchgeführt werden. Dabei erfolgen potentiell schmerzhafte Maßnahmen unter präventiver analgetischer Abschirmung. Die Analgesie wird auf der Intensivstation vorwiegend Opioidbasiert durchgeführt, [bib_ref] Short term analgesia based sedation in the Intensive Care Unit: morphine vs..., Carrer [/bib_ref] , [bib_ref] Remifentanil for tracheal tube tolerance: a case control study, Machata [/bib_ref] , [bib_ref] Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse..., Memis [/bib_ref]. Die Rolle von Nicht-Opioid-Analgetika wird neu diskutiert, weil beispielsweise NSAID ein vergleichsweise geringes analgetisches Potential bei einem gleichzeitig für Intensivpatienten ungünstigen Nebenwirkungsprofil aufweisen. Eine patientenkontrollierten Analgesie wird empfohlen, sobald der Zustand des Patienten dies ermöglicht (RASS 0/-1 und kein Delir). Auch eine Kombination mit Regionalverfahren ist möglich [bib_ref] Protective effects of epidural analgesia on pulmonary complications after abdominal and thoracic..., Pöpping [/bib_ref] (Tabelle 11). ## Sedierung Die aktuelle Evidenz belegt, dass eine messbare Sedierung immer vermieden werden soll, solange keine zwingende Indikation für eine solche vorliegt [bib_ref] Efficacy and safety of a paired sedation and ventilator weaning protocol for..., Girard [/bib_ref] , [bib_ref] Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation, Kress [/bib_ref]. Eine tiefe Sedierung auch innerhalb der ersten 48 h geht mit einer erhöhten Mortalität, einer prolongierten Beatmungsdauer und einer verlängerten Intensiv-und Krankenhausverweildauer einher, [bib_ref] SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Delirium..., Shehabi [/bib_ref] , [bib_ref] Early deep sedation is associated with decreased in-hospital and two-year follow-up survival, Balzer [/bib_ref] , [bib_ref] Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials..., Shehabi [/bib_ref]. Außerhalb spezieller Indikationen (z.B. chirurgische Indikationen, Hirndrucksymptomatik mit drohender Einklemmung oder zur Reduktion des Sauerstoffverbrauchs bei drohender Hypoxie), soll das Ziel ein wacher, kooperativer Patient, der die intensivmedizinisch erforderlichen Maßnahmen gut toleriert (RASS 0/-1) sein. Grundlage ist die suffiziente Analgesie, die von einer möglichst spezifischen Therapie von Symptomen, wie Halluzinationen, Stress und Angst begleitet wird [bib_ref] Management of sedation in mechanically ventilated patients, Hogarth [/bib_ref] , [bib_ref] Sedation in the intensive care unit, Young [/bib_ref] , [bib_ref] A protocol of no sedation for critically ill patients receiving mechanical ventilation:..., Strom [/bib_ref]. Patienten bedürfen keiner Aufwachversuche, wenn keine Sedierung durchgeführt wird. Der Stellenwert von täglichen Sedierungsunterbrechungen (daily sedation interruption (DSI)) zeigt sich in einem aktuellen systematischen Review nicht mehr der protokollbasierten Sedierung überlegen. Der Ziel-RASS 0/-1 soll so früh wie möglich etabliert werden, da die ersten 48h der Intensivbehandlung entscheidend für das Behandlungsergebnis sehen. Daher sollte ein Sedierungsprotokoll dem Prinzip der "early goal directed therapy" folgen (Tabelle 12). ## Moderate oder tiefe sedierung ## Pharmakologische therapie des delirs Präventive Maßnahmen zur Vermeidung eines Delirs sind effektiv und sicher durchführbar [bib_ref] Pharmacological treatments of non-substance-withdrawal delirium: a systematic review of prospective trials, Friedman [/bib_ref]. Falls ein Delir dennoch auftritt, muss es zeitnah symptomorientiert behandelt werden. Die Behandlung von produktiv-psychotischen Symptomen (im Rahmen eines Delirs oder auch ohne Delir) kann mit niedrig-dosierten Neuroleptika erfolgen [bib_ref] Atypical antipsychotics in the treatment of delirium, Wang [/bib_ref]. Ebenfalls ist der Einsatz von Alpha-2-Agonisten zur Delirtherapie geeignet, [bib_ref] MIND Trial Investigators. Feasibility, efficacy, and safety of antipsychotics for intensive care..., Girard [/bib_ref]. Eine Besonderheit stellt das Alkoholentzugsdelir auf Intensivstationen dar, bei dem langwirksame Benzodiazepine indiziert sind(Tabelle 15). ## Entwöhnung von der beatmung Das Prozedere der Beatmungsentwöhnung wird in der neuen S2k-Leitlinie "Prolongiertes Weaning" über die AWMF-Leitlinie (020/015) dargestellt. Das Management von Analgesie, Sedierung und Delirmanagement beeinflusst den Weaning-Prozess maßgeblich [bib_ref] Weaning from mechanical ventilation and sedation, Luetz [/bib_ref]. Um das Weaning zu einem frühestmöglichen Zeitpunkt beginnen zu können, empfiehlt sich ein Weaningsprotokoll mit einem Sedierungsprotokoll zu kombinieren (Tabelle 16). ## Neuromuskuläre blockade (nmb) ## Kardiochirurgische patienten Fast-track-Konzepte nach unkomplizierten kardiochirurgischen Verläufen beinhalten eine postoperative Kurzzeitsedierung in den ersten zwei Stunden nach der Operation. In diesem Setting haben sich zahlreiche Analgesieund Sedierungsprotokolle als vorteilhaft erwiesen [bib_ref] A greater analgesia, sedation, delirium order set quality score is associated with..., Dale [/bib_ref]. Fast-track-Konzepte scheinen somit die Inzidenz für ein postoperatives Delir zu reduzieren [bib_ref] Meta-analysis of factors which influence delirium following cardiac surgery, Lin [/bib_ref]. Gerade bei kardiochirurgischen Patienten wurde eine durch ein Delir erhöhte Mortalität nachgewiesen [bib_ref] Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and..., Witlox [/bib_ref]. Daher ist ein Delirscreening mit validem Instrumentwie im allgemeinen Teil empfohlen -besonders wichtig [bib_ref] Postoperative delirium in a substudy of cardiothoracic surgical patients in the BAG-RECALL..., Whitlock [/bib_ref] , [bib_ref] Pregabalin has an opioidsparing effect in elderly patients after cardiac surgery: a..., Pesonen [/bib_ref] (Tabelle 25). ## Patienten mit extrakorporalen herz-und lungenersatzverfahren Patienten mit extrakorporalen Herz-und Lungenersatzverfahren befinden sich bezüglich des Grades an zu erzielender Wachheit in einem Spannungsfeld zwischen Sicherheitsaspekten und der Möglichkeit wach aktiv den eigenen Heilverlauf zu beeinflussen. Patienten an extrakorporalen Herz-und Lungenersatzverfahren weisen etliche Risikofaktoren für das Auftreten eines Delirs auf. Agitation und ein hyperaktives Delir stellen ein vital bedrohliches Sicherheitsrisiko dar. Daher ist ein engmaschiges Monitoring und eine symptomorientierte Therapie von Stress, Angst, Delir, Schmerzen und Schlaflosigkeit essentiell, um einen Ziel-RASS = 0 bei Patienten an extrakorporalen Herz-und Lungenersatzverfahren sicher durchzuführen [bib_ref] Extracorporeal Co2 removal in hypercapnic patients at risk of noninvasive ventilation failure:..., Sorbo [/bib_ref] , [bib_ref] Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation, Fuehner [/bib_ref] , [bib_ref] Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide removal in patients failing..., Kluge [/bib_ref] , [bib_ref] Extracorporeal CO2 removal as bridge to lung transplantation in life-threatening hypercapnia, Schellongowski [/bib_ref] ,(Tabelle 26). ## Patienten mit spezieller lagerungstherapie Lagerungstherapien dienen der Prophylaxe und Behandlung von pulmonalen Funktionsstörungen und bedürfen eines individuellen Sedierungsziels. Positionsänderungen stellen häufig eine Herausforderung für die symptomorientierte Therapie von Angst, Stress und Schmerzen dar. Ihre symptomorientierte Therapie muss daher während einer Lagerungstherapie angepasst werden. Zur Umlagerung im Rahmen der Lagerungstherapie kann eine tiefe Sedierung indiziert sein , . Auch dabei muss eine Übersedierung vermieden werden. [bib_ref] Burn injuries benefit from massage therapy, Field [/bib_ref] , [bib_ref] Childrens' distress during burn treatment is reduced by massage therapy, Hernandez-Reif [/bib_ref] , [bib_ref] Psychological approaches during dressing changes of burned patients: a prospective randomised study..., Frenay [/bib_ref]. Downgrading: Verfügbarkeit [bib_ref] Burn injuries benefit from massage therapy, Field [/bib_ref] 1b [bib_ref] Childrens' distress during burn treatment is reduced by massage therapy, Hernandez-Reif [/bib_ref] 1b [bib_ref] Psychological approaches during dressing changes of burned patients: a prospective randomised study..., Frenay [/bib_ref] 1b B B3a.3 Zur prozeduralen Sedierung zum Verbandswechsel brandverletzter Kinder kann Dexmedetomidin verwendet werden [bib_ref] A comparison of dexmedetomidine and midazolam for sedation in severe pediatric burn..., Fagin [/bib_ref]. Downgrading: off-label-use [bib_ref] A comparison of dexmedetomidine and midazolam for sedation in severe pediatric burn..., Fagin [/bib_ref] 1b 0 [bib_ref] Increased risk of adrenal insufficiency following etomidate exposure in critically injured patients, Cotton [/bib_ref] [bib_ref] Adrenal suppression following a single dose of etomidate for rapid sequence induction:..., Hildreth [/bib_ref] [bib_ref] Single-dose etomidate for rapid sequence intubation may impact outcome after severe injury, Warner [/bib_ref] ,. Upgrading: Inkonsistente Evidenz1a [bib_ref] Increased risk of adrenal insufficiency following etomidate exposure in critically injured patients, Cotton [/bib_ref] 3b [bib_ref] Adrenal suppression following a single dose of etomidate for rapid sequence induction:..., Hildreth [/bib_ref] 1b [bib_ref] Single-dose etomidate for rapid sequence intubation may impact outcome after severe injury, Warner [/bib_ref] 2b [fig] Figure 1: Algorithm for monitoring of sedation, delirium, and pain in adult patients RASS: Richmond Agitation, Sedation Scale; CAM-ICU: Confusion Assessment Method for the Intensive Care Unit; ICDSC: Intensive Care Delirium Screening Checklist; BPS: Behavioral Pain Scale; BPS-NI: Behavioral Pain Scale, not intubated; CPOT: Critical Care Pain Observation Tool; FPS-R: Faces Pain Scale, revised 8 hours) with a validated clinical scores and instruments (Figure 1). [/fig] [table] Table 1: Risk factors for ICU-delirium [/table] [table] Table 2: Prevention and risk reduction [/table] [table] Table 3: Long-term consequences [/table] [table] Table 4: Monitoring -general aspects [/table] [table] Table 5: Monitoring of analgesia [/table] [table] Table 6: Monitoring of sedation [/table] [table] Table 7: Monitoring of delirium [/table] [table] Table 8: Monitoring of anxiety [/table] [table] Table 9: Monitoring of sleep [/table] [table] Tabelle 22: Das brandverletze Kind B4.1 Ketamin kann in Kombination mit Midazolam und/oder Propofol für Kurzeingriffe benutzt werden. Etomidate sollte nicht mehr für eine prozedurale Sedierung bei polytraumatisierten Patienten verwendet werden [/table] [table] 1a B: Tabelle 23: Polytraumatisierte Patienten Tabellen S. 12/18 Patienten mit erhöhtem intrakraniellen Druck LoE GoR B5.1 Anhand der aktuellen Datenlage kann keine Empfehlung für die Anwendung eines bestimmten Instruments zum Monitoring von Analgesie oder Sedierung bei intensivmedizinisch-behandelten Patienten mit schwerem SHT und intrakranieller Hypertension gegeben werden. Eine neurologische Untersuchung soll bei diesen Patienten engmaschig durchgeführt werden(50). Eine adäquate Analgesie und Sedierung nach Ziel-RASS soll in der Therapie von Patienten mit schwerem Schädel-Hirn-Trauma und/oder intrakranieller Hypertension durchgeführt werden(200). Razemat sollte bei kontrollierter Beatmung (paCO2 konstant) und additiver Sedierung mit GABA-Rezeptor-Agonisten (Unterdrückung der exzitatorischen Komponente) auch bei Schädel-Hirn-traumatisierten Patienten mit intrakranieller Hypertension erwogen werden(201,202). Ein Ketamin-Razemat/Midazolam-basiertes oder ein Opioid/Midazolam-basiertes Sedierungs-Regime sollten bei mechanisch beatmeten Schädel-Hirn-traumatisierten Patienten mit intrakranieller Hypertension eingesetzt werden(201,202). Ketamin/Methohexital-basiertes oder ein Fentanyl/Methohexital-basiertes Sedierungs-Regime können bei mechanisch beatmeten Schädel-Hirn-traumatisierten Patienten mit intrakranieller Hypertension eingesetzt werden (203), (204). Eine kontinuierliche intravenöse Applikation von Opioiden (Remifentanil, Sufentanil, Fentanyl, Morphin) sollte bei Patienten mit intrakranieller Hypertension stets unter Kontrolle des MAP erfolgen (203-205). Auf Grund der günstigen Pharmakokinetik und der damit verbundenen raschen neurologischen Beurteilbarkeit sollte Remifentanil im Vergleich mit anderen Opioiden vorrangig zur Analgosedierung von Neurointensivpatienten verwendet werden, sofern die Analgosedierung als kurzfristig erforderlich eingeschätzt wird (maximal 72 Stunden) (51), (206-209). Bolusgaben von Opioiden sollten möglichst vermieden werden und nur in Ausnahmen unter MAP-und ICP-Kontrolle gegeben werden (210). Ein Propofol-basiertes oder ein Midazolam-basiertes Sedierungs-Regime zur Sedierung Schädel-Hirn-traumatisierter Patienten sind gleichermaßen sicher. Wenn rasche neurologische Beurteilbarkeit gewünscht ist, sollte Propofol bevorzugt werden (210). B5.10 Eine hochdosierte Barbiturat-Therapie zur Prophylaxe einer intrakraniellen Hypertension soll bei Patienten mit schwerem Schädel-Hirn-Trauma nicht erfolgen (200), (211), (212). Eine hochdosierte Barbiturat-Therapie unter EEG-Monitoring sollte bei Patienten mit schwerem Schädel-Hirn-Trauma nur bei anderweitig (medikamentös und chirurgisch) nicht beherrschbarer intrakranieller Hypertension eingesetzt werden, sofern hämodynamische Stabilität gewährleistet ist (213-216). Tabelle 24: Patienten mit erhöhtem intrakraniellen Druck Tabellen S. 13/18 B6.1 Für die Analgesie additiv zur Sedierung sollten kurz-wirksame Opioid-Analgetika wie beispielsweise Remifentanil (217, 218) verwendet werden. Bei wachen, adäquaten Patienten sollte eine "Patient-Controlled-Analgesia" einer "Nurse-Controlled-Analgesia" vorgezogen werden (219). Patienten mit extrakorporalen Herz-und Lungenersatzverfahren LoE GoR B7.1 Besonders unter der Anwendung extrakorporaler Herz-und Lungenersatzverfahren soll ein zielgesteuerter Wachheitsgrad durch regelmäßiges klinisches Monitoring und kontinuierliche Dosisanpassung an den Sedierungsbedarf erreicht werden. Der Ziel-RASS an extrakorporalen Herz-und Lungenersatzverfahren sollte folgende Faktoren berücksichtigen: Patienten an extrakorporalen Herz-und Lungenersatzverfahren haben etliche Risikofaktoren für das Auftreten einer PTSD (220), ein höherer Grad an Wachheit ist mit der Möglichkeit zur aktiven Teilnahme an physiotherapeutischen Übungen verbunden (221) und ein Ziel-RASS = 0 ist sicher durchführbar (57-61). Tabelle 26: Patienten mit extrakorporalen Herz-und Lungenersatzverfahren Tabellen S. 14/18 Monitoring von Analgesie bei Kindern LoE GoR C.1.a.1 Altersgemäße, validierte Scoringsysteme sollen bei Kindern zur Therapiesteuerung und Überwachung von Analgesie, Sedierung und Delir eingesetzt werden (65). C.1.a.2 In der pädiatrischen Intensivmedizin sollen patientenorientierte Therapiekonzepte zur Analgesie, Sedierung, Angst und Delir mit individueller patientenspezifischer Festlegung von Therapiezielen angewendet werden. Kinder sollen nach Möglichkeit ihre Schmerzen selbst einschätzen (66). Bei Kindern sollen Verhaltensmerkmale wie Gesichtsausdruck, Weinen, Motorik, Körperhaltung, Aktivität, Ruhelosigkeit, Apathie und die äußere Erscheinung von der Schmerzerfassung als stichhaltige Indikatoren für das Vorhandensein von Schmerz berücksichtigt werden (222, 223). Für Kinder etwa ab dem 4. Lebensjahr soll zur Selbsteinschätzung am besten die Faces Pain Scale -Revised (67) verwendet werden. Ab dem Schulalter ist auch der alternative Einsatz numerischer Rating-Skalen oder visueller Analog-Skalen möglich. Die kindliche Unbehagen-und Schmerz-Skala (KUSS) oder die Comfort-B Scale sollen als validierte und praktikable Fremdbeurteilungsskala zur Einschätzung des akuten postoperativen Schmerzes bei nicht-beatmeten Säuglingen bis zu Kindern von etwa 4 Jahren verwendet werden (224, 225). C.1.a.7 Die Comfort-B Scale soll zur Fremdbeurteilung des akuten postoperativen Schmerzes bei beatmeten Säuglingen bis zu Kindern von etwa 4 Jahren verwendet werden (225). [225] 1b A C.1.a.8 Für die Beurteilung von Schmerzen bei Kindern und Jugendlichen, die sich auf Grund schwerer kognitiver Beinträchtigung nicht mitteilen können, sollen speziell validierte Messinstrumente (z.B. Paediatric Pain Profile oder Non-Communicating Children's Pain Checklist Revised) verwendet werden (226, 227). Eine Evidenz-basierte Empfehlung für eine bestimmte neonatale "Schmerz"-Skala kann derzeit nicht ausgesprochen werden. Bei prolongierten Schmerzzuständen können z.B. die COMFORTneo scale oder die Neonatal Pain, Agitation and Sedation Scale (N-PASS) angewandt werden (225, 228). C.1.a.10 Die Möglichkeit eines Opioid-Entzugssyndroms sollte nach kontinuierlicher Therapie bedacht werden (229). Als Messinstrumente zur Beurteilung eines Opioid-Entzuges können im Neugeborenenalter der Finnegan-Score bzw. bei älteren Kindern und Jugendlichen die SOS (230) oder das WAT-1 (231) eingesetzt werden. Tabelle 27: Monitoring von Analgesie bei Kindern Tabellen S. 15/18 Monitoring von Sedierung bei Kindern LoE GoR C.1.b.1 Die Neonatal Pain, Agitation and Sedation Scale (N-PASS) oder die COMFORTneo scale können für die Beurteilung von Sedierungstiefe bei Früh-und Reifgeborenen verwendet werden (228, 232-237). Die Comfort-B Scale soll zur Fremdbeurteilung der Sedierungstiefe von Säuglingen und Kindern verwendet werden (238). Die Möglichkeit eines Sedativa-Entzugssyndroms (insbesondere Krampfanfälle) sollte nach kontinuierlicher Therapie bedacht werden. Als Messinstrumente zur Beurteilung eines Sedativa-Entzuges können im Neugeborenenalter der Finnegan-Score bzw. bei älteren Kindern und Jugendlichen die SOS oder das WAT-1 eingesetzt werden (229-231). Monitoring des Delirs bei Kindern LoE GoR C.1.c.1 Es soll ein regelmäßiges gezieltes Screening auf delirante Symptome mit einem validierten, pädiatrischen Delir-Score (z.B. pCAM-ICU, CAP-D oder PAED-Scale) durchgeführt werden (72-74). Tabelle 29: Monitoring des Delirs bei Kindern Analgesie bei Kindern LoE GoR C.2.a.1 Kritisch kranke Kinder auf Intensivstationen sollen eine an die individuelle Situation angepasste Schmerztherapie erhalten, unabhängig von der Notwendigkeit einer Sedierung (239). Die kontinuierliche intravenöse Infusion eines Opiods sollte auf der neonatologischen und pädiatrischen Intensivstation bei starken Schmerzen angewendet werden (240), (241). Zur Vermeidung eines Opioid-Entzugssyndroms sollten Opioide nach kontinuierlicher Therapie nach Möglichkeit ausgeschlichen werden. Upgrading: hohe klinische Relevanz und praktische Erfahrung 5 B C.2.a.4 Bei starken Schmerzen soll bei älteren Kindern eine Schmerzbekämpfung mittels eines Opioides in Kombination mit einem Nichtopioid erfolgen (242-245). Lokale und regionale periphere und rückenmarksnahe Analgesieverfahren sollten bei der analgetischen Therapie berücksichtigt werden (246). Patienten-kontrollierte Analgesie (PCA) kann nützlich sein bei Kindern ab ca 5 Jahren, bei Kindern < 6 Jahren kann eine Eltern-und/oder Pflege-kontrollierte Analgesie eingesetzt werden (247). Zusätzliche Maßnahmen zur Schmerzreduktion sollen bei akuten, prozeduralen Schmerzen des Neugeborenen erwogen werden, wie die Gabe von oralen Zuckerstoffen (z.B. Glukose oder Saccharose), sowie der Einsatz nicht-pharmakologischer Maßnahmen (nicht-nutritives Saugen, Stillen, Fascilitated tucking, Känguruhpflege, etc.) (248, 249). Tabellen S. 16/18 Nicht-pharmakologische Maßnahmen bei Kindern LoE GoR C.2.b.1 Bei Kindern sollte auf jeden korrigierbaren Umgebungsfaktor geachtet werden und eine fürsorgliche Behandlung gewährleistet sein (250). Ein normales Schlafmuster sollte gefördert werden, insbesondere sollte auf eine adäquate Beleuchtung, Reduktion von Lärm und einen möglichst angepassten Tag-Nacht-Rhythmus der Patienten geachtet werden (239). Tabelle 31: Nicht-pharmakologische Maßnahmen bei Kindern Bei Notwendigkeit einer Dauersedierung sollte eine sorgfältige Titration auf die niedrigst mögliche Dosis erfolgen. Ein Sedierungskonzept, das in randomisierten kontrollierten Studien geprüft wurde, liegt im Kindesalter nicht vor (251, 252). Midazolam kann zur Sedierung älterer, kritisch kranker Kinder verwendet werden, die einer intravenöser Sedierung bedürfen. Diese kann kontinuierlich verabreicht werden (253). C.2.c.3 Zur Sedierung von pädiatrischen ICU-Patienten kann die kontinuierliche intravenöse Applikation von Alpha2-Agonisten (Clonidin oder Dexmedetomidin) zur vegetativen Dämpfung adjuvant oder alternativ zur Sedierung mit Midazolam verwendet werden (254-257). Tägliche Sedierungspausen können bei Säuglingen und Kleinkindern erwogen werden, um eine Übersedierung zu vermeiden (258, 259). Bei älteren, kritisch kranken Kindern sollten nach Möglichkeit frühzeitig enterale Sedativa eingesetzt werden (260). Eine dauerhafte Sedierung von Neonaten soll nur in absoluten Ausnahmefällen, z.B. bei lebensbedrohlichen, nicht anderweitig beeinflussbaren Unruhezuständen, und unter besonderer Berücksichtigung des Nutzen-Risiko-Verhältnisses erfolgen (261). Wenn im Einzelfall bei Neonaten eine Sedierung notwendig ist, sollte bevorzugt Morphin gegenüber Midazolam eingesetzt werden (262). Downgrading: nicht ausreichende Evidenz in diesem Punkt des Reviews Bei Neonaten und Frühgeborenen sollte der Einsatz von Chloralhydrat und Phenobarbital nur im begründeten Einzelfall und nach sorgfältiger Risiko-/Nutzenabwägung erfolgen, insbesondere im Hinblick auf die zerebrale Entwicklung (263-269) und einer Verlängerung der Beatmungsdauer. Zur Vermeidung eines Sedativa-Entzugssyndroms können diese Medikamente nach kontinuierlicher Therapie nach Möglichkeit ausgeschlichen werden. Tabelle 32: Sedierung bei Kindern Tabellen S. 17/18 Delirtherapie bei Kindern LoE GoR C.2.d.1 Die Therapie des Delirs bei Kindern sollte symptomorientiert, pharmakologisch, nichtpharmakologisch, mit psychosozialen Interventionen erfolgen und eine Differentialdiagnostik zur kausalen Ursachen beinhalten (75, 270, 271). Tabelle 33: Delirtherapie bei Kindern Es soll ein regelmäßiges, aktives Screening für Delir insbesondere bei älteren Patienten, erfolgen, da Alter ein starker Prädiktor für ein hypoaktives Delir bei intensivmedizinisch-behandelten Patienten ist (272), (119), (120). Bei Patienten mit fortgeschrittener Demenz kann die "BESD" (Beurteilung von Schmerzen bei Demenz) zur Schmerzeinschätzung eingesetzt werden (273), (274). Die Faces Pain Scale (FPS) und die Numeric Rating Skala (NRS) sind reliabel und valide und sollen bei älteren Patienten zur Erfassung der Schmerz-Intensität eingesetzt werden (275). Tabelle 34: Monitoring bei älteren Patienten Therapeutische Konzepte bei älteren Patienten LoE GoR D2.1 Prophylaktisch sollte bei geriatrischen Patienten mit weiteren Risikofaktoren für ein Delir niedrig dosiertes Haloperidol oder Rivastigmin eingesetzt werden (98, 276) Prophylaktisch sollte bei geriatrischen Patienten zur Prävention eines Delirs nachts Melatonin eingesetzt werden (81). Benzodiazepine sollen bei älteren Patienten nur nach strenger Indikationsprüfung zur Sedierung verwendet und auch nur titriert nach Ziel-RASS verwendet werden (277). Anticholinerge Medikamente sollen auf Grund ihres hohen Delir-Risikos bei älteren Patienten gemieden werden (278). Tabelle 35: Therapeutische Konzepte bei älteren Patienten Tabellen S. 18/18 Ökonomie, Qualitätssicherung und Implementierung der Leitlinie LoE GoR E.1 Analgesie, Sedierung und Delirmanagement auf der Intensivstation sollen Leitlinien konform erfolgen und einer Qualitätssicherung unterliegen (82). Unter der Voraussetzung, dass das Intensivpflegepersonal (Fachpflegestandard) spezielle und qualifizierte Kenntnisse, Erfahrungen und Fertigkeiten vorweist, kann die Steuerung der Analgesie und Sedierung (mittels einer Spritzenpumpe) nach vorgegebenen Protokollen und ärztlicher Anordnung durch das Pflegepersonal erfolgen (141, 279, 280). Mit dem Ziel die Therapiesicherheit zu erhöhen und Entscheidungsfindungen zu erleichtern, soll die Implementierung klinikinterner Standards zur Analgesie, Sedierung und Delirtherapie (einschließlich der Anwendung von Sedierungsprotokollen) erfolgen (21, 281). Zur konsequenten Umsetzung von Leitlinien bzw. Standards soll eine Schulung des Personals in deren Anwendung erfolgen (83, 282, 283). Tabelle 36: Ökonomie, Qualitätssicherung und Implementierung der Leitlinie [/table]	None	None	In 2010, under the guidance of the DGAI (German Society of Anaesthesiology and Intensive Care Medicine) and DIVI (German Interdisciplinary Association for Intensive Care and Emergency Medicine), twelve German medical societies published the “Evidence- and Consensus-based Guidelines on the Management of Analgesia, Sedation and Delirium in Intensive Care”. Since then, several new studies and publications have considerably increased the body of evidence, including the new recommendations from the American College of Critical Care Medicine (ACCM) in conjunction with Society of Critical Care Medicine (SCCM) and American Society of Health-System Pharmacists (ASHP) from 2013. For this update, a major restructuring and extension of the guidelines were needed in order to cover new aspects of treatment, such as sleep and anxiety management. The literature was systematically searched and evaluated using the criteria of the Oxford Center of Evidence Based Medicine. The body of evidence used to formulate these recommendations was reviewed and approved by representatives of 17 national societies. Three grades of recommendation were used as follows: Grade “A” (strong recommendation), Grade “B” (recommendation) and Grade “0” (open recommendation). The result is a comprehensive, interdisciplinary, evidence and consensus-based set of level 3 guidelines. This publication was designed for all ICU professionals, and takes into account all critically ill patient populations. It represents a guide to symptom-oriented prevention, diagnosis, and treatment of delirium, anxiety, stress, and protocol-based analgesia, sedation, and sleep-management in intensive care medicine.
546f5f0a6e5453c7ec22d21c1ae07235f10e8e5d	pubmed	Diagnosis and management of small bowel obstruction in virgin abdomen: a WSES position paper	Diagnosis and management of small bowel obstruction in virgin abdomen: a WSES position paper Background: Small bowel obstruction (SBO) is a common surgical emergency, causing high morbidity and healthcare costs. The majority of SBOs are caused by adhesions that result from previous surgeries. Bowel obstruction, however, also occurs in patients without previous operation or known pathology, a so called virgin abdomen. It is unknown if small bowel obstruction in the virgin abdomen (SBO-VA) can be managed according to the same principles as other cases of small bowel obstruction. The aim of this position paper is to evaluate the available evidence on etiology and management of small bowel obstruction in the virgin abdomen.Methods: This is a narrative review with scoping aspects. Clinical topics covered in this review include epidemiology and etiology of SBO-VA, diagnosis and imaging, initial assessment, the role of surgical management in SBO-VA, and the role of non-operative management in SBO-VA.Results: Our scoping search revealed seven original studies reporting original patient data related to SBO-VA. All the included studies are retrospective cohorts, with populations ranging between 44 and 103 patients with SBO-VA. Adhesions were found to be the cause of the obstruction in approximately half of the reported cases of SBO-VA. A relatively high number of cases of SBO-VA were managed surgically with studies reporting 39-83%. However, in cases where a trial of non-operative management was started, this was generally successful. Conclusion: The data available suggest that etiology and treatment results for patients with SBO-VA are largely comparable to the results in patients with SBO after previous abdominal surgery. We therefore propose that patients with a virgin abdomen could be treated according to existing guidelines for SBO and adhesive small bowel obstruction. # Background Small bowel obstruction (SBO) is a common surgical emergency, accounting for almost 50% of all emergency laparotomies with significant in-hospital morbidity and costs. Most patients with SBO have undergone previous abdominal operations (80%), with adhesions as the single most common cause (60-75%) of SBO. However, SBO also occurs in patients who had no prior abdominal surgery, referred to as a virgin abdomen. In the past decade, a paradigm shift in the treatment of SBO in patients with previous abdominal surgery has been implemented. Today, the majority of small bowel obstructions are managed non-operatively, treatment comprising bowel decompression, water-soluble contrast agents, and fluid resuscitation. Non-operative management has been found safe and efficacious in 70% of SBOs caused by adhesions (ASBO). Many authors, however, suggest that surgical exploration is still mandatory in the case of SBO in the virgin abdomen (SBO-VA), based on the assumption that SBO-VA is usually caused by other etiologies than adhesions, such as malignancy, internal hernia, and bezoars as the most prominent causes. On the other hand, recent studies suggest a high incidence of adhesions also in patients with SBO-VA. The origin of adhesions in the virgin abdomen can be congenital, or the results of (unrecognized) abdominal inflammation in the patients' history. The observation that most SBO-VA are caused by adhesions could have important implications for treatment, signifying that guidelines on the management of ASBO might also apply to the majority of patients with SBO-VA. The present paper aims to provide an overview of the literature on the etiology and management of SBO-VA and to generate recommendations for clinical management and future research. # Methods This is a narrative review with scoping aspects. A formal systematic review and meta-analysis were not feasible due to the many aspects of diagnosis and management of SBO-VA we would like to cover. Moreover, because of the paucity of literature, we will also discuss papers that might not meet strict inclusion criteria as applied in a systematic review. Therefore, a scooping review search framework was found more appropriate to guide our position paper. In contrast to systematic reviews, where a focused research question with narrow parameter should be chosen, a scoping search allows for a broad research question, adjusting the inclusion and exclusion criteria according to available literature, and the quality of the chosen studies is not a priority. Data might be extracted mainly for qualitative assessment; the quality of the studies found and the data extracted are used to identify gaps in the literature. Our scooping study followed the 5-step pathway as described by Arksey and O'Malley framework: ## Main questions -What is the etiology of SBO-VA? -What are the outcomes of operative management of SBO-VA? -Is a non-operative trial appropriate in patients with SBO-VA? ## Search strategy for relevant topics PubMed, the Cochrane database, EMBASE database, and Google Scholar were searched to March 2020 without date restrictions. PubMed studies were identified using the following MeSH terms: "intestinal obstruction, " "small intestine," "ileum," "jejunum," and "aged" and keywords "small bowel obstruction," "Virgin abdomen," "non-operative management," "water-soluble contrast agents," and "Gastrografin." Similar search strategies were performed in Embase and Google scholar. The Cochrane database was searched for all articles relating to small bowel obstruction. After performing the different searches, duplicates were identified and deleted. To increase the yield of our search to detect relevant publications, we also searched reference list of relevant articles and guidelines for the treatment of patients with SBO. ## Relevant studies selection All the studies that included data for a (sub)cohort of SBO-VA patients relating to our search questions were included. ## Data extraction From included studies, we extracted data related to clinical topics including epidemiology and etiology of SBO-VA, diagnosis and imaging, initial assessment, the role of surgical management in SBO-VA, and the role of non-operative management in SBO-VA. All the relevant data was charted in tables. ## Collation, summarizing, and reporting The charted data was combined, categorized, and compared across the included studies. All relevant information was reported and discussed to answer the study questions. ## Definitions ## Small bowel obstruction Small bowel obstruction is a surgical emergency in which a mechanical obstruction of the small intestine hinders the passage of intestinal contents. Typical symptoms of small bowel obstruction are abdominal pain, vomiting, distension, and constipation. However, not all these symptoms may be present especially in the elderly population. Small bowel obstruction can be classified as partial (incomplete) or complete obstruction. Imaging studies such as water-soluble contrast agents (WSCA) or CT can help differentiate between complete and incomplete obstruction. In case of a partial obstruction, there is a higher likelihood that a bowel obstruction can be managed by non-operative means. ## Virgin abdomen The term "virgin abdomen" refers to the abdomen of a patient without prior surgery, radiotherapy, or known peritoneal inflammatory disease in history. There is no consensus in the literature about primary abdominal wall hernias that are not related to a previous incision. In our results, we will describe whether patients with a primary abdominal wall hernia have or have not been included among patients with virgin abdomen. ## Peritoneal adhesions Peritoneal adhesions are defined as fibrous scar tissue that connects surfaces of intra-peritoneal organs that are normally separated. Peritoneal adhesions may be classified as congenital or acquired. Most adhesions are acquired and result from the peritoneal healing response upon injury, typically abdominal operation; other less common etiologies of acquired adhesions include malignancy, radiotherapy, abdominal or pelvic inflammations, and endometriosis. Congenital adhesions are defined as anomalous intraperitoneal adhesions that are not related to a previous abdominal disease or operation; these might result as remnants of physiological organogenesis. # Results Our scooping search revealed seven original studies reporting original patient data related to SBO-VA. All the included studies are retrospective cohorts, with populations ranging between 44 and 103 patients with SBO-VA. Six studies are single-center, and one study was a multicenter cohort. Five studies reported data on the etiology and operative findings in patients with SBO-VA. One of the studies additionally compared the operative findings between patients with SBO-VA and patients with SBO after previous abdominal surgery. The accuracy of computed tomography in identifying the cause of the SBO was discussed in 2 studies, in which the findings in computed tomography were compared to the operative findings. Data on the treatment options were discussed in 6 studies, including a comparison between operative management and non-operative management. In 2 studies, water-soluble contrast agents (WSCA) were used in the non-operative management. Meanwhile data on recurrence, follow-up, and further investigations were reported in 4 studies. ## Epidemiology and etiology In three cohort studies, SBO-VA accounted for 5-16% of all cases of SBO. Most of these cohorts were single center, and the number of patients with SBO screened was roughly between 600 and 850 in each studies. Population-based studies are lacking. Based on the available data, SBO-VA seems more common among males (65-83%) with a median age of diagnosis between 58 and 65. Between 39 and 83% of the patients with SBO-VA were reportedly treated by operation, which compares high to the number of operations performed in recent cohorts of SBO patients who did have prior surgery. Several recent studies retrospectively analyzed the etiology of small bowel obstruction in patients with SBO-VA. Among patients operated for SBO-VA, etiology of SBO was adhesions in 26-100%. In two studies, 75-100% of patients conservatively treated were diagnosed with adhesion. In total, adhesions were the cause of bowel obstruction in 134/ 280 (47.9%) cases of SBO-VA reported in the studies included. Most studies did not specify the type or the location of the adhesions. Skoglar et al. reported that 13 out of 20 patients (65%) with SBO-VA caused by adhesions had solitary band adhesion and 7 (35%) had more extensive matted adhesions. In contrast, the study reported that the majority of patients with previous surgery had matted adhesions (67%). Other etiologies reported for SBO-VA include malignant or benign tumors, arising primarily from the small bowel (NETs, lymphoma, and carcinomas), mesentery and retroperitoneum, or a metastatic origin (most commonly from a colonic, ovarian, or prostatic origin). Based on the results from the operative findings in the included studies, malignancy as the cause of SBO-VA was encountered in 4-13%. Other less common causes of SBA-VA include bezoar, small bowel volvulus, intussusception, Meckel's diverticulum, gallstone ileus, internal hernia, and newonset IBD. Detailed results of the etiology of SBO-VA are found in. Two studies reported negative laparotomies, where an apparent cause of SBO-VA could not be established in 6% and 40% of the study population respectively. Diagnostics in SBO-VA Initial assessment As for SBO in general, one of the main priorities in the initial assessment of the patient with SBO-VA is to identify indications for emergent surgical exploration. Indications for emergency operation are signs of peritonitis, strangulation, and ischemia. History taking and physical examination might also reveal clues about the etiology of the obstruction. During physical examination, the physician should seek abdominal wall hernias, including groin hernias. The initial assessment should also comprise an evaluation of nutritional status and sequelae of SBO such as dehydration. Laboratory tests should include blood count, CRP, lactate, electrolytes, BUN/creatinine, and coagulation profile; elevated CRP, leukocytosis with left shift, and elevated lactate might be helpful indicating the presence of peritonitis and bowel ischemia, although normal values cannot exclude ischemia. ## Imaging studies abdominal plain radiography There are no studies discussing the diagnostic value of plain radiography specifically in patients with SBO-VA. Abdominal plain radiography is still used as first-line imaging in a patient with suspected of SBO, but it has limited value as complementary to the initial clinical assessment. Sensitivity and specificity of plain Xrays for SBO is approximately 60-70%. Moreover, plain radiographs do not provide additional information on the etiology of the obstruction nor the need to perform emergency surgery. ## Water-soluble contrast Water-soluble contrast agents (WSCA) imaging has an established place in the management of ASBO in cases where a CT scan is not required. WSCA has both prognostic and potential therapeutic value in the management of patients with small bowel obstruction; several studies have shown promising results in the management of ASBO. The appearance of contrast in the colon within 4-24 h after the administration had a sensitivity of 96% and specificity of 98% in predicting resolution of SBO with conservative therapy; if the contrast did reach the colon on an abdominal X-ray taken 24 h following administration of the contrast, this was highly indicative of a failure of non-operative management. Only two studies reported on the use of WSCA imaging in SBO-VA. Collom et al. reported WSCA to have been used less frequently in patients with SBO-VA (35.6%), as compared to patients with SBO after previous surgery (52.2%). A potential explanation might be that an adhesive etiology in the case of SBO-VA cannot be assumed, requiring a CT to establish the cause of the obstruction. Nevertheless, in the study of Fukami et al., WSCA seems to be equally effective in 44 patients with SBO-VA compared to 794 patients with surgery in history. There were no significant differences in the duration of nasogastric tube decompression between patients with and without virgin abdomen (2.2 versus 2.5 days, p = 0.40), and intervals until the initiation of oral intake were also comparable (2.4 versus 2.6 days, p = 0.55). The overall operative rate was 16% in the VA and 17% in the group with previous surgery (p = 1.000). ## Computed tomography The ability of computed tomography (CT) to provide information related to the underlying cause of SBO, and predict the need for emergency surgery, makes CT the primary diagnostic tool of choice in patients with SBO. However, two of the included studies on SBO-VA reported that the accuracy of CT in establishing the exact cause of obstruction seems to be low (53% and 76%). A possible explanation for this finding is that cases of SBO-VA were included over many years and (parts of) these cohorts were not recent. The introduction of multidetector-row computed tomography (MDCT) has improved the diagnostic accuracy with high sensitivity and specificity for the etiology of SBO (87 and 90%, respectively). CT scan plays a key role in the decision on the management of patients with SBO; its importance is not just in the confirmation of the diagnosis of SBO, but also in identifying the underlying cause of obstruction and predicting the need for emergency surgery. Moreover, CT scan is also able to provide information about an alternative diagnosis if no signs of bowel obstruction are present. Findings on CT scan help define the potential location of the obstruction (e.g., high in the jejunum or deep in the pelvis), the grade of the obstruction, partial or complete, and may also identify a possible transition zone. The use of water-soluble contrast optimizes the diagnostic value of CT scan, and X-ray can evaluate the progress of the contrast at 24 h after CT. Findings on the CT scan that predict the need for operative management, include a closed-loop obstruction, markers of bowel ischemia (mesenteric edema, free intraperitoneal fluid), and the "small bowel feces sign", and additional radiological scores can be used to predict the need for surgery. There is increasing evidence that adhesions are a major cause of SBO-VA, similar to SBO in general. Although adhesions are not directly visible even on CT, the absence of other etiologies and a transition zone are highly predictive for adhesions as the cause of the obstruction. When adhesive etiology is established by CT, patients with SBO-VA can be treated according to the same management algorithms as other patients with ASBO. ## Management of sbo-va initial decision making Most studies report a high rate for surgery SBO-VA ranging from 39 to 83%. This compares relative high to SBO in general, in which 70% is treated non-operatively and the indication of most operations is a failure of non-operative trial. Only in the cohort of Fukami et al. a low rate of 16% operative treatment was reported with the use of WSCA. Most SBO-VA cohorts did not precisely report on the indications for surgical exploration nor if surgery was chosen as the initial treatment. Possibly, the presumption that SBO-VA has different causes than adhesions that do not resolve with conservative management explains the relatively high rate of surgical treatment. ## Operative management Operative intervention can be on an urgent basis for patients with signs of bowel compromise or later intervention when non-operative management fails. This distinction in the indication for surgery was reported in only one of the studies on SBO-VA. In 32 of 43 operated patients (74%) with SBO-VA in this cohort, surgical exploration was performed as the primary treatment. It was not reported if there were signs of peritonitis or ischemia in these patients as the indication of surgery, nor was data related to bowel resections reported. In the remaining 11 patients in whom a conservative trial was started, 5 were operated on after failure of non-operative management. The cohort of Collom et al. and Strajina et al. excluded patients with signs of compromised bowel. Nevertheless, the operative rates remained high, reporting 39% and 83% respectively to have been treated surgically. Fukami et al. reported a lower operative rate of 16% in patients with SBO-VA by applying WSCA according to the same protocol as in patients with SBO and previous surgery in history. ## Surgical technique Laparotomy was the surgical approach of choice in patients with SBO-VA. Two studies reported results related to the laparoscopic approach. Ng et al. reported a laparoscopic approach to have been used in 5/43 patients. Three patients were converted to laparotomy, two for open adhesiolysis, and one for better assessment of small bowel viability. Strajina et al. reported that surgical exploration was completed laparoscopically in 18 out of 50 operated patients with SBO-VA (35%); it was not reported if there were conversions from an initial laparoscopic approach. A higher rate of negative explorations was reported following laparoscopy compared to open surgery. The use of adhesion barriers can reduce recurrence rates in case of a small bowel obstruction caused by adhesions. None of the studies on SBO-VA reported on the use of barriers or other means to reduce the recurrence of adhesions. ## Results of surgical treatment A few studies reported that the cause of obstruction could not be identified even in some cases even with operative exploration. Strikingly Strajina et al. reported negative finding in as many as 20 (40%) of surgical explorations. In only three of these patients, the etiology of obstructive symptoms was established during follow-up, including one case of a neuroendocrine tumor, a motility disorder, and angioedema. Few data were available on the morbidity and mortality related to the surgical treatment of SBO-VA. Fukami et al. reported a zero mortality rate. Strajina et al. reported 30-day morbidity in patients with a therapeutic exploration of 39% (11 patients), compared to a significantly lower rate of 10% in patients with negative laparotomies. Recurrence rates after initial operative management in patients with SBO-VA ranged between 1 and 10%; the findings were listed in two of the studies as shown in. ## Non-operative management Non-operative management was used in the treatment of SBO-VA patients in 17-87% of patients. Most studies did not explicitly report criteria for non-operative or operative management. Beardsley et al. relied on the absence of previously known abdominal disease and the absence of pathological findings on the CT in the diagnosis of adhesions by exclusion. In this study, non-operative treatment was successful in all patients in whom a trial of nonoperative management was started. In the study of Ng et al., non-operative management failed in 5 (17%). reported that the success of conservative management depended on the use of WSCA; in the group of patients who received WSCA, a 17% failure rate was reported, as opposed to 50% in the group without WSCA. In accordance with their findings, Fukami et al. reported only one patient treated by non-operative management including WSCA required surgery for the failure of non-operative management. As with ASBO in patients with previous surgery, the cornerstone of the non-operative management is fasting, fluid and electrolytes replacement, and bowel decompression by nasogastric tube. Detailed information such as the duration of the non-operative trial and type of decompression tubes was not reported. Two of the studies reported the use of WSCA in patients assigned for non-operative management. The protocol for administration of WSCA in the study of Collom et al. was not detailed. In the cohort by Fukami et al., all patients who were assigned for non-operative management received 100 ml Gastrografin within 24 h after admission; abdominal X-rays were taken after WSCA administration, and the obstruction grade was classified into two major categories, complete obstruction group and incomplete obstruction. ## Follow-up and recurrence Recurrence during follow-up was not consistently reported. A few studies did mention recurrences though. In the study of Tavangari et al., 5 out of 63 nonoperatively treated patients had a recurrence, all were treated successfully without intervention in the recurrence episode, and data related to further investigations and findings in the follow-up after those patients were not reported. None of the studies reported the use of a preestablished follow-up and surveillance program for patients treated non-operatively. Strajina et al. reported a median follow-up of 53 months after patients treated non-operatively; one patient had transverse colon cancer diagnosed at colonoscopy 3 months later; 2 patients suffered recurrent SBO, one patient required bowel resection due to endometriosis, and the other had resection of benign small bowel stricture. Ng et al. reported that only 5/29 patients in the nonoperative group had a colonoscopy or small bowel study in the follow-up, and the remaining 24 patients did not have any further evaluation. Interestingly, only two out of the 29 patients required readmission for recent SBO at follow-up.. # Discussion SBO-VA is a relatively uncommon subgroup of small bowel obstructions, and there are only a few reports dedicated to patients in this subgroup. The available evidence however contradicts the opinion suggesting that most cases of SBO-VA have nonadhesion cause, and all patients with SBO-VA, therefore, require surgical exploration. The data from the reviewed studies shows that etiology and treatment results for patients with SBO-VA are largely comparable to the results in patients with SBO after previous abdominal surgery. CT scan has a pivotal role in the assessment of SBO-VA to assess the etiology and to evaluate if the bowel is compromised, demanding early surgery. Moreover, modern high resolution CT is also useful in minimizing the risk of failure to detect a malignant cause. As with ASBO in general, the majority of cases with SBO-VA can be treated by non-operative trial initially. Nevertheless, a laparotomy remains indicated in case of a non-resolving obstruction. Based on the findings in our review, SBO-VA mostly has a benign cause; this is in contrast to older literature and surgical textbooks that suggest malignancy as the main cause of obstruction in patients with a virgin abdomen. Possibly, improvements in imaging and diagnostics techniques in past decades have contributed to the diagnosis of abdominal pathologies, including malignancies, at an earlier stage, resulting in fewer cases presenting as a bowel obstruction. For example, recent studies have shown that improved diagnostics and screening programs have resulted in a stage shift in the diagnosis of colon carcinoma, with more tumors diagnosed at an early stage in both the USA and Europe. Although such epidemiological data is not available for small bowel disease, a similar trend might also be applicable. It is clear from the presented data that an initial operative management was favored in SBO-VA; such an approach could expose patients to a high rate of avoidable laparotomies and associated morbidity. The data also suggested that the use of non-operative trial achieved a spontaneous resolution of the SBO in most of the patients; moreover, as Collom et al. showed, the use of WSCA significantly reduced the need for operative intervention. Following successful conservative treatment of SBO, diagnosis and management of potential underlying causes can be performed electively as needed. Based on the etiologic findings in the presented studies, fear of the previously assumed high rate of malignancies is not justified. As a consequence, the need to perform surgical exploration in every patient with SBO-VA can also be waived. Nevertheless, non-invasive diagnostics with high accuracy for detection of malignancy or follow-up is mandatory as approximately one in ten cases of SBO-VA is still caused by malignancy. # Conclusion Although several aspects in diagnosis and treatment of SBO-VA have not been clearly described in the few available studies, the overall results are comparable to the results of studies on SBO in patients with previous abdominal surgeries in history. We therefore propose that patients with a virgin abdomen could be treated according to existing guidelines for SBO and ASBO.	None	https://wjes.biomedcentral.com/counter/pdf/10.1186/s13017-021-00379-8	None
161869975b27c6290639fff80aa0adaa8267a4a5	pubmed	Imaging in head and neck cancer: United Kingdom National Multidisciplinary Guidelines	Imaging in head and neck cancer: United Kingdom National Multidisciplinary Guidelines This guideline is endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper summarises the current imaging modalities in use for head and neck cancer evaluation. It highlights their role in the management with recommendations on modality choice for each cancer subsite.Recommendations- Offer appropriate radiological imaging, based on tumour extent, site and local expertise, to stage tumours and plan treatment for patients diagnosed with head and neck cancer. (G) - Consider positron emission tomography combined with computed tomography (PET-CT) imaging if conventional cross-sectional imaging identifies no primary site. (R) - Offer PET-CT imaging 12 weeks after non-surgical treatment to detect residual disease. (R) # Introduction Imaging in head and neck cancer has developed enormously over the last few decades. Advanced cross-sectional imaging modalities allow accurate staging of disease and contribute significantly to management decisions and prognosis. As a core member of a multidisciplinary team, the radiologist has a key role in presenting relevant multi-modality findings that define disease extent, help with surveillance and highlight pertinent co-morbidities.This approach also aids pre-treatment counselling and patient consent. Prior to imaging, the primary site and the presence or absence of neck metastases of a head and neck cancer has often been established clinically and it is not unusual for a histological diagnosis to have been secured from a representative biopsy. Therefore, the primary role of radiology is in accurately staging the full extent and distant spread of disease with the current tumour-node-metastasis (TNM) system, with an emphasis on features that will influence surgical or non-surgical treatment options. The areas that radiological assessment should focus on are: - Local extent of the primary tumour - Spread to locoregional cervical lymph nodes - Detection of metastatic disease precluding cure and synchronous primary tumours of the lung and upper aero-digestive tract. ## Imaging modalities Computed tomography (CT) Contrast-enhanced CT is the mainstay for imaging primary disease. It is widely available and established in practice. It incurs a significant radiation penalty and iodinated contrast medium is contraindicated in those with severe renal impairment. Conventionally, centres would image the neck and chest at presentation from the skull base to below the diaphragm. Spatially good but at a radiation cost, CT provides limited soft tissue resolution. Bone detail such as with mandibular or skull base involvement is a major strength. Modern multislice, slip-ring CT detector technology rapidly acquires images without movement artefact as potential head and neck cancer patients may have difficulty with breathing, swallowing secretions and lying flat. Multiplanar and volume rendered images are easily reconstructed. Contrast-enhanced CT allows opacification of vascular structures whilst tumours generally tend to be slower to enhance with a reduced wash out. ## Magnetic resonance imaging (mri) Magnetic resonance imaging reflects biochemical tissue characteristics and is largely influenced by proton density and other in situ paramagnetic substances such as blood products and melanin content. Alongside the permanent bore magnet, additional transient magnetic gradients allow the development of an ever increasing array of sequences that are able to reflect pathological processes from normal surrounding tissues. Multiple manufacturers may have differing terms for sometimes similar sequence parameters. T1-weighted 'anatomical' images have excellent spatial resolution, whilst T2-weighted images preferentially highlight oedema and therefore pathology. A short tau inversion-recovery (STIR) sequence retains the positive attributes of a T2-weighted image and suppresses surrounding fat signal in normal or invaded tissues to best depict abnormal tissue as a bright, high signal. Magnetic resonance imaging has the ability to dramatically improve tissue contrast resolution when compared with CT and, in compliant patients without contraindications, it is the imaging modality of choice for defining the primary extent of oral and oropharyngeal cancers. Detrimentally, when compared with CT, scan times are much longer and can vary from about 2-10 minutes for each sequence, during which the patient must keep relatively still. Intravenous gadolinium contrast agents allow static and dynamic vascular assessments of a tumour and, when combined with fat suppression techniques, this can increase the conspicuity of occult pathology. Dental amalgam can reduce the image quality both for CT and MR imaging that makes interpretation more challenging. ## Positron emission tomography combined with ct (pet-ct) Positron emission tomography combined with CT whole-body imaging uses various labelled tracers to fuse conventional, anatomical CT images with a functional 'map' of the disease process. This is conducted on a single gantry at a single appointment. The commonest tracer is 18 fluoro-deoxyglucose, which is preferentially transported and trapped into hypermetabolic cancerous or inflamed tissues. It is detected with a gamma camera array. The patient's fasted baseline glucose level should be measured and the isotope is injected intravenously approximately 1 hour before imaging. The patient refrains from talking or chewing. Actual image acquisition takes about 30-45 minutes. Modern scanner design accurately co-registers metabolic tissue activity with its precise anatomical location. In 2013, the Royal College of Radiologists published evidence-based guidelines for PET-CT use in head and neck cancer. Evaluating the patient with malignant cervical adenopathy from an unknown primary is one of the main, up-front indications. Positron emission tomography will detect an occult primary in approximately one third of cases. Positron emission tomography combined with CT is also valuable in the assessment of suspected recurrence of head and neck cancer when there are extensive, confounding posttreatment changes on conventional imaging modalities. Its added benefit in routine surveillance following treatment is still being assessed. Along with other modalities, it has a role in staging malignant thyroid disease including medullary thyroid carcinoma. ## Ultrasound Offered as part of a modern one-stop service, ultrasound, alongside fine needle aspiration cytology, allows rapid imaging assessments for those with an undiagnosed neck lump or suspected metastatic disease in the neck. This technique can be notoriously operator dependent, but has no detrimental patient effects. Following slide preparation, best cytological practice recommends prompt adequacy assessments and, ideally, the cytologist should be onsite for diagnostic advice. In reality, a shortage of radiology and histopathological input makes such universal service developments difficult. Ultrasonography comfortably delineates thyroid pathology and can detect occult pathological nodes (necrosis, microcalcification, etc.) that may feel clinically normal in size. A normal node should remain ovoid in shape with a short axis diameter less than 10 mm with a preserved echogenic hilum. Retropharyngeal and superior mediastinal nodes cannot be assessed with this modality. Current doctrine dictates that clinically and radiologically N0 disease from high-risk primary sites is presumed to have small volume nodal micrometastasis that routinely requires prophylactic first-line treatment as no available tests can guarantee a true pathological N0 status. ## Fluoroscopy There are a variety of scenarios when contrast swallows and fluoroscopy are used in head and neck cancer, although the availability of local expertise can be variable. Contrast swallows can be used to assess the length of a malignant proximal oesophageal stricture, while the risk of airway aspiration or penetration is dynamically assessed by videofluoroscopy. Alternative, nononcological causes for dysphagia such as a pharyngeal pouch may be diagnosed. Water soluble contrast studies are advised when the risk of aspiration is high, for instance, following recurrent chest infections or diminished pharyngeal sensory/motor function after surgery or radiation. The integrity of a surgical anastomosis or the tract of an entero-cutaneous fistula can also be well evaluated. These studies are often jointly performed with a speech and language therapist to facilitate decision making and may improve functional outcomes. ## Chest imaging With common aetiological factors, patients with head and neck cancer have higher incidences of synchronous and metachronous primary lung tumours that may be disseminated at presentation. At staging, CT imaging of the thorax is routinely advised. The most common protocol for patients with a head and neck cancer will therefore be to image the primary site by either contrast-enhanced CT or magnetic resonance imaging (MRI), perform CT imaging of the chest and PET-CT for the unknown primaries. ## Specific tumour sites This section deals with specific tumour sites and highlights areas where radiological evaluation is particularly important and often difficult. Oral cavity Preferred imaging modality: MRI Tongue tumours are routinely evaluated with MRI to aid treatment choices and prognosis. Early or advanced cancers of the buccal mucosa, retromolar trigone, palatal and floor of mouth are more difficult to evaluate reliably by imaging alone and good clinical correlation is essential. Perineural and marrow involvement is best defined at MRI. In an attempt to avoid osteoradionecrosis, orthopantomograms are still requested to proactively treat dental caries and peri-apical disease. Oropharynx Preferred imaging modality: MRI Small or subclinical primaries in the tonsil and tongue base that often present with cervical lymphadenopathy can be difficult to identify with all forms of imaging including PET-CT. These tumours are often best evaluated at MRI with STIR sequences and often, may only be localised retrospectively after examination and biopsy under anaesthesia. Extension of mucosal tumours into the adjacent structures and neck spaces is well depicted with MR imaging. ## Nasopharynx Preferred imaging modality: MRI Nasopharyngeal tumours commonly present at an advanced stage with palpable nodal neck disease. Magnetic resonance imaging allows accurate classification of the primary site and nodal disease as per the TNM classification, based on disease extent. ## Hypopharynx ## Preferred imaging modality: mri In those patients who have difficulty with swallowing, aspiration or breathing when supine, a CT scan will need to be strongly considered. ## Larynx Preferred imaging modality: MRI Disease at the level of the vocal cords presents early with dysphonia and is well localised. Imaging is often unnecessary for T1 disease unless extralaryngeal disease, cartilage involvement, nodal metastasis or chest pathology is suspected. MRI with contrast is the gold standard for depiction of cartilage involvement. ## Recommendations - Offer appropriate radiological imaging, based on tumour extent, site and local expertise, to stage tumours and plan treatment for patients diagnosed with head and neck cancer (G) - Consider PET-CT imaging if conventional cross-sectional imaging identifies no primary site (R) - Offer PET-CT imaging 12 weeks after non-surgical treatment to detect residual disease (R) ## Salivary glands Malignant salivary glands neoplasms are a very heterogenous group of tumours, where tumour behaviour and prognosis is dictated by the histology. Ultrasound techniques have a significant role to play in assessing the parenchymal mass, local adenopathy and guiding biopsies. Perineural or skull base involvement often requires a combined multi-modality CT and MR approach. The best imaging modality may be guided by site-specific characteristics such as respiratory motion artefact. Sinuses MRI with contrast is the modality of choice to assess surgical resectability issues around intracranial and orbital disease spread. Skull base involvement usually requires a complementary CT study. ## Post-operative imaging The choice of imaging in the post-operative scenario is determined by the specific clinical question posed. Complications are frequent with difficult head and neck resections. When the specific question is over potential residual or recurrent disease, following either surgery or chemoradiotherapy, the choice for baseline imaging mainly falls between a contrast CT of the neck and chest and a timely PET-CT study. As an exception, MRI has a large role to play specifically for nasopharyngeal, sinonasal and skull base tumour follow up.Early detection of residual disease is vital to planning further curative attempts. The timing of the scan is important. Dedicated CT gives better resolution and anatomical detail at the primary site as well as detecting subcentrimetre early metastatic disease in the lungs. Obliteration of fat planes and anatomical distortions makes interpretation difficult. A negative, normal PET-CT 12 weeks post-treatment likely offers the best prognostic reassurance currently. [bib_ref] PETCT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer, Mehanna [/bib_ref] PET-CT fails to reliably distinguish inflammatory elements from malignant foci. Ultrasound guided procedures still have a role to play in sampling indeterminate, persistent enlarged cervical nodes. ## Key points - Accurate image interpretation and staging heavily influences optimal treatment strategies - Contrast-enhanced computed tomography of the skull base, neck and chest is ubiquitous in nature, readily available and the workhorse for routine tumour-node-metastasis staging of head and neck cancers - Positron emission tomography combined with computed tomography is of proven diagnostic benefit when searching for the unknown primaries, when conventional imaging is non-informative - In compatible patients, magnetic resonance imaging has superior soft tissue characterisation at several primary sites including oropharynx, nasopharynx/ skull base and sinuses that greatly aid surgical planning and resections - Ultrasound image guided diagnostic fine needle and core biopsies are well established and cost-effective in the context of good cytological/histological support - In certain instances, multi-modality approaches are complementary to each other but should not adversely impact on the speed of the diagnostic pathway. © JLO (1984) Limited, 2016. This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. doi:10.1017/S0022215116000396	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/53890D66AEACE9BFA9BB95654A2A9470/S0022215116000396a.pdf/div-class-title-imaging-in-head-and-neck-cancer-united-kingdom-national-multidisciplinary-guidelines-div.pdf	Abstract This guideline is endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper summarises the current imaging modalities in use for head and neck cancer evaluation. It highlights their role in the management with recommendations on modality choice for each cancer subsite. Recommendations • Offer appropriate radiological imaging, based on tumour extent, site and local expertise, to stage tumours and plan treatment for patients diagnosed with head and neck cancer. (G) • Consider positron emission tomography combined with computed tomography (PET–CT) imaging if conventional cross-sectional imaging identifies no primary site. (R) • Offer PET–CT imaging 12 weeks after non-surgical treatment to detect residual disease. (R)
636874c15b17a850e988bfa997225d7d37e8a925	pubmed	Dutch Guideline on Knee Arthroscopy Part 2: non-meniscus intra-articular knee injury: a multidisciplinary review by the Dutch Orthopaedic Association	Dutch Guideline on Knee Arthroscopy Part 2: non-meniscus intra-articular knee injury: a multidisciplinary review by the Dutch Orthopaedic Association ## Funding and potential conflicts of interest The guideline development was financially supported by the Dutch Orthopaedic Association (NOV), using governmental funding from the Quality Foundation of the Dutch Association Background and purpose -A guideline committee of medical specialists and a physiotherapist was formed on the initiative of the Dutch Orthopedic Association (NOV) to update the Guideline Arthroscopy of the Knee: Indications and Treatment 2010. This next Guideline was developed between June 2017 and December 2019. In part 1 we focused on the meniscus; this part 2 addresses all other aspects of knee arthroscopy. Methods -The guideline was developed in accordance with the criteria of the AGREE instrument (AGREE II: Appraisal of Guidelines for Research and Evaluation II) with support of a professional methodologist from the Dutch Knowledge Institute of Medical Specialists. The scientific literature was searched and systematically analyzed. Conclusions and recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Recommendations were developed considering the balance of benefits and harms, the type and quality of evidence, the values and preferences of the people involved, and the costs. In this part 2 we focus on anterior knee pain, patellar tendinopathy, the role of arthroscopy in the osteoarthritic knee, arthroscopy and patellar dislocation, and osteochondral fractures, and additionally ask what the role is of arthroscopy in bacterial arthritis or ligamentous injury of the knee, and whether arthroscopy is supplemental in the treatment of tibial plateau fractures. We did not address the role of arthroscopy in the discoid meniscus and osteochondritis dissecans in children. The guideline is published online, in Dutch, and is available from the Dutch Guideline Database (https://richtlijnendatabase.nl/?query=Artroscopie+van+de+knie+&specialism=) of Medical Specialists in the Netherlands. The authors declare that there is no relevant conflict of interest. # Method See Dutch Guideline on Knee Arthroscopy, Part 1 ## Recommendation - Do not perform arthroscopy in patients with AKP, because there is no difference in level of pain or function in patients with AKP after arthroscopy compared with nonoperative treatment. In patients with apexitis patella or patellar tendon tendinopathy, most patients do well with nonoperative treatment, but there was a positive effect of arthroscopic shaving compared with nonoperative treatment on level of pain. ## Is there a role for arthroscopy of the knee in patient with osteoarthritis? ## Recommendation - Do not perform an arthroscopy in patients with osteoarthritis of the knee with or without debridement or lavage except if the knee is locked due to a sizable loose fragment in the knee. ## Is arthroscopy indicated after patellar dislocation? ## Recommendation - Do not perform an arthroscopy in patients in the acute phase after a patellar dislocation; only consider an arthroscopy in case of osteochondral fracture. ## Is arthroscopy indicated for treatment of (osteo) chondral fracture? ## Recommendation - Do not perform a diagnostic arthroscopy in patients with a suspected chondral lesion. Consider an arthroscopy in the treatment of an osteochondral fracture. ## Is there a role for arthroscopy in the case of septic arthritis of the knee? ## Recommendation - An arthroscopic treatment of septic arthritis combined with systemic antibiotics provides a good treatment option. ## Is arthroscopy indicated for ligamentous injury of the knee? ## Recommendation - Do not perform a diagnostic arthroscopy in patients with suspected ligamentous injury. ## Is arthroscopy helpful in the treatment of tibial plateau fracture? ## Recommendation - Arthroscopy can have added value in the treatment of unicondylar tibial plateau fracture. # Discussion For each question, the scientific level of evidence on which the conclusion was based was graded using the 4 levels of evidence of the GRADE approach. RCTs start with a high level of evidence but must be downgraded if risk of bias (RoB) exists. The RoB tables for RCTs are based on the recommendation made by the Cochrane Collaboration . The recommendations given are influenced by many considerations apart from the scientific evidence-such as patient preferences, availability of facilities, or organizational aspects. The recommendations for each question have been based on the scientific evidence, combined with the most important considerations, such as input from the guideline committee experts and feedback from the participating medical societies. The 1st question addresses the role of arthroscopy in patients with anterior knee pain (AKP). The term "anterior knee pain" is a descriptive term that covers all the pain surrounding the patellofemoral joint. It is therefore not a diagnosis in the narrow sense, but a symptom. The working group regarded pain and self-reported knee function as the 2 critical outcome measures. The evidence for this is low grade, because of the small sample size of the included RCT, which found no difference between the effect of arthroscopy and the effect of nonoperative therapy on level of pain and self-reported function in patients with patellofemoral pain syndrome. In patients with apexitis patella (jumper's knee) or patellar tendinopathy there was low-grade evidence that there was a positive effect of arthroscopy compared with nonopera-tive therapy on level of pain in patients with apexitis patella (jumper's knee) or patellar tendinopathy ). Due to this low grade of evidence a reticent approach with regard to advising arthroscopy for patients with apexitis is advisable. The 2nd question regards the relevance of whether arthroscopy of the knee is of value in patients with osteoarthritis, because in older patients a degenerative meniscal lesion can be diagnosed in up to 50% in men in the age range 70-90 years old , and it can be difficult to differentiate between symptoms caused by the degenerative meniscal injury and symptoms due to early osteoarthritis of the knee. The guideline committee considered self-reported pain scores and self-reported knee function to be critical outcome measures for decision-making. and complications to be an important outcome measure. It was concluded with moderate-grade evidence that knee arthroscopy did not result in an extra reduction in pain scores or function in the short or long term when compared with nonoperative management in patients with osteoarthritis. The level of evidence was downgraded by 1 level due to serious risk of bias (4 out of 5 trials did not blind the participants, care providers, or outcome assessors). With low-grade evidence it was concluded that arthroscopy may have a small risk of venous thromboembolism and a very small risk of infection compared with nonoperative management in patients with degenerative knee disease. The level of evidence for the outcomes VTE and infections was downgraded for both by 2 levels due to serious risk of bias (used data were not collected for the study) and serious inconsistency. To diagnose (early) osteoarthritis of the knee the working group advises making a standing full weight-bearing conventional radiograph in AP, lateral, and fixed flexion in patients over 50 years old. Additional imaging, such as MRI, is necessary only in the absence of osteoarthritis. Arthroscopy in osteoarthritis can be considered when repeated or persistent locking occurs, which is based on engagement of sizable loose fragments in the knee. The 3rd question addresses the treatment of knee complaints after patellar dislocation. After a patellar dislocation chondral fractures frequently occur; osteochondral fractures are seen less often. Chondral and osteochondral fragments can form loose bodies in the knee and arthroscopic removal of the loose bodies is propagated by some surgeons, sometimes combined with other arthroscopic or open operative procedures. This early surgical repair is now more common, without clear evidence to support this approach. We found no recent literature in the databases Medline (via OVID) and Embase (via Embase.com) between 2009 and January 17, 2018 that met the selection criteria. The guideline committee concluded (expert opinion) that only in patients with accompanying osteochondral fractures that can possibly be reattached is arthroscopic or open surgery indicated; in all other cases conservative treatment is the best first treatment option. The 4th question addresses the indication for arthroscopy in the case of knee complaints caused by chondral or osteochondral fractures in the acute phase. The working group regarded the development of osteoarthritis and response to treatment as critical outcome measures. We found no recent literature that met the selection criteria, the old guideline concerned 3 case series and a dissertation on fixation techniques that are not eligible according to the current selection criteria. The guideline committee advises, based on expert opinion, that arthroscopy is not indicated in case of chondral fracture, but can be considered in the case of refixation of an osteochondral fracture or removal of sizable fragments engaging persistent or recurrent locking. Concerning the clinical questions 5 to 7 we could not find new literature in our search that we could analyze according to the GRADE criteria; therefore the old text of the guideline Knee Arthroscopy 2010 was adopted. The 5th question addresses the treatment of ligamentous injury of the knee. Because the treatment of anterior cruciate ligament (ACL) injury is described in a separate guideline (Meuffels et al. 2012), ACL injury is excluded from this guideline. In former years the use of arthroscopy to address concomitant injury in case of hemarthrosis was widespread because the incidence of additional injury is high: in more than 50% of patients 1 or more ligamentous injuries are present. Based on expert opinion, the working group concludes that there is no role for diagnostic arthroscopy. Clinical examination, conventional radiographs (to exclude fractures), and MRI are the diagnostic tools of choice. The treatment of septic arthritis, addressed in the 6th question, is controversial, and differences persist between clinical specialties (orthopedic surgeons, rheumatologist, family physicians). We found no recent literature that met the selection criteria; all evidence on the treatment of septic arthritis is based on older, retrospective studies. Based on these studies and expert opinion, the working group concludes that arthroscopic debridement of septic arthritis seems to provide favorable results when combined with systemic antibiotics. In addition, arthroscopic debridement in the acute phase seems to provide better results than recurrent needle aspiration (Ayral 2005). In the case of persistent septic arthritis arthroscopic debridement can be repeated. In the case of tibial plateau fractures (question 7), arthroscopy was advocated in the literature in the 1990s (Jackson 1995). More recent literature focused on selected fractures (unicondylar fractures type II [split depression], and type III [isolated depression]). In these fracture types arthroscopic-assisted techniques resulted in fewer complications and faster rehabilitation. Based on the limited literature and expert opinion the working group concludes that arthroscopic treatment can be indicated in the treatment of unicondylar tibial plateau fracture. Diagnostic arthroscopy is not indicated in the treatment of tibial plateau fracture. In recent years evidence has accumulated that questions the effectiveness and rationalization of arthroscopy for the treatment of AKP and osteoarthritis. This observation might have induced a more critical appraisal of other indications for arthroscopy, such as after a patellar dislocation, osteochondral fracture, bacterial arthritis, ligamentous injury of the knee, or tibial plateau fracture. This guideline provides evidence-based consideration of the current indications for arthroscopy. The updated systematic literature search resulted in 221 hits. Studies were selected based on the following criteria: systematic reviews and randomized controlled trials (RCTs) that compared arthroscopy with conservative treatment or open surgery in patients with patellofemoral pain syndrome, apexitis patella (jumper's knee), or patellar tendinopathy. 1 or more of the following outcomes had to be studied: pain, selfreported knee function and stability, and range of motion. Self-reported knee function had to have been measured with either the KOOS, Kujala, or IKDC questionnaire. In addition, studies with patients aged ≥ 16 years were eligible for inclusion. ## Supplementary data 26 studies were initially selected based on title and abstract. After reading the full text, 24 studies were excluded and 2 studies were included. Based on hand search of the reference list of 1 of the included studies, one additional study was included. In the previous version of this guideline, one systematic review was included. This systematic review contained one RCT, which was not eligible for inclusion in the current literature analysis as patients < 16 years were included. Therefore, in total, 3 studies were included in the literature analysis, 1 on the treatment of patients with apexitis patella (jumper's knee) or patellar tendinopathy and 2 on the patients with AKP. 1. Pain. compared sclerosing polidocanol injections with arthroscopic shaving to treat patellar tendinopathy/jumper's knee and measured pain at rest and pain at sport activity via a VAS (0-100, where a higher score indicated more pain) and reported that pain during follow-up was lower in patients who had received arthroscopic shaving compared with patients who had received sclerosing injections. For pain at rest, mean score was 5 (SD 8) in the intervention group compared with 19 (SD 23) in the control group. For pain on activity, mean score was 13 (SD 19) in the intervention group compared with 41 (SD 29) in the control group.compared knee arthroscopy and exercise versus exercise only for chronic patellofemoral pain syndrome at short (9 and 24 months) and mid-term (5 years) follow-up. Pain was measured when descending stairs, when ascending stairs, and when standing from a sitting position via a VAS (0-100). At 9 months and 5 years' follow-up pain did not differ between patients who received arthroscopy and nonoperative treatment, mean difference in change scores between groups, at 9 months and 5 years respectively corrected for baseline scores, was 1 (95% CI -10 to 12), -4 (CI -16 to 8) for pain when descending stairs, 13 (CI 10 to 15), -3 (CI -15 to 8) for pain when ascending stairs, and 4 (CI -7 to 15), -6 (CI -17 to 5) for pain when standing from a sitting position, respectively. 2. Self-reported knee function. measured the PROM "self-reported satisfaction with treatment result" via a VAS and found that during follow-up this was higher in patients who had received arthroscopic shaving compared with patients who had received sclerosing injections. The mean score was 87 (SD 21) in the intervention group, compared with 53 (SD 33) in the control group.measured knee function by the Kujala score (0-100, where a higher score indicated better function). There was no difference in change scores between groups; mean scores corrected for baseline were 1 (CI -7 to 5), 3 (CI -4 to 10), and 1 (CI -8 to 6) respectively. ## Stability and range of motion. No data on stability and range of motion was reported in either of the studies. ## Level of evidence Pain: There are 4 levels of evidence: high, moderate, low, and very low. RCTs start at a high level of evidence. With regard to outcome measure "pain" the level of evidence in patients with apexitis patella (jumper's knee) or patellar tendinopathy function was downgraded by 2 levels due a small sample of patients (N = 45) and risk of bias ). Risk of bias was suspected due to insufficient blinding of the participants, care providers, and outcome assessors. In addition, it was not specified whether an intention-to-treat analysis was performed. The level of evidence for the outcome measure "pain" in patients with AKP was downgraded by 2 levels due a relatively small sample of patients (N = 56) and risk of bias. Risk of bias was suspected due to insufficient blinding of the participants, care providers, and outcome assessors and due to differences in loss to follow-up between the intervention and control group. Self-reported knee function: The level of evidence for the outcome measure function was also downgraded by 2 levels in patients with AKP. In patient with apexitis patella (jumper's knee) or patellar tendinopathy function was not evaluated as there were no studies that assessed this outcome. ## Stability and range of motion: The level of evidence for the outcome measure stability and range of motion was not evaluated as there were no studies that assessed this outcome in patients with AKP, apexitis patella (Jumper's knee) or patella tendinopathy. ## Question 2 Brignardelloset out to determine the effects and complications of arthroscopic surgery compared with conservative management strategies in patients with degenerative knee disease. Their literature search identified 13 RCTs; 5 trials included more than 50% of patients with radiographic osteoarthritis. As these complications are related to arthroscopy and not to osteoarthritis, all observational studies, which included also studies not related to osteoarthritis, were included. 1. Pain. Short-term benefits (< 3 months) were reported in all 5 RCTs. The pooled difference in change from baseline was on average 5.1 (CI 0.6-9.7). Long-term benefits (1 to 2 years) were also reported in all RCTs. The pooled difference in change from baseline was on average 1.3 (CI -2.6 to 5.2). With a minimal important difference (MID) of 12, the benefits of arthroscopy in pain scores, both short and long term, were not different from nonoperative treatment in patients with osteoarthritis. 2. Function. Short-term and long-term data on function was available in all 5 trials. The mean score difference from baseline in function after 3 months was 4.3 (CI -0.2 to 8.8) in favor of arthroscopy and after 1 to 2 years 2.5 (CI -1.6 to 6.5). With a MID of 13, the benefits of arthroscopy in function scores, both short and long term, were no different from conservative treatment in patients with osteoarthritis. ## Complications. In line with the systematic review by, the working group chose to report the outcomes "venous thromboembolism" (VTE) and "infections" as potential complications. The difference in proportion of patients with a VTE between arthroscopy versus nonoperative management was 5 per 1,000 patients (CI 2-10). Arthroscopy may have a small risk for VTE. For infections, the difference between arthroscopy versus nonoperative management was 2 per 1,000 patients (CI 1-4). Arthroscopy may have a very small risk for infection. ## Level of evidence Pain: The level of evidence for the outcome "pain" (both short and long term) was downgraded by 1 level due to serious risk of bias (4 out of 5 trials did not blind the participants, care providers, or outcome assessors). ## Function: The level of evidence for the outcome "function" (both short and long term) was downgraded by 1 level due to serious risk of bias (4 out of 5 trials did not blind the participants, care providers, or outcome assessors). Complications: The level of evidence for the outcomes VTE and infections were both downgraded by 2 levels due to serious risk of bias (data was used not collected for the study) and serious inconsistency. There was no evidence of publication bias. ## Question 3 The literature search resulted in 364 hits. Studies were selected based on the following criteria: systematic reviews and randomized controlled trials (RCTs) that compared arthroscopy with nonoperative treatment in patients with (recurrent) patellar dislocation. 1 or more of the following outcomes had to have been studied: pain, self-reported knee function, or quality of life. Self-reported knee function had to have been measured with either the KOOS, Kujala, or IKDC questionnaire. In addition, studies with patients aged ≥ 16 years were eligible for inclusion. 21 articles were initially selected based on title and abstract. After reading the full text all 21 articles were excluded. ## Question 4 The literature search resulted in 369 hits. Studies were selected based on the following criteria: systematic reviews and randomized controlled trials (RCTs) that compared arthroscopy and fixation with arthroscopy without fixation in case of patients with (osteo)chondral fractures; systematic reviews and RCTs that compared arthroscopy and fixation with nonoperative treatment in case of patients with osteochondritis dissecans. 1 or more of the following outcomes had to be studied: arthrosis, quality of life (IKDC, KOOS), physical activity (Tegner score), or response to treatment (WOMAC). In addition, studies with patients aged ≥ 16 years were eligible for inclusion. 8 studies were initially selected based on title and abstract. After reading the full text, all 8 studies were excluded (reason for exclusion: 4 narrative reviews, 1 pediatric population, 3 case report or case series). ## Question 5 In the search between 2010 and 2017, we could not find new literature that could be analyzed according to the GRADE criteria; therefore the old text of the guideline Knee Arthroscopy 2010 was adopted. We advise that when an acute bacterial arthritis is suspected a puncture of the knee is indicated. If a puncture confirms the suspicion of a bacterial arthritis the knee can be lavaged, which can be done using arthroscopy. If bacterial arthritis cannot be excluded by puncture a patient must be treated as if bacterial arthritis of the knee is confirmed. ## Question 6 We could not find new literature that could be analyzed according to the GRADE criteria; therefore the old text of the guideline Knee Arthroscopy 2010 was adopted. The working group concludes that an isolated ligamentous injury is not an indication for an arthroscopy, but concomitant injury can warrant an indication for an arthroscopy. In the acute phase of a suspected multiligamentous injury of the knee an MRI scan is the imaging technique of choice; if osseous injury is suspected a CT can be considered. The working group considers that patients with acute knee injuries should have access to a hospital 24 hours a day, 7 days a week. For optimal care, an orthopedic surgeon or trauma surgeon must be available for consultation. ## Question 7 We could not find new literature that could be analyzed according to the GRADE criteria therefore the old text of the guideline Knee Arthroscopy 2010 was adopted. The working group considers that there is no indication for diagnostic arthroscopy for tibial plateau fractures. Arthroscopy may be of added value in the treatment of unicondylar tibial plateau fractures.	None	https://www.tandfonline.com/doi/pdf/10.1080/17453674.2020.1850081?needAccess=true	Background and purpose — A guideline committee of medical specialists and a physiotherapist was formed on the initiative of the Dutch Orthopedic Association (NOV) to update the Guideline Arthroscopy of the Knee: Indications and Treatment 2010. This next Guideline was developed between June 2017 and December 2019. In part 1 we focused on the meniscus; this part 2 addresses all other aspects of knee arthroscopy. Methods — The guideline was developed in accordance with the criteria of the AGREE instrument (AGREE II: Appraisal of Guidelines for Research and Evaluation II) with support of a professional methodologist from the Dutch Knowledge Institute of Medical Specialists. The scientific literature was searched and systematically analyzed. Conclusions and recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Recommendations were developed considering the balance of benefits and harms, the type and quality of evidence, the values and preferences of the people involved, and the costs.
7788f0cb85e0b3448ecd035333a24507bf17f4e1	pubmed	European Guidelines for Quality Assurance in Cervical Cancer Screening. Second Edition—Summary Document	European Guidelines for Quality Assurance in Cervical Cancer Screening. Second Edition—Summary Document European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises 250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community. provide the overall programmatic framework essential to implementation of quality assurance and are therefore crucial to the success of any cervical cancer screening programme. Establishment of screening registries and linkage of individual screening data with cancer registry data, taking into account appropriate data protection standards and methods, are essential tools of monitoring and evaluation. The first edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening [bib_ref] European Guidelines for Quality Assurance in Cervical Cancer Screening. Europe against cancer..., Coleman [/bib_ref] established the principles of organised population-based screening and was pivotal in initiating pilot projects in Europe. A number of countries have in the meantime developed organised population-based screening approaches, which are illustrated in Section 2.4.2 of the second edition. It is hoped that this new guideline edition will have a greater impact on those countries in which opportunistic, rather than organised, population-based screening has been the preferred model in the past. Transformation of these programmes to the populationbased approach with quality assurance at all appropriate levels has the potential to substantially improve the accessibility, the effectiveness and the cost-effectiveness of the respective services. At the same time, substantial numbers of unnecessary screening examinations could be avoided by adhering to the interval for cervical cancer screening recommended in the European guidelines . Towards this end, considerable attention has been given to the essential aspects of developing an organised population-based programme policy that minimises the adverse effects and maximises the benefits of screening. The current recommendations are also particularly relevant to planning new cervical cancer screening programmes in Europe. Different solutions fulfilling the recommended methodological standards need to be implemented in different countries and regions with diverse levels of resources and general health care infrastructure. More than a decade has passed since the publication of the first guideline edition. The current expanded edition therefore also includes extensive updates on technical details and documentation, as well as assessment of new technologies, e.g. liquid-based cytology (LBC), automated interpretation of Pap smears and testing for human papillomaviruses (HPVs). The scope of the current guideline has also been extended to include comprehensive instructions prepared by a multidisciplinary team of experts for general practitioners, gynaecologists and cytopathologists. Much more extensive recommendations on follow-up, diagnosis and management of women with positive cervical cytology have been added. This necessitated the incorporation in the second edition of a separate chapter on techniques and quality assurance in histopathology and, for the first time, detailed guidance for clinicians in dealing with abnormal cytology, including management according to the severity of cytological abnormalities and management of histologically confirmed cervical epithelial neoplasia. A major further addition has been the inclusion of uniform indicators for monitoring programme performance and for identifying and reacting to potential problems at an early time. The indicators deal with screening intensity, test performance and diagnostic assessment and treatment and address aspects of the screening process that influence the impact as well as the human and financial costs of screening. Standard tables have been provided for documenting screening policies and for tabulating the person-based data used to generate the uniform performance indicators. The availability of these standardised tools will substantially improve data comparability and the exchange of experience and results between screening programmes in Europe. Such exchange, in turn, is essential to effective Pan-European collaboration in implementing and continuously improving the quality and effectiveness of cervical cancer screening programmes. Cervical cytology still is the cornerstone of cervical cancer prevention programmes in Europe, although new perspectives for other screening technologies are developing rapidly. The principles of quality assurance, performance monitoring and evaluation and many of the procedures and methodological standards laid down in the current guideline edition are of equal relevance to cervical cancer screening on the basis of other conceivable methods. It is therefore expected that the publication of the updated and revised second edition will also promote rigorous standards in the evaluation and application of new screening technologies, thereby improving the effectiveness of cervical cancer prevention in Europe. Over the short and medium term, screening for cervical cancer precursors and management of screen-detected lesions will remain the most effective tool for cervical cancer prevention in Europe. However, the field of cervical cancer prevention is rapidly developing due to better understanding of the natural history of the disease. Persistent infection with one of 13-16 oncogenic HPV types is now known to be a key prerequisite for development of cervical cancer [bib_ref] Carcinogenicity of human papillomaviruses, Cogliano [/bib_ref] [bib_ref] Epidemiologic classification of human papillomavirus types associated with cervical cancer, Muñ Oz [/bib_ref]. The overwhelming evidence linking HPV infection to cervical cancer has prompted the development of test systems to detect its nucleic acids as well as prophylactic and therapeutic vaccines. Primary prevention by prophylactic vaccination against the HPV types that are causally linked with most cervical cancers in Europe is likely to become a feasible option for cervical cancer control, provided the current cost of inoculation regimens is substantially reduced. While prophylactic vaccination, primarily in young girls, may provide important future health gains, cervical screening will need to be continued [bib_ref] Review of current knowledge on HPV vaccination: an appendix to the European..., Arbyn [/bib_ref]. Neglecting cervical cancer screening due to the current availability of a vaccine could paradoxically lead to an increase in cancer cases and deaths. Development of comprehensive European guidelines on prevention of cervical cancer that appropriately integrate screening and vaccination strategies is a key aim of the next phase of guideline development activities supported by the EU Health Programme. ## Guideline development process The current updated and expanded second guideline edition has been prepared by a multidisciplinary team of experts appointed by the European Commission from the former European Cervical Cancer Screening Network (ECCSN) established under the Europe Against Cancer Programme. In addition to the cytopathologists, epidemiologists, general practitioners, gynaecologists, histopathologists, virologists and specialists in social science serving as editors and authors, experts from outside ECCSN were also invited to write, review and contribute to the development of the second edition. Besides the input of the 48 experts from 17 member states directly involved in the production of the guidelines, numerous comments and suggestions were provided by experts attending meetings held in Denmark, Finland, Greece, Hungary and Luxembourg from 2003 to 2006 by ECCSN and the European Cancer Network (ECN) in which the former cancer screening networks have been consolidated. A draft-revised guideline was made available for public consultation on the internet in December 2003. The results of this consultation were incorporated into a new draft, which was reviewed by experts invited by the International Agency for Research on Cancer (IARC) to Lyon, France, in June 2005. Two or three reviewers were invited for each chapter, in order to comment on the contents and to ensure that all relevant references available had been considered. The further revised guideline content was subsequently discussed with screening experts from 23 member states and 1 applicant country of the EU at the ECN meeting in February 2006. Since then, IARC has provided technical and scientific support to the editorial board and the authors for the final preparation of the guideline document. The final recommendations and standards of best practice in the revised and updated second guideline edition are on the basis of the expert consensus in the editorial board after the above-mentioned consultations and discussions. They take into account the available evidence of screening and diagnostic procedures and programmes. For assessing evidence of effectiveness, two criteria were used: study type and study outcomes. Study types were ranked from high-to low-level evidence as follows: (i) randomised clinical trials, (ii) observational studies: case-control studies and cohort studies and (iii) correlational studies (time trends, geographical comparisons). Outcomes of studies were ordered as follows: (i) reduction of mortality from cervical cancer, (ii) reduction of incidence of invasive cervical cancer, (iii) reduction of incidence of cervical intraepithelial neoplasia (CIN) 3 or cancer (CIN3+), (iv) increased detection of high-grade histologically confirmed CIN (CIN3+ or CIN2+), (v) increased test positivity rate without or with small loss in positive predictive value for CIN2+. Throughout this guideline, scientific evidence on which the recommendations are based is indicated by references in the text. Where no observed data were available, outcomes simulated by mathematical models and expert opinion were accepted as lowest level of evidence. The authors conducted systematic literature searches and used available systematic reviews and published metaanalyses. Publication of the handbook for cervical cancer prevention by the IARC Working Group on the Evaluation of Cancer Preventive Strategies in 2005, which included several ECN experts, was also helpful. Several pioneering populationbased randomized trials have been conducted in recent years, or are currently being conducted, in various member states: LBC (Italy, The Netherlands), automated cytological screening (Finland); HPV-based versus cytology and combined (cytology + HPV) screening (Finland, Italy, The Netherlands, Sweden, UK). The results available from these trials were taken into account during the preparation of the second guideline edition up to July 2007. In addition, several metaanalyses were carried out to assess the level of evidence of new screening or management methods: LBC versus conventional cytology; HPV testing in triage of minor cytological lesions to identify women needing further follow-up, in follow-up after treatment of CIN to predict success or possible failure of treatment and in primary screening. In the meta-analyses carried out for the current guideline edition, it was only possible to assess cross-sectional outcomes (outcome types [bib_ref] European Guidelines for Quality Assurance in Cervical Cancer Screening. Europe against cancer..., Coleman [/bib_ref] ; an insufficient number of trials had reached longitudinal outcomes before final closure of chapter revisions in mid-2007. One additional meta-analysis concerned obstetrical adverse effects of treatment of precancerous lesions. Due to the rapid accumulation of evidence on new technologies and prevention strategies, review and updating of the current guidelines has already been initiated under the current EU Health Programme [European Cooperation on Development and Implementation of Cancer Screening and Prevention Guidelines (ECCG-ECN)]. ## Fundamental points and principles screening policy The Council of the EU has recommended implementation of population-based cervical cancer screening programmes to the EU member states, with quality assurance at all levels and in accordance with European guidelines. Screening recommended by the European Council and the European Guidelines is set up as a population-based public health programme, with identification and personal invitation of each woman in the eligible target population. In addition to invitation, the other steps in the screening process and the professional and organisational management of the screening service, including quality assurance, monitoring and evaluation, are well defined by programme policy, rules and regulations at the regional and national level. Designing a cervical cancer screening programme includes defining the screening policy, i.e. choosing the screening test systems, determining the target age group and the screening interval between normal test results (3 or 5 years) and establishing follow-up and treatment strategies for screenpositive women, taking into account the variation in background risk in target populations and the natural history of the disease, which is characterised by a rather long detectable preclinical period and substantial regression rates of the precancerous lesions. Cervical cytology is the currently recommended standard test for cervix screening, which should start in the age range 20-30, but preferentially not before age 25 or 30 years, depending on the burden of the disease in the population and the available resources. It is recommended to continue screening at 3-to 5-year intervals until the age of 60 [bib_ref] European Code Against Cancer and scientific justification: third version, Boyle [/bib_ref] or 65 [bib_ref] European Guidelines for Quality Assurance in Cervical Cancer Screening. Europe against cancer..., Coleman [/bib_ref]. Stopping screening in older women is probably appropriate among women who have had three or more consecutive previous (recent) normal cytology results. Special attention should be paid to the problem of older women who have never attended screening as they exhibit increased risk for cervical cancer. Opportunistic screening, which takes place in clinical settings and depends on the initiative of the individual woman or her doctor, should be discouraged. Such activities are often characterised by high coverage in selected parts of the population which are screened too frequently, coexisting with a low coverage in other population groups with less socioeconomic status, and heterogeneous quality, resulting in limited effectiveness and poor cost-effectiveness. ## Screening organisation, monitoring and evaluation The programme design must permit evaluation. An experimental design that is suitable for evaluation of new screening policies in organised settings is recommended. The success of a screening programme requires adequate communication with women, health professionals and persons responsible for the health care system. Moreover, a well-organised screening programme must reach high population acceptance and coverage and must ensure and demonstrate good quality at all levels. The communication strategy for cervical cancer screening must be underpinned by robust ethical principles and ensure that the information developed is evidence based, 'women centred' and delivered effectively, taking into account the needs of disadvantaged groups and enabling women to make an informed choice about participation at each step in the screening process [bib_ref] Improving the quality of communication in organised cervical cancer screening programmes, Giordano [/bib_ref]. Population-based information must be established for continuous monitoring of screening process indicators. An appropriate legal framework is required for registration of individual data and linkage between population databases, screening files and cancer and mortality registers. Indicators of screening programme extension and quality need to be published regularly. The information system is an essential tool for managing the screening programme; computing the indicators of attendance, compliance, quality and impact; and providing feedback to involve health professionals, stakeholders and health authorities. ## New screening technologies An observation that a new screening method detects more precursor lesions than the standard Pap smear does not sufficiently demonstrate improved effectiveness. Due to frequent regression of precursor lesions, high specificity is also required to avoid anxiety, unnecessary treatment and side-effects. Evidence of effectiveness should preferentially be on the basis of reduction of cancer morbidity and mortality. Nevertheless, reduction in incidence of grade 3 cervical intraepithelial neoplasia (CIN3) is a surrogate indicator of effectiveness. Before routine implementation of a new screening strategy, the feasibility, cost-effectiveness and quality assurance should be verified and the necessary training and monitoring should be organised. A randomised screening policy, which permits quality-controlled piloting of a new test or procedure in the context of an organised screening programme, is a particularly powerful tool for timely evaluation under real-life conditions. cytological methods. The occurrence of false-negative and unsatisfactory Pap smears has prompted the development of LBC and automated screening devices. The quality of the evaluation of the performance of these technologies often was poor and rarely on the basis of histologically defined outcomes using randomised study designs. In general, the proportion of unsatisfactory samples is lower in LBC compared with conventional cytology, and the interpretation of LBC requires less time. The cost of an individual LBC test is considerably higher, but ancillary molecular testing, such as high-risk HPV testing in the case of atypical squamous cells of undetermined significance (ASC-US), can be carried out on the same sample. The economic advantage of LBC due to the reduction of recalls for a new sample depends on the existing rates of inadequate Pap smears, which are highly variable throughout Europe. An Italian population-based randomised study recently confirmed that the sensitivities of LBC and conventional cytology are similar [bib_ref] Accuracy of liquid based versus conventional cytology: overall results of new technologies..., Ronco [/bib_ref]. Computer-assisted screening using LBC is currently being evaluated, but insufficient evidence is available for guidelines. ## Hpv detection. Several applications for HPV DNA detection have been proposed: (i) primary screening for oncogenic HPV types alone or in combination with cytology; (ii) triage of women with equivocal cytological results; (iii) follow-up of women treated for CIN to predict success or failure of treatment. HPV infections are very common and usually clear spontaneously, especially in younger women. Detection of HPV DNA thus carries a risk of unnecessary colposcopies, psychological distress and possibly of overdiagnosis. The need to carry out cervical cancer screening in an organised programme, rather than in an opportunistic setting, therefore applies particularly to screening on the basis of HPV testing. Evidence from randomised studies and meta-analyses shows that triage of women with equivocal cytological lesions by HPV testing with the Hybrid-Capture 2 assay is more sensitive and equally specific in finding high-grade CIN compared with repeat cytology. There is also evidence indicating that HPV DNA detection predicts treatment failure more quickly than cytological follow-up. The high sensitivity of current HPV DNA detection methods yields very high negative predictive values even for adenocarcinoma precursors that often escape cytological detection. Recent cohort studies indicate a prolonged duration (up to 10 years) of the negative predictive value of HPV testing. Nevertheless, further longitudinal research is necessary, preferably in an organised setting guaranteeing optimal follow-up, using randomised designs and targeting relevant outcomes. Current randomised controlled trials may demonstrate lower cumulative incidence of CIN3 and invasive cervical cancer as joint or separate outcomes in HPV-negative compared with cytology-negative women. The results of these trials are needed before screening policies for general primary HPV screening can be recommended in Europe. Such policies would also have to ensure that possible increases in the detection and management of less severe lesions are kept to an appropriate minimum. Introduction of primary HPV screening will require appropriate triage and counselling of HPV-positive women. As for any screening policy, future recommendations on primary HPV screening should not be made without specifying the age group to be targeted, the screening interval and the essential elements of quality assurance required for programme implementation. Piloting with validated HPV DNA testing can be recommended if carried out in an organised screening programme with careful monitoring of the quality and systematic evaluation of the aimed outcomes, adverse effects and costs. Women <30 years of age should not be screened for HPV, due to the high rate of viral clearance. Rollout towards national implementation can be considered only after the pilot project has demonstrated successful results with respect to effectiveness (relative sensitivity, positive predictive value of the screening test, triage and diagnostic assessment) and cost-effectiveness and after key organisational problems have been adequately resolved. HPV screening in an opportunistic setting is not recommended because adherence to appropriate intervals and requisite quality control cannot be adequately assured under such conditions. ## Guidelines for cytology laboratories Professional and technical guidelines must be followed to assure the collection and preparation of an adequate cervical cell sample [bib_ref] European guidelines for quality assurance in cervical cancer screening: recommendations for collecting..., Arbyn [/bib_ref]. The quality of a cervical cytology laboratory depends on adequate handling and staining of the samples, screening and interpretation of the slides and reporting of the results. An appropriate balance must be achieved between the best patient care possible, laboratory quality assurance and costeffectiveness [bib_ref] European guidelines for quality assurance in cervical cancer screening: recommendations for cytology..., Wiener [/bib_ref]. Uniform grading of cellular abnormalities is an essential condition for registration and comparisons over time and between different settings. Laboratories should apply only a nationally agreed terminology for cytology that is translatable into the Bethesda Reporting System [bib_ref] European guidelines for quality assurance in cervical cancer screening: recommendations for cervical..., Herbert [/bib_ref]. The CIN terminology should be reserved for describing histology. ## Guidelines for histopathology Histopathology provides the final diagnosis on the basis of which treatment is planned and serves as the gold standard for quality control of cytology and colposcopy. It is also the source of the diagnostic data stored at the cancer registry and used for evaluation of screening programmes. It is therefore important that histopathology standards are monitored and are on the basis of CIN or other internationally agreed-upon terminology. Histopathologists should be aware of, and familiar with, the nature of cytological changes that may be relevant to their reports. The accuracy of the histopathological diagnosis of tissue specimens depends on adequate samples, obtained by colposcopically directed punch biopsies (with endocervical curettage if necessary) or excision of the transformation zone or conisation. An accurate histological diagnosis further depends on appropriate macroscopic description, technical processing, microscopic interpretation and quality management correlating cytological and histological diagnosis. guidelines for management of screen-positive women A woman with a high-grade cytological lesion, a repeated low-grade lesion or an equivocal cytology result and a positive HPV test should be referred for colposcopy. The role of colposcopy is to identify the location of the abnormal cells, to target taking of biopsies and to decide whether any treatment is required. Colposcopy should only be carried out by adequately trained health professionals [bib_ref] European guidelines for quality assurance in cervical cancer screening: recommendations for clinical..., Jordan [/bib_ref] [bib_ref] Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis..., Arbyn [/bib_ref]. Guidelines are provided for the management of ASC-US and high-grade squamous intraepithelial lesions. Guidelines for low-grade squamous intraepithelial lesions (LSIL) are difficult to delineate because current evidence does not indicate that any method of management is optimal. Repeat cytology or colposcopy are acceptable options, but HPV testing as an initial management option is not sufficiently selective for all women with LSIL. However, HPV testing in older women with LSIL can be considered [bib_ref] European guidelines for quality assurance in cervical cancer screening: recommendations for clinical..., Jordan [/bib_ref]. Quality assurance and collection of data on patient management are important elements of the management and follow-up of women referred with an abnormal cervical smear [bib_ref] European guidelines for clinical management of abnormal cervical cytology, part 2, Jordan [/bib_ref]. Colposcopy is sometimes proposed as an alternative screening method, but its specificity (and probably also its sensitivity) in primary screening is too low for this purpose. ## Complementary strategies of cervical cancer prevention Efforts to establish or improve cervical cancer screening should be planned and implemented in the framework of a comprehensive cancer control programme taking into account overall health care needs and priorities as well as feasible and cost-effective complementary preventive strategies, such as evidence-based primary prevention interventions [bib_ref] European Parliament resolution of 10 April on combating cancer in the enlarged, Parliament [/bib_ref]. As a matter of editorial policy, the second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening provides recommendations on prevention of cervical cancer through early detection programmes for cervical lesions. An appendix on prophylactic HPV vaccination has been added to the second guideline edition in order to summarise the evidence available up to July 2007 but not to formulate European recommendations in this area [bib_ref] Appendix 2: HPV vaccination, Arbyn [/bib_ref]. There are two prophylactic HPV vaccines containing HPV16 and HPV18 licensed in the EU. These HPV types are causally linked with 70% of cervical cancers in Europe [bib_ref] Against which human papillomavirus types shall we vaccinate and screen? The international..., Muñ Oz [/bib_ref] [bib_ref] Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions:..., Smith [/bib_ref]. Phase 2 and 3 trials have demonstrated strong immunogenicity and good safety profiles over the duration of the studies. Moreover, among girls and young women, aged 15-26 years not infected with those types at the time the vaccine was administered, excellent results were observed regarding protection against cervical cancer precursors and other diseases associated with the vaccine types, over the time span that data are available [bib_ref] Appendix 2: HPV vaccination, Arbyn [/bib_ref]. European guidelines on HPV testing and vaccination are currently being developed in the framework of the ECCG-ECN project. In the meanwhile, it is important to note the uncertainty about the long-term efficacy of currently available vaccines as well as uncertainty about the future impact of oncogenic HPV types which are not targeted by currently available vaccines. Given current knowledge, population-based screening will continue to be necessary in coming decades in the cohorts of women already exposed to oncogenic HPV types. Screening fulfilling the quality assurance principles recommended in the current European cervical screening guidelines may also be necessary to adequately control cervical cancer in women vaccinated before exposure to HPV, although screening protocols and procedures will presumably require modification. As with any public health intervention, quality assurance of complementary strategies of cervical cancer prevention should also take into account organisational aspects essential to programme effectiveness and particularly costeffectiveness. The potential importance of a populationbased approach and programme monitoring and coordination to achieving and maintaining high coverage should not be overlooked. Resource limitations and the need to balance competing health priorities require adequate consideration of the marginal cost and benefit of combining cervical cancer screening and vaccination strategies. Consideration should also be given to the high costs of current HPV vaccines, which constitute a major barrier for several member states of the EU. ## Appendix 1 key performance indicators A list of key performance indicators is provided for monitoring the screening process and for identifying and reacting to potential problems at an early time [bib_ref] Key performance indicators, Ronco [/bib_ref]. The indicators address aspects of the screening process which influence the impact as well as the human and financial costs of screening. The present parameters assume that cytology is used as the primary screening test, which is currently recommended. However, most of the present parameters may also be applied, with only small changes, if a different screening method (e.g. HPV DNA testing) is used. Depending on the respective screening test and the screening policy, the values of some parameters (e.g. detection rates of CIN, positive predictive values or specificity) will change. Before calculation of the recommended performance parameters, it is essential to verify key programme conditions which may influence the applicability and the further interpretation of respective parameters. As a minimum, the conditions indicated in [fig_ref] Table 1: Key characteristics of cervical cancer screening programme [/fig_ref] should be reported. For more information, see Annex 1 of Chapter 2 of the full guideline document [bib_ref] City of Luxembourg, Grand Duchy of Luxembourg: Office for Official Publications of..., Anttila [/bib_ref]. Three groups of indicators can be distinguished: Screening intensity: the proportion of the target population actually screened within the recommended interval is the main determinant of the success of a screening programme. However, too frequent testing increases financial and human costs with only marginal gain in reduction of incidence and mortality. The duration of the recommended screening interval must therefore be taken into account in monitoring and evaluating screening intensity. Indicators include review Annals of Oncology programme extension, compliance with invitation, coverage and smear consumption (Appendix [fig_ref] Table 1: Key characteristics of cervical cancer screening programme [/fig_ref]. Screening test performance: essential indicators include the referral rates for repeat cytology and for colposcopy, as well as the positive predictive value of referral for colposcopy, the specificity of the screening test and the rate of detection of histologically confirmed CIN (Appendix . Diagnostic assessment and treatment: indicators include compliance to referral for repeat cytology and for colposcopy; treatment of high-grade lesions is also an essential performance indicator. The proportion of women hysterectomised for CIN serves as an indicator of extreme over-treatment (Appendix . Widespread application of the following uniform parameters to report programme performance should facilitate collaborative studies and comparison between countries and regions and should thereby help to develop an evidence base for setting future Pan-European quality standards. definition of performance parameters in cervical cancer screening The rationale and approach for calculation of the following parameters are provided in Sections 7.2-7.4 of Chapter 7 of the full guideline document [bib_ref] Key performance indicators, Ronco [/bib_ref]. Specific instructions are indicated in Section 7.5 of Chapter 7 and are reproduced below. Most of the key performance indicators can be directly computed from the tables presented in the annex of Chapter 2 in the full guideline document (Full pdf guideline version: http://bookshop.europa.eu/eubookshop/ publicationDetails.action?pubuid=547021) [bib_ref] City of Luxembourg, Grand Duchy of Luxembourg: Office for Official Publications of..., Anttila [/bib_ref]. However, a number of indicators are on the basis of the incidence of invasive cervical cancers in women with different screening history. These indicators provide a more direct evaluation of the impact of screening, but they need to be computed over longer periods of time and linkage of screening registry data with cancer registry data is required for some indicators; see also Section 5 in Chapter 2 in the full guideline document. For short-term monitoring purposes, the calculations in the annex to Chapter 2 in ref. [bib_ref] City of Luxembourg, Grand Duchy of Luxembourg: Office for Official Publications of..., Anttila [/bib_ref] are on the basis of annually aggregated data. Additional aggregation over different periods of time is recommended, particularly over the full screening interval of a given screening programme (3 or 5 years), and is required for some of the performance parameters. Wherever possible, longer and shorter evaluation periods should also be considered. For calculations for a given period of time, such as the recommended screening interval (3 or 5 years), the dates on which the period starts and ends and the procedure for determining the target population should be recorded. For calculations on the basis of the size of the target population, use the average over the given time period. Note that parameters 6 (Incidence of invasive cancer in unscreened women), 14 (Cancer incidence after normal cytology) and 19 (Incidence of invasive cancer after abnormal cytology) require linkage with cancer registry data. The followup periods recommended for calculation of cervical cancer incidence are 6 months longer than the recommended screening interval of the respective programme (3.5 or 5.5 years). The purpose of adding one-half year to the screening interval is to include screen-detected cancer at the next screening episode. Calculations on the basis of longer follow-up periods are also recommended. [table] Table 1: Key characteristics of cervical cancer screening programme [/table]	None	http://www.annalsofoncology.org/article/S0923753419383176/pdf	European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises ∼250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community.
b8c7ae48b042b62f7ee0c0e3eb7f40fa85efa100	pubmed	Measurement of blood pressure in people with atrial fibrillation	Measurement of blood pressure in people with atrial fibrillation ## Executive summary Current validation protocols for assessing the accuracy of blood pressure monitors exclude people with atrial fibrillation, except in special circumstances. Hypertension guidelines advise manual blood pressure measurement in the presence of arrhythmia. They also promote home and ambulatory monitoring for diagnosis of hypertension, which necessarily requires automated devices. Few studies of automated blood pressure measurement with atrial fibrillation have been undertaken, and none in full accordance with internationally recognised protocols. We recently reported a systematic review and meta-analysis of accuracy of oscillometric devices for blood pressure measurement in atrial fibrillation. The recommendations presented here are based on that review, supplemented by consensus expert opinion of the Blood Pressure Measurement Working Party of the British and Irish Hypertension Society (BIHS). # Full statement Office or clinic blood pressure measurement in atrial fibrillation Office blood pressure measurements should be carried out using an auscultatory method with a calibrated analogue sphygmomanometer. Current and forthcoming BIHS/National Institute for Health and Care Excellence guidance regarding cuff size, seating and avoidance of other causes of error in blood pressure measurement should be followed. Cuff deflation should be no faster than 2-3 mmHg per second. Auscultatory methods are recommended due to the lack of evidence for accuracy of most oscillometric devices in the presence of atrial fibrillation. Measurements should be repeated at least three times, regardless of absolute blood pressure, since there is increased intra-person variation in blood pressure with atrial fibrillation. Using an average of these multiple measurements is advised on the basis of expert opinion. ## Home or clinic based automated blood pressure measurement Due to the absence of evidence for accuracy for most automated monitors designed for home or clinic use, and the increased individual variation in blood pressure with atrial fibrillation, we recommend comparison with multiple auscultatory clinic blood pressure readings for all individuals, when automated devices are used. This may be achieved by taking a sequence of at least three device readings alternating with three auscultatory readings made on the same arm, using a professional analogue device (such as the Accoson Green Light 300). Limited data do exist to suggest that two monitors, designed for professional use, are accurate in measuring systolic, but not diastolic blood pressure: Philips SureSigns VSi and Welch Allyn Vital Signs 300 devices. For home use, data from one other study suggest that the Tensoval duo control device is accurate in measuring systolic and diastolic blood pressure. The Microlife Watch BPA 100 Plus device may be accurate for systolic but not diastolic blood pressure. ## Ambulatory blood pressure measurement Given the absence of evidence for accuracy of most ambulatory monitors, and the increased individual variation List of members of the Blood Pressure Measurement Working Party of the British and Irish Hypertension Society is listed below Acknowledgement in blood pressure with atrial fibrillation, we recommend comparison of such devices with multiple auscultatory clinic blood pressure readings for all individuals. This may be achieved by taking a sequence of at least three device readings alternating with three auscultatory readings made on the same arm, using a professional analogue device (such as the Accoson Green Light 300). Limited data obtained by static comparison of oscillometric ambulatory blood pressure monitors with mercury readings suggest accuracy for systolic but not diastolic blood pressures measured by the SpaceLabs 90207 and the A&D TM-2430 devices. ## Devices with atrial fibrillation detection Some devices detect pulse irregularity to indicate potentially undiagnosed atrial fibrillation. Such devices are not inherently more accurate in measuring blood pressure with atrial fibrillation, nor can they be assumed to be, in comparison with monitors lacking such technology. ## Automated devices shown to be inaccurate in atrial fibrillation Based on published evidence, a number of devices have been shown to be inaccurate for blood pressure measurement with atrial fibrillation, and cannot be recommended. # Conclusion Manual measurement should be used where possible for measuring blood pressure with atrial fibrillation. Limited data exist to suggest that some automated devices can accurately measure systolic, but not diastolic, blood pressure in the presence of atrial fibrillation. Further work is needed to evaluate the many commonly used devices lacking such data. Future comparisons should follow internationally recognised protocols to ensure validity and facilitate comparisons. Members of the BIHS Blood pressure measurement working party are N. Chapman, P. Chowienczyk, E. Denver, P. Lacy, P. Lewis, U. Martin, A. Neary and J. Sheppard ## Compliance with ethical standards Conflict of interest CEC is currently chief investigator for an unrelated non-sphygmomanometer based study of AF detection: imPulse: Sensitivity and Specificity of a mobile lead-one ECG like device for the detection of Atrial Fibrillation. ClinicalTrials.gov Identifier NCT03524625. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license 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 license, visit http://creativecommons. org/licenses/by/4.0/. Copal UA-251Systolic: Philips SureSigns VSiMicrolife BP A6Systolic: Welch Allyn Vital Signs 300Omron HEM 711ACSystolic and diastolic: Tensoval duo controlOmron HEM-750CPTakeda UA-751Ambulatory measurement Welch Allyn 52000Systolic: A&D TM-2430 device. Systolic: SpaceLabs 90207 device. Diastolic: SpaceLabs 90207	None	https://www.nature.com/articles/s41371-019-0261-4.pdf	None
1d478be12f8de85f44fe4edb323ab91caec1c5cd	pubmed	Diagnostic and Therapeutic Approach to Sleep Disorders, High Blood Pressure and Cardiovascular Diseases: A Consensus Document by the Italian Society of Hypertension (SIIA)	Diagnostic and Therapeutic Approach to Sleep Disorders, High Blood Pressure and Cardiovascular Diseases: A Consensus Document by the Italian Society of Hypertension (SIIA) Hypertension is a major contributor to fatal/nonfatal cardiovascular diseases, and timely identification and appropriate management of factors affecting hypertension and its control are mandatory public health issues. By inducing neurohormonal alterations and metabolic impairment, sleep disorders have an impact on a variety of cardiovascular risk factors, including hypertension, and ultimately increase the risk of cardiovascular events. There is evidence that qualitative and quantitative sleep disorders are associated with resistant hypertension and with impaired circadian blood pressure variations. However, sleep disturbances are often unrecognized, or heterogeneity exists in their management by non-specialists in the field. This document by the Italian Society of Hypertension summarizes the updated evidence linking sleep disorders to hypertension and cardiovascular diseases, the major underlying mechanisms, and the possible management strategies. A simplified, evidence-based diagnostic and therapeutic algorithm for comorbid hypertension and common sleep disorders, namely obstructive sleep apnoea and insomnia, is proposed. # Introduction A proper sleep-wake cycle markedly influences a multitude of neuroendocrine systems, all of which are deeply involved in cardiovascular and metabolic homeostasis. Accordingly, qualitative and/or quantitative sleep disorders adversely affect the physiology of the hypothalamic-pituitary-adrenal axis, the glycolipid metabolism and the cardiovascular system, thus exerting a considerable impact on the overall cardiometabolic risk. Specifically, observational studies and experimental evidence fully support the existence of a close link between sleep disorders and arterial hypertension, cardiovascular disease, diabetes mellitus and/or obesity. Because of the burden that all these diseases represent for the national health system, the risks of workplace accidents and traffic collisions and, finally, the losses due to reduced productivity, sleep disorders and excessive daytime sleepiness exert a relevant economic and social impact that fully justifies their inclusion among public health issues. In this context, adequate knowledge of sleep disorders and related solutions is essential for the clinician involved in the prevention and treatment of cardiovascular and metabolic diseases. Among sleep disorders affecting blood pressure (BP), obstructive sleep apnoea (OSA) has been consistently associated with increased risk of incident hypertension and treatment-resistant hypertension, as well as impaired nocturnal physiological BP reduction ("dipping"), and is now recognised as one of the modifiable aggravating factors of the global cardiovascular risk. In fact, OSA events are accompanied by acute changes in cardiovascular parameters, such as large fluctuations in BP and heart rate, associated with long-term changes in fluid homeostasis, all of which increase the risk of fatal and non-fatal cardiovascular events. Delaying sleep onset also increases the likelihood of hypertension, with an estimated risk of 300% (odds ratio 3.27; 95% confidence interval 1. . In women, sleep deprivation might represent a peculiar cause of vulnerability to hypertension and cardiovascular events. In addition, the expression of more than 700 genes involved in multiple functions, including metabolic control and redox status, is modified by sleep deprivation. In parallel, a U-shaped association between sleep duration and all-cause mortality as well as increased cardiovascular risk has been described. On these bases, hypertension guidelines emphasise the importance of investigating the possible presence of sleep disorders in patients with resistant arterial hypertension and loss of physiological nocturnal BP dipping, as well as the need for a multidimensional approach of the problem that includes both lifestyle changes (diet, exercise, weight loss) and medications. He triad of "correct and timely diagnosis"-"lifestyle changes"-"resetting of the correct sleep-wake cycle" is gradually becoming the pillar of a correct approach to the issue of sleep disorders in cardiovascular prevention. Thus, accurately collecting a history of possible sleep disorders is essential in the evaluation of the patient with hypertension and/or increased cardiovascular and/or metabolic risk. Lifestyle interventions, including diet and exercise, are especially relevant when excess weight is believed to favour a disordered sleep. Restoring the correct function of the melatonin system-e.g. through oral administration of prolonged release melatonin at adequate dosages-might contribute to sleep restoration and cardiometabolic protection. Melatonin, in fact, is a hormone whose low levels have been frequently associated with the development of arterial hypertension, and whose administration in insomnia is also indicated in adults with cardiovascular comorbidities. The document that follows this brief premise is promoted by the Italian Society of Hypertension in order to provide a summary of the state of the art of cardiovascular and metabolic implications of sleep disorders. The purpose of the document is to generate an updated and shared training and information tool, with the aim of standardising the approach of clinicians to the problem and optimising the multidimensional management of the hypertensive patient. ## Physiology and pathology of sleep As Heraclitus of Ephesus wrote: "To those who are awake, there is one world in common, but of those who are asleep, each is withdrawn to a private world of his own.", implying that the concept of sleep is an active process and is unique to each individual. Sleep is one of the most important behavioural characteristics of humans and animals, which forces them to spend a significant proportion of life in a state where reactions to environmental stimuli are inhibited and during which important cognitive processes are developed. Although there are still many aspects to be defined, in particular concerning the meaning and function of sleep, research in the neurophysiology field over the last 30 years has made it possible to clarify some fundamental concepts such as the sleep-wake cycle and circadian rhythms. As anticipated, sleep is a reversible state of interruption of motor interactions with the environment and is present in many animal species, even in simple organisms such as yeast. It is divided into rapid eye movement (REM) sleep, contrasted with non-REM sleep, where this oculographic feature does not occur. This descriptive definition is associated with the presence/absence of a series of physiological functions that characterise REM and non-REM sleep. In the former, in addition to the known eye movements, there is a marked muscular atony of the antigravity muscles which spares the diaphragm. Non-REM sleep, which accounts for about 80% of total sleep time, is further divided into 4 categories, according to the first classification by Rechtschaffen and Kales, reduced to 3 (N1, N2 and N3) in 2007 after a re-evaluation by the American Academy of Sleep Medicine . During non-REM sleep, the brain works in a low-consumption mode that is visible at the electroencephalographic level through slow and broad waves; heart rate, respiratory rate and BP decrease in absolute values and become less variable. The alternation of REM and non-REM sleep occurs several times (on averageduring the night at intervals of about 90-120 min. Stage N3 of non-REM sleep is more prominent in the first part of sleep, while REM sleep is more pronounced in the second part. The alternation of sleeping and waking is part of a more complex process called a circadian rhythm. The circadian rhythm is a broader concept that is defined with a fundamental characteristic: it is an endogenous process that can occur even independently from the variation of the environmental features. However, at the same time, it is a process that is able to adapt to environmental stimuli while maintaining its own periodicity. The ability of a cell or complex organism to keep track of time is inherent in a series of molecular mechanisms, the discovery of which earned Jeffrey C. Hall, Michael Rosbash and Michael W. Young the Nobel Prize in 2017 thanks to a series of studies on Drosophila melanogaster. The presence of such molecular mechanisms that can establish the circadian rhythm universally in the different cells and tissues of an organism poses a risk of lack of synchronisation. This risk is minimised by the presence of a hierarchical organisation of cells capable of maintaining a circadian rhythm, at the top of which is the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN is located in a strategic area which is near the optic chiasm. In this way it can receive optical stimuli from one of the most important external factors (Zeitgeber, from the German, "time giver"), able to synchronise a biological clock, i.e. light. The extraordinary ability of the SCN to coordinate the biological clock of an organism has been confirmed in experiments where, by dispersing the single SCN neurons in culture, the molecular rhythms of each neuron were observed which, however, were out of step with one another. In the intact SCN nucleus, on the other hand, a precise coordination of the various neurons is observed through the synaptic terminations, which use various neurotransmitters, including gamma-aminobutyric acid (GABA), allowing a common and synchronised output. The activity of the SCN nucleus characterises a wide variety of cells and tissues of our body, starting from the paraventricular nucleus (PVN) of the hypothalamus on which it exerts an inhibitory action by conditioning the activity of the endocrine system and the autonomic nervous system with particular regard to the production of melatonin. Therefore, since the activity of SCN is dependent on light stimuli, an increase in SCN activity during exposure to light is effectively able to reduce the production of melatonin by the pineal gland. Melatonin is a fundamental neurohormone for the synchronisation of the biological clock. It is produced by the pineal gland during the night hours reaching maximum concentrations in the blood between 2:00 a.m. and 4:00 a.m. and then gradually decreasing as the morning approaches. Neurones located in the brain stem are also involved in the circadian regulation of sympathetic and vagal activity and the relative modulation by the autonomic nervous system of the cardiovascular system between day and night. Sleep disorders can be grouped according to different classifications, one of the most widely used is the International Classification of Sleep Disorders (ICSD), which is now in its third edition and produced by the American Academy of Sleep Medicine. This classification divides sleep disorders into the following categories: 1) Insomnia 2) Sleep-related breathing disorders 3) Central disorders of hypersomnolence 4) Circadian rhythm sleep-wake disorders 5) Parasomnias 6) Sleep-related movement disorders. The first group includes insomnia, which is defined as a disorder characterised by difficulty in falling asleep or staying asleep, or by nonrestorative sleep. This disorder affects the subjective feeling of well-being, even causing daytime psychic, cognitive and somatic alterations. This is the most frequently reported sleep disorder in clinical practice and in the general population. It is frequently associated with other disorders; in particular, the most well-known and described link in the scientific literature is undoubtedly with mental disorders. In particular, it has been shown that the presence of insomnia is capable of predicting the onset of a depressive episode, anxiety, alcohol abuse, or psychosis and represents a risk for the development of suicidal ideation and behaviour. Insomnia is also associated with high cardiovascular morbidity and mortality, particularly when accompanied by a short sleep duration. One possible explanation of this could be the altered BP profile over 24 h of sleepless patients with reduced dipping and nocturnal hypertension. The second group encompasses all respiratory disorders that occur during sleep, the most prevalent being OSA syndrome (OSAS). OSAS is determined by a transient but repeated interruption of breathing during sleep. This phenomenon causes a qualitative change in night-time rest, which may lead to symptoms during waking, such as excessive daytime sleepiness and fatigue. As previously seen, sleep induces a state of general muscle relaxation, particularly in the REM stage. The loss of muscle tone can cause the upper airway walls (hypopharynx) to narrow and begin to vibrate, thus producing the wellknown snoring phenomenon. In extreme conditions, an actual collapse of the walls can occur, or even the complete airway obstruction. In this case our brain briefly interrupts sleep by awakening; this leads to the recovery of adequate muscle tone, stopping the apnoea phenomenon. Patients suffering from OSA, however, may not be aware of the many awakenings associated with apnoea, because sometimes wakefulness and lighter sleep are not so intense or prolonged that the individual reaches a state of consciousness. At morning awakening, however, there may often be a feeling of not having had a restful night's sleep and symptoms such as excessive sleepiness, fatigue or headache-characteristic expressions of poor sleep quality-may also appear. Numerous studies have demonstrated the association between hypertension and OSAS both from a pathophysiological point of view, documenting transient pressure rises due to an increase in sympathetic tone during obstructive events, and from an epidemiological point of view. In addition to obstructive apnoea, central apnoea is also frequently found in patients with cardiovascular diseases such as heart failure. During central apnoea there is no obstruction to the upper airways; instead, pauses in breathing occur due to lack of inspiratory chest or abdominal movements. The causes of this disorder are manifold and may be found in the mechanism of respiratory control in the central nervous system (CNS). Respiratory stimulation to the major muscles involved in breathing, such as the diaphragm, depends on several stimuli, including nerve afferents originating in chemoreceptors. Unstable breathing that predisposes to hyperventilation and drops in PaCO 2 below the apnoeic threshold results in a reduction in the output to the respiratory muscles and therefore in central apnoea. Many of the respiratory sleep disorders result in daytime hypersomnia due to sleep disturbed by apnoea and other respiratory events. There are other sleep disorders that are characterised by daytime hypersomnia not secondary to significant functional sleep disruptions. This is the case with primary hypersomnias, which include narcolepsy-a pathology characterised by excessive daytime sleepiness, often experienced as recurrent involuntary sleep attacks, which occur during the day. It is caused by an inability of the brain to regulate the sleep-wake cycle in a physiological manner. In patients with narcolepsy, there is a rapid and atypical emergence of REM sleep, in the 15-20 min that elapse after falling asleep, and an intrusion of REM sleep during the day. Narcolepsy affects on average 1 in 2000 people (0.05% of the population) and is characterised, in addition to daytime sleepiness, by three key symptoms caused by the intrusion of REM sleep during wakefulness: cataplexy, a sudden, brief, reversible episode of muscle weakness that occurs in conjunction with emotional stimuli; sleep paralysis, an experience that occurs while sleeping, during which the subject suddenly feels unable to move or speak and hypnagogic or hypnopompic hallucinationsvivid dreamlike experiences that occur on falling asleep or waking from sleep respectively. The ICSD classification also includes circadian rhythm disorders that result from a lack of synchronisation between sleep-wake cycles and the schedules imposed by social needs, resulting in fatigue, poor work and school performance and sleep disorders, particularly difficulty in falling asleep or waking up at the desired times. Circadian rhythm disorders include: delayed sleep phase syndrome, in which subjects tend to fall asleep between 3:00 a.m. and 6:00 a.m. and wake up between 12:00 p.m. and 3:00 p.m.; advanced sleep phase disorder-in these subjects there is a tendency to fall asleep and wake up early compared to the conventional setting; jet-lag disorder, in subjects who travel across at least two different time zones; and shift work sleep disorder, frequent in workers with shifts that alternate between day and night. Parasomnias represent a broad and heterogeneous group of sleep disorders that consist of anomalous and involuntary They are further divided into NREM sleep parasomnias, such as sleepwalking and night terrors, and REM sleep parasomnias, such as REM sleep behaviour disorder. The latter is characterised by the loss of physiological muscle paralysis during REM sleep. Therefore, during the episodes, patients present excessive motor activity, often characterised by abrupt behaviours (such as screaming, punching and kicking), in relation to the content of their dreams. This disease can be associated in 40% of cases with some neurodegenerative diseases, such as Parkinson's disease, multisystem atrophy and some forms of dementia. Finally, sleep movement disorders are characterised by the appearance of simple and repetitive movements that disturb sleep and its onset. Restless legs syndrome (RLS) is common, and manifests itself with a feeling of restlessness in the lower limbs at rest, typically in the evening, which induces the subject to move his or her legs and to walk, compromising falling asleep and the continuity of sleep. It often comes with rhythmic movements of the limbs during sleep, which disturb sleep and are associated with microawakenings as well as transient increases in heart rate and BP during sleep. Given the impact of periodic movements to the lower limbs on night-time BP, RLS has been associated with the development of cardiovascular diseases. However, this report needs confirmation from subsequent longitudinal studies. ## Sleep disorders and cardiovascular diseases For many years, the role of sleep in human pathophysiology has been the subject of attention almost exclusively by psychologists and neuroscience experts, but in more recent times the concept of sleep as a restorative process in the wider sense has become more established, extending to the physiological functions of the whole body. The link between abnormal sleep duration and diseases had already been hypothesised by Hippocrates, who had observed that "Both sleep and insomnolency, when immoderate, are bad". The pace of modern life has caused a significant change in sleep duration and quality compared to the past, with an increase in the proportion of people claiming to sleep less than 7 h a day in recent years (from 22% observed in 1977 to 29% in 2009). In particular insomnia, which is the most prevalent sleep disorder, seen in about a third of the people in the general population in Europe, has been associated with a number of pathological conditions. Over time, evidence has accumulated to support a significant relationship between sleep disorders and metabolic and cardiovascular diseases. ## Sleep duration and cardiovascular risk factors A short sleep duration (SSD), defined as < 6 or 7 h a day of sleep, is associated with a higher prevalence of obesity. The results of some longitudinal studies also seem to support a relationship between SSD and incident obesity, with an increase in risk of 55%; the correlation seems particularly evident when the duration of sleep falls below 4 h. Case studies indicate that people with SSDs tend to have more snacks between meals, have more irregular eating habits, consume more calories and eat more fat. Even those who sleep too much, or "long sleepers" (LS), are more often obese and tend to consume more calories and less healthy food. The relationship between abnormalities in sleep duration and energy consumption is a more complex and less researched area, although the role of an alteration in the relationship between energy intake and calorie consumption in both SSD and LS subjects seems evident. Abnormalities in sleep duration are also associated with a higher prevalence of diabetes mellitus. A meta-analysis that included more than 10,000 subjects showed a significant risk of developing diabetes in those who sleep less than 5-6 h or more than 8-9 h per night, with a relative risk of developing diabetes of 1.28 and 1.48, respectively, during an average follow-up of approximately 10 years. Some studies have also reported a relationship between short sleep duration and arterial hypertension, but the data are quite heterogeneous. The most recent meta-analysisappears to indicate a U-shaped relationship in crosssectional studies, with an increased risk of hypertension for both those with reduced sleep duration and those with increased sleep duration. In longitudinal studies, however, there is a significant relationship with arterial hypertension for subjects with short sleep duration but not for LS. This relationship seems to be more evident in younger ages: a recent analysis of the available data showed an increase in the risk of arterial hypertension of 51% among adolescents with short sleep duration, in the absence of significant associations with long sleep duration. ## Sleep duration and overt cardiovascular disease The association described so far between sleep duration and obesity, metabolic abnormalities and arterial hypertension is also a valid prerequisite for a relationship with overt cardiovascular diseases, which has been described in various studies, although with a slight heterogeneity in the reported results. Among the most recent, a cross-sectional analysis carried out on 32,152 subjects within the National Health and Nutrition examination Survey (NHANES)showed a significant association between sleep duration and cardiovascular diseases, and in particular, in patients with short sleep duration, a higher prevalence of subjects with a clinical history of cerebral stroke (odds ratio, OR The meta-analysis showed inconclusive results with regard to total cardiovascular events and cardiovascular mortality; this finding may in part be linked to a less precise definition of the events on which the analysis is based, but it could also be justified by the presence of confounding factors not considered in the multivariate model adopted in this study and which could have influenced other similar studies in literature as well. The analysis of data from the United Kingdom Biobank (500,000 healthy adult subjects) recently confirmed the increased risk of myocardial infarction in subjects with less than 6 h of sleep (20% increase in risk). It also showed a 34% increase in risk associated with sleeping longer than 9 h. The results, in the same study, of the Mendelian randomisation analysis supported a causal link between short sleep duration and risk of acute myocardial infarction. Very little data is available regarding the relationship between sleep duration and cardiovascular events in patients with confirmed cardiovascular disease. Kim et al. recently analysed the relationship between sleep duration and risk of events in about three thousand patients with confirmed coronary artery disease included in the "Emory Cardiovascular Biobank". Short or long sleep duration has been associated with a significant increase in the risk of death from all causes during an average follow-up of 2.8 years. When the authors focused on mortality from cardiovascular causes, a significant relationship with short sleep duration but not with long sleep duration emerged, after correction for possible confounding factors. As for the relationship between sleep duration and atrial fibrillation, the data available in the literature are not conclusive, although some, but not all, case studies seem to suggest a U-shaped relationship, as for cerebrovascular and coronary events. In conclusion, epidemiological data, although heterogeneous, convincingly supports the presence of a relationship between short sleep duration and risk of cardiovascular events; this relationship is also reasonably supported by the possible role of hormonal alterations associated with a reduced sleep duration (possible increase in cortisol levels, suppression of leptin levels and increase in ghrelin, reduction of melatonin levels, alterations in the endocannabinoid system), insulin resistance, disruption in eating behaviour that can lead to being overweight and obesity, release of proinflammatory cytokines. The relationship with long sleep duration and risk of cardiovascular complications seems to be less well established. Indeed, many confounding factors may play a significant role in this relationship. Prospective studies with strict standardisation, with analysis of all possible confounding factors and quantitative evaluation of sleep duration may better define the relationship between sleep duration and cardiovascular events. ## Qualitative sleep abnormalities and cardiovascular risk Disturbances in the quality of sleep are a further element that, other than sleep duration, could exert a negative influence on the cardiovascular system. It is not easy to correctly classify the presence of qualitative sleep abnormalities. In fact, for a correct diagnosis, it is often needed to undergo complex investigations, such as polysomnography, which are difficult to apply as a screening method in the general population. Moreover, it is not always possible to discriminate to what extent qualitative sleep abnormalities cause unfavourable effects on the cardiovascular system regardless of their repercussions on the duration of the sleep itself. Qualitative sleep disturbances may include frequent nocturnal awakenings which cause excessively fragmented sleep, respiratory sleep disorders, including OSA, and periodic movements of the limbs in sleep, a feature of restless leg syndrome. One aspect toward which the scientific interest is constantly growing is represented by circadian rhythm sleep disorders, which often affect shift workers who frequently switch between daytime and night-time shifts. The presence of fragmented sleep, interrupted by frequent awakenings, regardless of their causes, has a negative effect on the cardiovascular system in that the structure of sleep, that is the temporal succession of the various phases of sleep, is altered. There is consistent scientific background attributing a protective significance to REM (rapid eye movement) sleep duration in relation to cardiovascular disease. This includes data from the Cardiovascular Health Study where it was observed a linear and inverse relationship between REM sleep duration and the risk of atrial fibrillation. Sympathetic tone is high during REM sleep, suggesting that those with less REM sleep may be characterized by higher levels of vagal tone, which may favor AF appearance. However, lower odds of AF were reported among those with a longer duration of slow-wave sleep, which is typically characterized by greater cardiac vagal modulation. The cross-sectional nature of the available evidence, however, does not allow to clarify whether differences in sleep architecture were an effect (rather than a cause) of AF. Among the mechanisms of damaging effect, an increase in sympathetic tone and a decrease in parasympathetic tone have been identified as factors that are also associated with high levels of nocturnal BP and reduced nocturnal BP drop. Although these are still preliminary observations, the results of some studies which have suggested a link between fragmented sleep, regardless of total duration, and the risk of developing arterial hypertension are important in this context. Obstructive sleep apnoea (OSA), a disease affecting about 49% of men and 23% of women living in Europe, is by far the most studied category of sleep disorders in relation to cardiovascular disease. Large-scale studies suggested a dosedependent link between the number of OSAs and the risk of developing arterial hypertension, which also increases for mild forms (between 5 and 15 apnoea-hypopnoea events per hour). In this context, there are interesting data supporting a link between OSA, atherogenic dyslipidaemiaand the onset of metabolic syndrome. One of the main mechanisms that affect the high cardiovascular risk in OSA is the so-called "hypoxic load"-a combined index of the frequency and extent of the episodes of oxygen desaturation during sleep, able to act as a trigger of endothelial dysfunction and systemic inflammation. The potential causal link between OSA and cardiovascular events is supported by the results of prospective longitudinal studies. In the Sleep heart Study, in subjects under 70 years of age, OSA was an independent predictor of the 5-year incidence of coronary events (HR 1.10), ischaemic stroke (HR 1.58) and congestive heart failure (HR 2.38). The potential protective effect of treating OSA in terms of reducing cardiovascular risk is currently unclear. Several screening tools exist to aid in identification of OSA patients, with five being fairly easy to administer: Stop, STOP-BANG (SB), Epworth Sleepiness Scale (ESS), the Berlin Questionnaire (BQ), and the 4-Variable screening tool (4-V). The ESS is a simple and validated questionnaire for assessing subjective daytime sleepiness or sleep propensity in adults in the context of sleep disorders. The BQ consists of 3 categories (snoring and apnoea frequency, daytime symptoms, and BP) related to the risk of having OSA, with individuals being at high risk if there are 2 or more categories where the score is positive, and low risk if there is only 1 or no categories where the score is positive. The 4-V is an equation consisting of four variables including gender, BMI, BP, and self-reported snoring. SB has the highest sensitivity (97.6%), followed by the BQ (87%), while the 4-V ≥ 14 has the highest specificity (74.4%), followed by the ESS . Recently, a weighted ESS scoring system was developed to improve the accuracy of the AHI prediction, resulting in strong capability in predicting the patients without OSAS or with severe OSAS and improvement in screening the patients with simple snoring. However, external validity and generalizability of the weighted ESS need further investigations. Periodic limb movements in sleep (PLMS) are often found during nocturnal apnoea-hypopnoea episodes in subjects with OSA. These abnormalities may also occur isolated (primary PLMS) or within the context of other diseases, such as peripheral neuropathies, nephropathy or psychiatric disorders (secondary PLMS). Subjects with PLMS typically have shorter phases of N3 sleep and REM sleep. Although this is sufficient to hypothesize a relationship between PLMS, arterial hypertension and cardiovascular risk, current epidemiological observations, in contrast to the initial observations, do not seem to support a relationship between PLMS and cardiovascular risk factors independently from the effect of the confounding factors. However, in the analysis of the relationship between PLMS and cardiovascular risk, if the field of investigation is restricted to those with symptoms compatible with restless leg syndrome (RLS), characterised by the discomfort that appears in the legs during rest, it is possible to find evidence of a possible relationship between this condition and cardiovascular risk. In the Nurses' Health Study, in fact, subjects who reported symptoms compatible with RLS appeared to be at increased risk of developing myocardial infarction (OR 1.8) and death from ischaemic heart disease (OR 1.5) over time; this risk was even greater when considering subjects with duration of symptoms greater than at least 3 years. In contrast, many other subsequent studies did not confirm this initial evidence, indicating the heterogeneity of the definition and classification of RLS, the methodologies adopted for diagnosis, and the concomitant impact on cardiovascular risk of conditions associated with secondary RLS such as diabetic neuropathy as possible explanations, which often were not adequately considered in the analysis of the results. The category of qualitative sleep disorders includes the cardiovascular consequences related to shift working, a condition to which an ever-increasing number of workers are exposed. It is estimated that around 18% of workers in Europe carry out at least 25% of their work at night. Although some of the adverse effects on the cardiovascular system of shift workers are due to sleep deprivation, there are other potential mechanisms of harm that can be identified in the disturbance of the circadian rhythm of sleep and in the increased predisposition to unbalanced diets and unhealthy lifestyles. In a meta-analysis that attempted to quantify the adverse effects of shift working on the cardiovascular system, it was observed that this condition increases the risk of cardiovascular events, particularly coronary events, by 17%. Moreover, this risk would appear to increase cumulatively from the fifth year of shift working. The potential impact of prolonged rest periods following night-time shift working and of the type of shift (clockwise, anti-clockwise) on quality of life, as well as on the cardiovascular risk associated with shift working, represents a subject of great interest for study in the scientific landscape of today. In conclusion, the data available in the literature, summarised in, support the existence of a significant relationship between qualitative sleep disturbances and confirmed cardiovascular disease. ## Treatment for sleep disorders In order to properly set up the treatment of sleep disorders, especially when associated with arterial hypertension or other cardiovascular risk factors, a correct hypnological diagnosis should be made based on proper gathering of medical history information, on physical examination and often on the performing of polysomnographic In addition to the general collection of patient data and the pharmacological history, the medical history should also be aimed at identifying sleep habits (sleep and waking schedule, number of awakenings during the night, daytime sleeps, etc.), and the presence of specific symptoms for different sleep disorders (e.g. snoring, daytime sleepiness, morning headache, degree of feeling rested in the morning, involuntary movements in sleep, etc.). The physical examination is mainly useful for identifying the signs associated with OSA, in particular obesity, mainly central, macroglossia, the conformation of the uvula, tonsils and palate, skeletal abnormalities of the upper and lower jaw, possible nasal obstruction which, although not a cause of the respiratory disorder, may complicate treatment management, in particular with positive pressure devices. The cardiothoracic physical examination is essential for any signs of lung disease, baseline heart disease or skeletal spinal diseases such as kyphoscoliosis. For all non-respiratory sleep disorders, an in-depth neurological physical examination is also indicated. Diagnostic investigations are usually required when specific symptoms and signs suggest the presence of a sleep apnoea, epilepsy with seizures during sleep, narcolepsy, periodic limb movements in sleep, or other disorders for which diagnosis is based on the identification of characteristic polysomnographic findings. In other cases (such as psychophysiological insomnia, bad sleep habits, transient stress, disrupted sleep from work shifts), polysomnographic investigations are not always necessary. In some cases, a video recording may be associated with polysomnographic monitoring and in this case the examination is performed in the sleep lab. In the vast majority of cases, however, the tests carried out at home with portable polysomnographs are sufficient to establish a correct diagnosis particularly in the context of respiratory sleep disorders. The therapeutic setting for sleep disorders is therefore closely linked to the specific diagnosis performed by the sleep medicine specialist. In this context, we will discuss in detail the treatment of the two sleep disorders most closely related to cardiovascular diseases and arterial hypertension: insomnia and OSA, also discussing the impact of these treatments on BP levels. ## Treatment of osa The treatment of choice for sleep respiratory disorders, in particular for OSA, is based essentially on the severity of the disorder, the general characteristics of the patient and the possible presence of comorbidities . Certainly, in the face of the presence of overweight/obesity, the first step is to obtain weight loss, aiming to modify the lifestyle with an increase in daily physical activity, in addition to dietary changes. It is also useful to avoid excessive consumption of alcohol in the evening and sedative drugs that can aggravate the respiratory sleep disorder. The gold standard of treatment of OSA is still the use of continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP) devices through nasal or oronasal masks, depending on the shape of the patient's face. These ventilation support devices provide positive airway pressure which allows the patency of the airways to be maintained during sleep. In order to be able to identify the specific therapeutic pressure for each patient capable of correcting OSA and snoring, it is necessary to titrate the pressure of the air delivered by the device by means of nocturnal adaptation polygraph. In the case of positional sleep apnoea (i.e., occurring when the patient sleeps in supine decubitus) it may be useful to use supine position distractor devices, which essentially force the patient to adopt a lateral decubitus position during sleep. In recent years, mandibular advancement devices (MAD) have been developed, which are worn during sleep and serve to fix the lower jaw slightly forward of the upper jaw, so that it does not tend to obstruct the airways during sleep. There are also a number of surgical solutions for snoring and for apnoea, ranging from upper airway surgery to bariatric surgery in severely obese patients. The type of intervention in the upper airways must however be evaluated by specialists experienced in sleep medicine after fibroscopic and functional investigations, in order to establish the correct surgical indication. ## Treatment of insomnia First-line treatment for insomnia is cognitive-behavioural therapy, which should ideally be performed before hypnotics are prescribed. Good sleep hygiene is one component of cognitive-behavioural therapy that is important whatever the cause and is often the only treatment that patients with mild problems need. Cognitive-behavioural therapy for insomnia focuses on managing common thoughts, worries and behaviours that interfere with sleep . General guidelines for the use of hypnotics aim to minimise abuse, misuse and dependence. All hypnotics (except ramelteon, low doses of doxepin and suvorexant) act on the benzodiazepine recognition site on the γ-aminobutyric receptor (GABA) and increase the inhibitory effects of γ-aminobutyric acid. Melatonin, which in Italy is registered as a drug in its 2 mg prolongedrelease formulation and has a specific first-line indication. Hypnotics differ mainly in terms of elimination, half-life and principle of action. Some hypnotics (e.g., first-generation benzodiazepines) have greater chances of inducing residual sedation in the morning, especially after prolonged use and/or in the elderly, in which they may also increase the risk of falls, episodes of confusion and impaired cognitive performance. In recent decades, selective hypnoinducers, so-called Z-drugs (such as zolpidem and zopiclone) have been developed, which can theoretically be taken even in conjunction with an infra-hypnic awakening provided that patients have the chance to sleep for at least 4 h after administration. Hypnotics should be used with caution in patients with respiratory failure. In the elderly, any hypnotic, even at reduced doses, can cause restlessness, psychomotor agitation, or exacerbation of states such as delirium and dementia. Difficulties can be minimised by using the lowest effective dose for brief periods and gradually reducing the dose before stopping the drug. It should also be recalled that both European guidelines and an Italian consensus indicate 2 mg prolonged-release melatonin as the first therapeutic choice in insomniac subjects over the age of 55 years for up to 13 weeks. In addition to benzodiazepines and hypno-inducing drugs, there are also many other drugs not specifically indicated for insomnia that are used to induce and maintain sleep. Antihistamines such as doxorubicin and diphenhydramine can induce sleep. However, their efficacy is variable; moreover, these drugs can cause adverse effects such as confusion, urinary retention and possible systemic anticholinergic side effects, which are potentially serious in the elderly. Antidepressants taken at low doses at bedtime (e.g. 5-20 mg paroxetine, 50 mg trazodone, 75-200 mg trimipramine) may improve sleep. However, they should be used at low doses mainly when standard hypnotics are not tolerated (rare), or in high doses (antidepressants) when concomitant depression of mood is present. Melatonin is a hormone that is secreted by the pineal gland (and is found naturally in some foods such as oats, almonds and corn, for example). Darkness stimulates secretion, whereas light inhibits it. By binding melatonin receptors in the suprachiasmatic nucleus, melatonin regulates the circadian rhythm and especially the sleep-wake cycle. Exogenous melatonin supplementation may be indicated in various sleep disturbance conditions: jet lag, fragmented sleep or delayed sleep phase syndrome. Oral melatonin can be administered in different dosages and formulations depending on the condition we are treating (typically from 0.5 to 5 mg before bedtime). The key element is the time of administration, which must be regular and chosen on the basis of the sleep disorder we are dealing with. The choice of the product to be taken is therefore key, since most of the available melatonin products are "over-the-counter" supplements and sometimes the actual dosage of melatonin they contain is not well regulated. In Italy there is only one product registered as a prolonged-release melatonin-based drug at a dose of 2 mg. Treatment response can be evaluated with the readministration of questionnaires first collected at baseline for the assessment of insomnia severity (Insomnia Severity Index, ISIor sleep related beliefs and attitudes in insomnia (Dysfunctional Beliefs and Attitudes about Sleep short version, DBAS-16. ## The impact of the treatment of sleep disorders on blood pressure ## Obstructive sleep apnoea Several studies have shown that treatment of OSA may allow a significant, albeit modest, reduction in BP. In particular, among the treatments specific to OSA, those that have been studied with regard to their effect on BP are CPAP devices and MAD. Recent meta-analyses indicate a significant but small reduction in BP values in OSA patients treated with CPAP, with more evident effects on patients with resistant hypertension and on overnight BP values. This is interesting because the role of nocturnal BP in the development of cardiovascular diseases and its association with cardiovascular mortality and morbidity both in hypertensive patients and in the general population has been confirmed in several longitudinal and population studies. In addition to higher baseline BP values, excessive daytime sleepiness and, in particular, increased treatment compliance are also associated with increased positive effects of CPAP treatment on BP. Oral devices are indicated for the treatment of mild to moderate OSA and their effect on BP values is promising, similar to that obtained with CPAP according to some studies. Recently, a meta-analysisA subgroup analysis showed that patients with higher BP values prior to treatment, patients < 60 years of age, and patients with higher hypoxic load were more likely to exhibit a more pronounced hypotensive effect in response to CPAP treatment. In terms of medical therapy, the most promising class of antihypertensive drugs capable of reducing both the severity of OSA and BP values are diuretics, particularly mineralocorticoid receptor antagonists, whose beneficial effects in this context are believed to derive from the reduction of peripheral oedema and volume overload, and the consequent reduction in the volume shift towards neck and central circulation which occurs when taking the supine position. In addition, other classes of antihypertensive drugs that showed convincing results have been tested. Eskandari. Furthermore, in a French study, it was shown that, in patients with OSA, treatment with valsartan resulted in a greater reduction in BP than in CPAP alone, not only during the day but also at night. ## Other sleep disorders With regard to non-respiratory sleep disorders, a systematic review of the effects of prolonged sleep time on cardiometabolic risk factorsincluded only three small-scale studies in which BP was evaluated. None of these reported a significant positive effect. Conversely, a recent study that applied cognitive-behavioural therapy to prolong sleep in "short sleeper" adults and with prehypertension or stage one hypertension found significant reductions in BP with treatment. There is little data on the beneficial effect of the treatment of insomnia and RLS on BP and it is often controversial. Encouraging data on the possibility of reducing BP in sleep disorders are available for evening administration of prolonged-release melatonin 2 mg. In patients with moderate to severe RLS, rotigotine compared to placebo appears to significantly reduce the acute spikes in BP associated with PLMS. Finally, there are few studies on the BP effects of sleep disorder treatment in shift workers. A recent systematic Cochrane review of the pharmacological interventions for sleepiness and sleep disorders caused by shift work highlighted the need for further and better-quality studies on the effects and costs of all pharmacological agents that induce sleep or promote alertness in shift workers, both with and without a diagnosis of shift work sleep disorder. # Conclusions This document by the Italian Society of Hypertension on qualitative and/or quantitative sleep disorders aimed to define a shared approach to a condition with a significant negative impact on overall cardiometabolic risk and related fatal/non-fatal events. At present, in fact, several open questions exist concerning the diagnosis, management and therapy of hypertensive patients with sleep disorders. Although guidelines on arterial hypertension recommend investigating sleep quality/quantity as well as the presence of OSA, and specifically treating the latter in the hypertensive patient, several relevant aspects remain undetermined. These include the severity of respiratory disorder and BP threshold for indications for specific therapies; the most appropriate BP measurement tools in this context; the predictive factors of BP response, including the effects of antihypertensive drugs and lifestyle/weight interventions; and the management of insomnia in patients with obstructive apnoea. In addition to the evidence supporting the benefit of CPAP in terms of BP reduction in hypertensive patients with OSA, there is no data supporting that this measure reduces the risk of major fatal/nonfatal events, independent of apnoea severity, duration of follow-up, or treatment adherence. At the same time, however, a certain degree of reversibility in the cardiovascular risk profile following treatment appears to be achievable. It is likely that the magnitude of this benefit might depend on concomitant nonmodifiable factors, such as age or pre-existing irreversible organ damage, which would therefore affect the indications for specific treatments. Consideration is also needed as to whether BP increases-both in terms of mean BP values and BP variability-that may potentially be observed during the use of CPAP depend on technical factors-such as air leaks from the mask or excessive positive pressure. These changes can be responsible for night-time awakening or represent a source of considerable discomfort for the patient, leading to discontinuation of treatment. Therefore, the appropriate management of patients with OSA and hypertension should be multifactorial, including: optimisation of type, number and doses of antihypertensive drugs; improvement of adherence to pharmacological and non-pharmacological treatments; implementation of lifestyle changes based on the overall cardiovascular risk; and identification and appropriate treatment of insomnia. Care to start treatment as early as possible in the clinical history of OSA, before structural cardiovascular changes might occur, also needs to be implemented. Further research is needed to better clarify the relationship between hypertension and sleep disorders, in the light of the many possible confounding elements. Similarly, dedicated studies that objectively assess the duration, quality, timing and regularity of sleep in relation to incident hypertension, identify the underlying genetic and molecular events, and define the role of more or less complex interventions (surgical procedures, use of intraoral devices, or selective nerve stimulation) in populations with different disease severity or baseline cardiovascular risk may clarify the significance of the observed associations. Pending these developments, it is mandatory to reduce the "time to diagnosis" of sleep disorders and relevant comorbidities in the hypertensive patient, especially if resistant to therapy and/ or at high cardiovascular risk, and to improve the available therapeutic strategies and adherence to them. In this context, it is worth it to investigate more thoroughly whether restoring the melatoninergic system through prolonged-release melatonin at suitable dosesmay represent, along with lifestyle changes, a widely applicable option. To date, the triad "lifestyle changes + medications + possible device" stands as the only evidence-based approach.	None	https://link.springer.com/content/pdf/10.1007/s40292-021-00436-y.pdf	None
c023a9d4002a85f7d20a6f86c0ba024896862b0f	pubmed	SHEA/APIC Guideline: Infection prevention and control in the long-term care facility	SHEA/APIC Guideline: Infection prevention and control in the long-term care facility ## Background demography and definitions The US population aged 65 to 85 years is increasing rapidly, and the population aged 85 years and older is expected to double by 2030. One of every 4 persons who reach the age of 65 can be expected to spend part of his or her life in a nursing home; more people occupy nursing home beds than acute care hospital beds in the US. Approximately 1.5 million persons in the US reside in a nursing home; there are 15,000 nursing homes in this country. Ninety percent of nursing home residents are over 65 years of age, and the mean age of residents is over 80 years. A LTCF is a residential institution for providing nursing care and related services to residents. It may be attached to a hospital (swing-bed) or free standing; the latter is often called a nursing home. A resident is a person living in the LTCF and receiving care, analogous to the patient in a hospital. ## Scope of position paper This position paper addresses all levels of care in the LTCF. The focus is specifically the LTCF, also known as the nursing home, caring for elderly or chronically ill residents. These recommendations generally also should apply to special extended care situations (such as institutions for the mentally retarded, psychiatric hospitals, pediatric LTCFs, and rehabilitation hospitals). However, other extended care facilities may have different populations (eg, the residents of institutions for the mentally retarded are much younger than nursing home residents), different disease risks (eg, hepatitis B in psychiatric hospitals), or different levels of acuity and technology (eg, higher acuity in long-term acute care facilities or LTACs). Thus, the recommendations may need to be adapted for these special extended care situations. Changes from prior Guideline. This position paper is similar to the 1997 Society for Healthcare Epidemiology of America (SHEA)/Association for Professionals in Infection Control and Epidemiology (APIC) guideline, although the present version reflects an updating of research and experience in the field. Several important areas of discussion are new or changed. ## Infections in the long-term care facility epidemiology In US LTCFs, 1.6 million to 3.8 million infections occur each year. In addition to infections that are largely endemic, such as urinary tract infections (UTIs) and lower respiratory tract infections (LRTIs), outbreaks of respiratory and gastrointestinal (GI) infections are also common.The overall infection rate in LTCFs for endemic infections ranges from 1.8 to 13.5 infections per 1000 resident-care days. For epidemics, good estimates are difficult to ascertain, but the literature suggests that several thousand outbreaks may occur in US LTCFs each year. The wide ranges of infections and resulting mortality and costs illustrate the challenge in understanding the epidemiology of infections and their impact in LTCFs. There are currently little data and no national surveillance systems for LTCF infections; the estimates have been calculated based on research studies and outbreak reports from the medical literature. As a part of aging, the elderly have diminished immune response including both phenotypic and functional changes in Tcells.However, these changes are of limited clinical significance in healthy elderly. Consequently, immune dysfunction in elderly residents of LTCFs is primarily driven by the multiple factors that result in secondary immune dysfunction such as malnutrition, presence of multiple chronic diseases, and polypharmacy, especially with medications that diminish host defenses (eg, immunosuppressants).In addition, LTCF residents often have cognitive deficits that may complicate resident compliance with basic sanitary practices (such as handwashing and personal hygiene) or functional impairments such as fecal and urinary incontinence, immobility, and diminished cough reflex. The elderly nursing home resident is known to have a blunted febrile response to infections.This parallels other agerelated immunologic abnormalities. A notable fever in this population often signals a treatable infection, such as UTI or aspiration pneumonia. While the use of urinary catheters in LTCF residents has decreased in recent years, utilization remains around 5%. In LTC residents, the use of invasive devices (eg, central venous catheters, mechanical ventilators, enteral feeding tubes) increases the likelihood of a device-associated infection. Of the over 15,000 LTCFs in the US in 2004, 42% provided infusion therapy, 22% had residents with peripherally-inserted central lines, and 46% provided parenteral nutrition. 14 Another challenge for preventing infections in LTCFs is the increasing acuity of residents, especially with the rapidly growing subpopulation of postacute residents. Postacute residents are hospitalized patients who are discharged to LTCFs to receive skilled nursing care or physical/occupational therapy. In the past, these patients, often frail, would have remained hospitalized, but, with increasing efforts to control hospital costs, these patients are now discharged to LTCFs. In addition to higher device utilization, these residents are more likely to receive antimicrobial therapy than long-stay LTCF residents.Much remains to be learned about resident and LTCF factors correlated with HAIs. There is evidence that institutional factors such as nurse turnover, staffing levels, prevalence of Medicare recipients, rates of hospital transfer for infection, intensity of medical services, and family visitation rates are associated with incidence of HAI in the LTC setting.The rate of deaths in LTCF residents with infections ranges from 0.04 to 0.71 per 1000 resident-days, with pneumonia being the leading cause of death. Infections are a leading reason for hospital transfer to LTCF residents, and the resulting hospital costs range from $673 million to $2 billion each year. LTCFs and acute care facilities differ in another key aspect: LTCFs are residential. As residences, LTCFs are required to provide socialization of residents through group activities. While these activities are important for promoting good physical and mental health, they may also increase communicable infectious disease exposure and transmission. Occupational and physical therapy activities, while vital toward restoring or maintaining physical and mental function, may increase risk for person-to-person transmission or exposure to contaminated environmental surfaces (eg, physical or occupational therapy equipment). ## Specific nosocomial infections in the long-term care facility ## Urinary tract infections In most surveys, the leading infection in LTCFs is UTI,although with restrictive clinical definitions, symptomatic urinary infection is less frequent than respiratory infection.Bacteriuria is very common in residents of these facilities but, by itself, is not associated with adverse outcomes and does not affect survival.Bacteriuria and UTI are associated with increased functional impairment, particularly incontinence of urine or feces.The symptoms of UTI are dysuria and frequency (cystitis) or fever and flank pain (pyelonephritis). The elderly may present with atypical or nonlocalizing symptoms. Chronic genitourinary symptoms are also common but are not attributable to bacteriuria.Because the prevalence of bacteriuria is high, a positive urine culture, with or without pyuria, is not sufficient to diagnose urinary infection.Clinical findings for diagnosis of UTI in the noncatheterized resident must include some localization to the genitourinary tract.The diagnosis also requires a positive quantitative urine culture. This is obtained by the clean-catch voided technique, by in and out catheterization, or by aspiration through a catheter system sampling port. A negative test for pyuria or a negative urine culture obtained prior to initiation of antimicrobial therapy excludes urinary infection. The prevalence of indwelling urethral catheters in the LTCF is 7% to 10%.Catheterization predisposes to clinical UTI, and the catheterized urinary tract is the most common source of bacteremia in LTCFs.Residents with long-term catheters often present with fever alone. Residents with indwelling urinary catheters in the LTCF are uniformly colonized with bacteria, largely attributable to biofilm on the catheter.These organisms are often more resistant to oral antibiotics than bacteria isolated from elderly persons in the community.Catheter-related bacteriuria is dynamic, and antimicrobial treatment only leads to increased antimicrobial resistance.Thus, it is inappropriate to screen asymptomatic catheterized residents for bacteriuria or to treat asymptomatic bacteriuria.Specimens collected through the catheter present for more than a few days reflect biofilm microbiology. For residents with chronic indwelling catheters and symptomatic infection, changing the catheter immediately prior to instituting antimicrobial therapy allows collection of a bladder specimen, which is a more accurate reflection of infecting organisms.Catheter replacement immediately prior to therapy is also associated with more rapid defervescence and lower risk of early symptomatic relapse posttherapy.Guidelines for prevention of catheter-associated UTIs in hospitalized patients 32 are generally applicable to catheterized residents in LTCFs. Recommended measures include limiting use of catheters, insertion of catheters aseptically by trained personnel, use of as small diameter a catheter as possible, handwashing before and after catheter manipulation, maintenance of a closed catheter system, avoiding irrigation unless the catheter is obstructed, keeping the collecting bag below the bladder, and maintaining good hydration in residents. Urinary catheters coated with antimicrobial materials have the potential to decrease UTIs but have not been studied in the LTCF setting. For some residents with impaired voiding, intermittent catheterization is an option, and clean technique is as safe as sterile technique.External catheters are also a risk factor for UTIs in male residents 34 but are significantly more comfortable and associated with fewer adverse effects, including symptomatic urinary infection, than an indwelling catheter.Local external care is required. The CDC guideline 32 briefly discusses care of condom catheters and suprapubic catheters, but no guideline for leg bags is available. Leg bags allow for improved ambulation of residents but probably increase the risk of UTI because opening of the system and reflux of urine from the bag to the bladder occur more frequently than with a standard closed system. Suggestions for care of leg bags include using aseptic technique when disconnecting and reconnecting, disinfecting connections with alcohol, changing bags at regular intervals, rinsing with diluted vinegar, and drying between uses. 36 A 1:3 dilution of white vinegar has been recommended for leg bag disinfection. 37 ## Respiratory tract infections Because of the impaired immunity of elderly persons, viral upper respiratory infections (URIs) that generally are mild in other populations may cause significant disease in the institutionalized elderly patient.Examples include influenza, respiratory syncytial virus (RSV), parainfluenza, coronavirus, rhinoviruses, adenoviruses, and recently discovered human metapneumovirus.Pneumonia. Pneumonia or lower respiratory tract infection (LRTI) is the second most common cause of infection among nursing home residents, with an incidence ranging from 0.3 to 2.5 episodes per 1000 resident care-days and is the leading cause of death from infections in this setting. Elderly LTCF residents are predisposed to pneumonia by virtue of decreased clearance of bacteria from the airways and altered throat flora, poor functional status, presence of feeding tubes, swallowing difficulties, and aspiration as well as inadequate oral care.Underlying diseases, such as chronic obstructive pulmonary disease and heart disease, further increase the risk of pneumonia in this population.The clinical presentation of pneumonia in the elderly often is atypical. While there is a paucity of typical respiratory symptoms, recent studies have shown that fever is present in 70%, new or increased cough in 61%, altered mental status in 38%, and increased respiratory rate above 30 per minute in 23% of residents with pneumonia.While acquiring a diagnostic sputum can be difficult, obtaining a chest radiograph is now more feasible than in the past. In general it is recommended that a pulse oximetry, chest radiograph, complete blood count with differential, and blood urea nitrogen should be obtained in residents with suspected pneumonia.Streptococcus pneumoniae appears to be the most common etiologic agent accounting for about 13% of all cases, 47,48 followed by Hemophilus influenzae (6.5%), Staphylococcus aureus (6.5%), Moraxella catarrhalis (4.5%), and aerobic gram-negative bacteria (13%).Legionella pneumoniae also is a concern in the LTCF. Colonization with methicillin-resistant S aureus (MRSA) and antibiotic-resistant, gram-negative bacteria further complicate diagnosis and management of pneumonia in LTCF residents.The mortality rate for LTCF-acquired pneumonia is significantly higher than for community-acquired pneumonia in the elderly population.Preinfection functional status, dementia, increased rate of respirations and pulse, and a change in mental status are considered to be poor prognostic factors. Several indices predictive of mortality have been developed and may be useful in managing residents with pneumonia.The CDC guideline for prevention of pneumonia 54 is oriented toward acute care hospitals but covers a number of points relevant to the LTCF, including respiratory therapy equipment, suctioning techniques, tracheostomy care, prevention of aspiration with enteral feedings, and immunizations. Examples of relevant recommendations for the LTCF include hand hygiene after contact with respiratory secretions, wearing gloves for suctioning, elevating the head of the bed 30 to 45 degrees during tube feeding and for at least 1 hour after to decrease aspiration, and vaccination of high-risk residents with pneumococcal vaccine.The evidence for the efficacy of pneumococcal vaccine in high-risk populations, including the elderly population, is debated.However, the vaccine is safe, relatively inexpensive, and recommended for routine use in individuals over the age of 65 years.Pneumococcal vaccination rates for a facility are now publicly reported at the Centers for Medicare and Medicaid Services (CMS).Influenza. Influenza is an acute respiratory disease signaled by the abrupt onset of fever, chills, myalgias, and headache along with sore throat and cough, although elderly LTCF residents may not have this typical presentation. The incubation period for influenza is approximately 1 to 2 days.It is a major threat to LTCF residents, who are among the high-risk groups deserving preventive measures.Influenza is very contagious, and outbreaks in LTCFs are common and often severe. Clinical attack rates range from 25% to 70%, and case fatality rates average over 10%.A killed virus vaccine is available but must be given annually. Influenza vaccine in the elderly is approximately 40% effective at preventing hospitalization for pneumonia and approximately 50% effective at preventing hospital deaths from pneumonia.Although concern has been expressed regarding the efficacy of the influenza vaccine in institutionalized elderly patients, most authors feel that the influenza vaccine is effective and indicated for all residents and caregivers.Recent surveys have shown an increased rate of influenza vaccination among LTCF residents, although significant variability exists.Influenza vaccination rates for a facility are now publicly reported at the Centers for Medicare and Medicaid (CMS) Web site http://www.medicare.gov/NHCompare/ home.asp. Staff immunization rates remain less impressive, with average immunization rates between 40% and 50% at best. While viral cultures from nasopharynx remain the gold standard for diagnosis of influenza, several rapid diagnostic methods (rapid antigen tests) such as immunofluorescence or enzyme immunoassay have been developed. These tests detect both influenza A and B viral antigens from respiratory secretions. Amantadine-resistant influenza has caused LTCF outbreaks and hence amantadine is not recommended for influenza prophylaxis.Zanamivir and oseltamivir are effective against both influenza A and B and have been approved for prophylaxis and treatment of influenza A and B. Oseltamivir is administered orally and is excreted in the urine requiring dose adjustments for renal impairment. Zanamivir is given by oral inhalation, which is a problem in a noncooperative LTCF resident. Rapid identification of cases in order to promptly initiate treatment and isolate them to prevent transmission remains the key to controlling influenza outbreaks. Other measures recommended during an outbreak of influenza include restricting admissions or visitors and cohorting of residents with influenza.Infected staff should not work. Tuberculosis. Tuberculosis (TB) also has caused extensive outbreaks in LTCFs, generally traced to a single ambulatory resident. Large numbers of staff and residents may be involved, with a potential to spread in the community.Price and Rutala 77 found 8.1% of new employees and 6.4% of new residents to be positive by the purified protein derivative (PPD) of tuberculin method in their North Carolina survey, with significant 5-year skin test conversion rates in both groups. The diagnosis of TB in the LTCF is problematic. Clinical signs (fever, cough, weight loss) are nonspecific. Chest radiographs, when obtained, often show characteristic pulmonary infiltrates (eg, cavities in the upper lung fields). Infection with TB usually causes a positive tuberculin skin test (TST), although occasional false positives and false negatives are seen. The specificity of the TST may be improved by an in vitro blood test of interferon release in response to TB peptides, such as the quantiferon test. The most specific diagnostic test is a sputum culture for TB, but a good specimen may be difficult to obtain. Recent advances in microbiology have facilitated the diagnosis of TB greatly. Diagnostics such as radiometric systems, polymerase chain reaction (PCR), as well as specific DNA probes help shorten the time for diagnosis of TB, although susceptibility testing requires several weeks. Guidelines discussing standards for control of TB in institutions are available.There appears to be a consensus that TST of residents and personnel in the LTCF should be undertaken on a regular basis, although many LTCFs have inadequate TB screening programs.The cost-effectiveness of using a 2-step TST to survey for the booster effect is not demonstrable for all populations, but the 2-step skin test is recommended by the CDC for initial screening of employees and residents. For LTCF residents without any known contact with a case of known TB or other significant risk factors such as human immunodeficiency virus (HIV) or immunosuppression, induration of 10 mm or greater to PPD injection is considered positive. Induration of 5 mm or greater is considered positive in any individual with recent contact with a known case of TB or other significant risk factors such as immunosuppression or changes on chest x-ray consistent with old TB.There was a resurgence of TB in the US in the mid-1980s; multidrug-resistant cases of TB have been seen, and nosocomial spread within health care facilities is a concern. 84 In response to this, guidelines have been promulgated by the CDC that address surveillance (identification and reporting of all TB cases in the facility including residents and staff); containment (recommended treatment under directly observed therapy and appropriate respiratory isolation and ventilation control measures); assessment (monitoring of surveillance and containment activities); and ongoing education of residents, families, and staff.Since most LTCFs do not have a negative-pressure room, residents with suspected active TB should be transferred to an appropriate acute care facility for evaluation. There should be a referral agreement with that facility. ## Skin and soft-tissue infections, infestations Pressure ulcers (also termed decubitus ulcers) occur in up to 20% of residents in LTCFs and are associated with increased mortality.Infected pressure ulcers often are deep soft-tissue infections and may have underlying osteomyelitis; secondary bacteremic infections have a 50% mortality rate.They require costly and aggressive medical and surgical therapy. Once infected, pressure ulcer management requires a multidisciplinary approach with involvement of nursing, geriatrics and infectious disease specialists, surgery, and physical rehabilitation. Medical factors predisposing to pressure ulcers have been delineatedand include immobility, pressure, friction, shear, moisture, incontinence, steroids, malnutrition, and infection. Reduced nursing time can also increase the risk of developing pressure ulcers. Several of these factors may be partially preventable (such as malnutrition and fecal incontinence). Prevention of pressure ulcers involves developing a plan for turning, positioning, eliminating focal pressure, reducing shearing forces, and keeping skin dry. Attention to nutrition, using disposable briefs and identifying residents at a high risk using prediction tools can also prevent new pressure ulcers. The goals are to treat infection, promote wound healing, and prevent future ulcers. Many physical and chemical products are available for the purpose of skin protection, debridement, and packing, although controlled studies are lacking in the area of pressure ulcer prevention and healing.A variety of products may be used to relieve or distribute pressure (such as special mattresses, kinetic beds, or foam protectors) or to protect the skin (such as films for minimally draining stage II ulcers, hydrocolloids and foams for moderately draining wounds, alginates for heavily draining wounds). Negative-pressure wound therapy (vacuum dressings) using gentle suction to provide optimal moist environment is increasingly being used in treatment of complex pressure ulcers.Nursing measures such as regular turning are essential as well. A pressure ulcer flow sheet is a useful tool in detecting and monitoring pressure ulcers and in recording information such as ulcer location, depth, size, stage, and signs of inflammation as well as in timing of care measures. Infection control measures include diligent hand hygiene and glove usage. Because all pressure ulcers, like the skin, are colonized with bacteria, antibiotic therapy is not appropriate for a positive surface swab culture without signs and symptoms of infection. Nonintact skin is more likely to be colonized with pathogens. True infection of a pressure ulcer (cellulitis, osteomyelitis, sepsis) is a serious condition, generally requiring broadspectrum parenteral antibiotics and surgical debridement in an acute care facility. Cellulitis (infection of the skin and soft tissues) can occur either at the site of a previous skin break (pressure ulcer) or spontaneously. Skin infections generally are caused by group A streptococci or S aureus. Outbreaks of group A streptococcal infections have been described, presenting as cellulitis, pharyngitis, pneumonia, or septicemia.Scabies is a contagious skin infection caused by a mite. Lesions usually are very pruritic, burrow-like, and associated with erythema and excoriations, usually in interdigital spaces of the fingers, palms and wrists, axilla, waist, buttocks, and the perineal area. However, these typical findings may be absent in debilitated residents, leading to large, prolonged outbreaks in LTCFs.Diagnosis in an individual with a rash requires a high index of suspicion in order to recognize the need for diagnostic skin scrapings. The presence of a proven case should prompt a thorough search for secondary cases. A single treatment with permethrin or lindane usually is effective, but repeated treatment or treatment of all LTCF residents, personnel, and families occasionally is necessary.Ivermectin, an oral antihelminthic agent, is an effective, safe, and inexpensive option for treatment of scabies. However, it has not been approved by the FDA for this indication. Therapy of rashes without confirming the diagnosis of scabies unnecessarily exposes residents to the toxic effects of the topical agents. Because scabies can be transmitted by linen and clothing, the environment should be cleaned thoroughly. This includes cleaning inanimate surfaces, hot-cycle washing of washable items (clothing, sheets, towels, etc), and vacuuming the carpet. ## Other infections Viral gastroenteritis (caused by rotavirus, enteroviruses, or noroviruses), 99,100 bacterial gastroenteritis (caused by Clostridium difficile, Bacillus cereus, Escherichia coli, Camplylobacter spp, C perfringens, or Salmonella spp), and parasites (such as Giardia lambia) are well-known causes of diarrhea outbreaks in LTCFs.The elderly are at increased risk of infectious gastroenteritis due to age-related decrease in gastric acid. In a population with a high prevalence of incontinence, the risk of cross infection is substantial. Person-to-person spread, particularly due to shared bathroom, dining, and rehabilitation facilities, plays a role in viral gastroenteritis and in Shigella spp and C difficile diarrhea.Foodborne disease outbreaks also are very common in this setting, 108 most often caused by Salmonella spp or S aureus. E coli O157:H7 and Giardia also may cause foodborne outbreaks, underscoring the importance of proper food preparation and storage. Bacteremiain the LTCF, although rarely detected, may be primary or secondary to an infection at another site (pneumonia, UTI). The most common source of secondary bacteremia is the urinary tract, with E coli being the culprit in over 50% of cases.As the acuity of illness in LTCF residents has risen, the prevalence of IV devices and related bacteremic complications appears to have increased. The CDC guideline for prevention of IV infections is a useful resource and generally applicable to the LTCF.Relevant points include aseptic insertion of the IV cannula, daily inspection of the IV for complications such as phlebitis, and quality control of IV fluids and administration sets. Conjunctivitis in the adult presents as ocular pain, redness, and discharge. In the LTCF, cases may be sporadic or outbreak-associated.Many cases are nonspecific or of viral origin; S aureus appears to be the most frequent bacterial isolate.Epidemic conjunctivitis may spread rapidly through the LTCF. Transmission may occur by contaminated eye drops or hand cross contamination. Gloves should be worn for contact with eyes or ocular secretions, with hand hygiene performed immediately after removing gloves. Many additional infections have been encountered in the LTCF, including herpes zoster, herpes simplex, endocarditis, viral hepatitis, septic arthritis, and abdominal infections. There has been a resurgence of ''pediatric'' infections in the LTCF (eg, pertussis, RSV, and H influenzae respiratory tract infections), reflecting the decline of the host's immunologic memory with aging. ## Epidemic infections in the ltcf Most LTCF HAIs are sporadic. Many are caused by colonizing organisms with relatively low virulence. Tissue invasion may be facilitated by the presence of a urinary catheter or chronic wound or following an aspiration event. Ongoing surveillance (see Surveillance section below) is required to detect epidemic clustering of transmissible, virulent infections. Outbreaks must be anticipated. Ideally, infection control surveillance and practices should be the responsibility of frontline staff as well as infection control staff. An outbreak or transmission within the facility may occur explosively with many clinical cases appearing within a few days or may, for example, involve an unusual clustering of MRSA clinical isolates on a single nursing unit over several months. On the other hand, a case of MRSA infection may follow a prolonged period of asymptomatic nasal colonization after an aspiration event or development of a necrotic wound.Outbreaks in LTCFs accounted for a substantial proportion (15%) of reported epidemics. Clustering of URIs, diarrhea, skin and soft tissue infection, conjunctivitis, and antibiotic-resistant bacteriuria have been noted.Major outbreaks of infection have also been ascribed to E coli, 117 group A streptococci, 92,118 C difficile 104,119 respiratory viruses,Salmonella spp,Chlamydia pneumoniae,Legionella spp,and gastrointestinal viruses.Nursing homes accounted for 2% of all foodborne disease outbreaks reported to the CDC and 19% of outbreak-associated deaths.Transmissible gastrointestinal pathogens may be introduced to the facility by contaminated food or water or infected individuals. High rates of fecal incontinence, as well as gastric hypochlorhydria, make the nursing home ideal for secondary fecal-oral transmission.Other epidemics include scabies, hepatitis B, 127 group A streptococcal infections, viral conjunctivitis, and many other infections. These outbreaks underscore the vulnerability of the elderly to infection, as well as the role of cross infection in residents with urinary catheters and open wounds or in those with incontinence who require serial contact care by staff.In addition, mobile residents with poor hygiene may interact directly. ## Antibiotic-resistant bacteria Multidrug resistant organisms (MDROs) such as MRSA, vancomycin-resistant enterococci (VRE), drugresistant S pneumoniae, and multidrug-resistant gramnegative bacteria (eg, Pseudomonas aeruginosa, Acinetobacter spp and extended-spectrum b-lactamase (ESBL)-producing enterobacteriaceae) are increasingly important causes of colonization and infection in LTCFs.In this setting, infection with MDROs has been associated with increased morbidity, mortality, and cost,although the attributable morbidity, mortality, and cost of MDROs has not yet been fully defined. Indeed, LTCF residence has been frequently identified as a risk factor for antibiotic-resistant infection in hospitalized patients.Elderly and disabled residents are at increased risk for colonization with resistant organisms, and colonization may persist for long periods of time (ie, months to years).Within the LTCF, length of stay in the facility and accommodation in rooms with multiple beds have been identified as risk factors for transmission of MRSA.Both infected and colonized residents may serve as sources for the spread of MDROs in the LTCF.When MRSA becomes endemic within a facility, elimination is highly unlikely.LTCFs can expect infections with MDROs to be a continuing problem. Strategies for curbing the emergence and spread of antimicrobial resistance in LTCFs are discussed below in ''Antibiotic Stewardship'' and ''Isolation and Precautions'' sections. ## The infection control program ## Evolution of programs The 1980s saw a dramatic increase in LTCF infection control activities, stimulated by federal and state regulations. Several studies provide insight into the extent of program development. A 1981 survey of Utah LTCFs 113 noted that all facilities had regular infection control meetings, but none performed systematic surveillance for infections or conducted regular infection control training. All LTCFs had policies regarding the maintenance and care of urinary catheters, although the policies were not uniform. Price et al 149 surveyed 12 North Carolina LTCFs in 1985 and found that, although all 12 had a designated ICP, none of the ICPs had received special training in this area. Also noted were deficiencies in isolation facilities, particularly an insufficient number of sinks and recirculated, inadequately filtered air. In a 1985 survey of Minnesota LTCFs, Crossley et al 150 found that the majority had an infection control committee (ICC) and a designated ICP, although substantial deficiencies in resident and employee health programs occurred. For instance, only 61% offered the influenza vaccine to residents, and one third did not screen new employees for a history of infectious disease problems. A 1988 Maryland surveyfound that one third of nursing homes still performed routine environmental cultures, and many lacked proper isolation policies. In 1990, a survey of Connecticut LTCFs found that most ICPs had received some training in infection control.Most LTCFs performed surveillance at least weekly, and most used written criteria to determine HAIs. More recent regional surveys of facilities from Maryland and New England in the mid-1990s and Michigan in 2005 noted increasing gains in time spent in infection control activities from 1994 to 2005.In New England, 98% of facilities had a person designated to do infection control, 90% were registered nurses, and 52% had formal training.In the 1990s, an average of 9 to 12 hours per week was spent on infection control; 50% to 54% of that time was spent on surveillance activities.Seventy-eight to 97% percent of the LTCFs reported a systematic surveillance system.Formal definitions were used by 95% of respondents; 81% used the McGeer criteria, and 59% calculated infection rates.All facilities reportedly used Universal Precautions in caring for their residents.By 2005, 50% of responding facilities in Michigan had a full-time ICP.The mean time spent on infectionHowever, part-time ICPs did not necessarily supervise smaller facilities with fewer subacute care beds or give fewer in-services than full-time staff. Despite these improvements, the number of ICPs per nursing home bed is 4-fold fewer than the number of ICPs available in acute care hospitals.LTCF-based ICPs are more likely to assume noninfection control functions than acute care ICPs regardless of bed size; in one survey, 98% of LTCF ICPs had other duties,while in a Michigan survey, 50% of 34 LTCFs had fulltime ICPs.Many of these noninfection control functions include employee health, staff education and development, and quality improvement.In addition, LTCF ICPs are still less likely to receive additional formal training in infection control (8%) compared with 95% of acute care ICPs.The results of this study from Maryland led to a state proposal that at least one ICP from each LTCF be formally trained in infection control.From these surveys, one can develop a composite picture of the LTCF ICP as a nurse who still has not necessarily received formal training in infection control.Many ICPs still work part-time on infection control activities regardless of the number of beds or patient acuity.While the time spent on infection control activities appears to have increased significantly from 36 to 48 hours per month in the 1990s to 90 to 160 hours per month in 2005, the ICP continues to have other duties such as general duty nursing, nursing supervision, in-service education, employee health, and quality assurance.Regulatory aspects LTCFs are covered by federal and state regulations as well as voluntary agency standards such as those written by The Joint Commission (TJC).Skilled nursing facilities are required by the Omnibus Budget Reconciliation Act of 1987 (OBRA) to have an infection control program.CMS has published requirements for LTCFs 159 that apply to LTCFs accepting Medicare and/ or Medicaid residents. CMS regulations address the need for a comprehensive infection control program that includes surveillance of infections; implementation of methods for preventing the spread of infections including use of appropriate isolation measures, employee health protocols, hand hygiene practices; and appropriate handling, processing, and storage of linens.For example, the LTCF is required to establish and maintain an infection control program designed to provide a safe, sanitary, and comfortable environment and to help prevent the development and transmission of disease and infection. Interpretive guidelines for surveyors further discuss definitions of infection, risk assessment, outbreak management and control, measures for preventing specific infections, staff orientation, antibiotic monitoring, sanitation, and assessment of compliance with infection control policies.Because the LTCF is an employer of health care workers (HCWs), it must comply with federal and/or state OSHA regulations. For infection control, those regulations 162,163 deal primarily with protection of workers from exposure to bloodborne pathogens such as HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) and from TB exposure.Adherence of LTCFs to infection control regulations is an OSHA priority. Other standards that apply to LTCFs include the federal minimum requirements for design, construction, and equipmentand TJC LTC Standards.The 2007 TJC Standards for LTC require a written infection control plan based on an assessment of risk; establishment of priorities, goals, and strategies; and an evaluation of the effectiveness of the interventions. The Standards also deal with managing an influx of patients with an infectious disease as well as leadership's involvement in the program.In addition, many states have statutory requirements for LTCFs that vary widely. On October 7, 2005, CMS published a final rule requiring LTCFs to offer annually to each resident immunization against influenza and to offer lifetime immunization against pneumococcal disease. LTCFs are required to ensure that each resident or legal representative receive education on the benefits and potential side effects of the immunizations prior to their being administered.The LTCF administrative staff should be knowledgeable about the federal, state, and local regulations governing infection control in order to implement and maintain a program in compliance with these regulations. The LTCF ICP ideally should be involved in the formation and revision of regulations, through local and national infection control and long-term care organizations, to help assure the scientific validity of the regulations. Experts in infection control in Canada have called for 1 full-time formally trained ICP per 150 to 250 long-term beds.The Consensus Panel from SHEA and APIC has recommended that nonhospital facilities including LTCFs provide adequate resources in terms of personnel, education, and materials to ICPs to fulfill their functions.While most of the current information has been derived from facilities serving older populations in North America, reports from LTCFs in Europe and Australia and those serving pediatric populations are increasing.Infection control program elements The structure and components of an infection control program are shown in, respectively. Several authors have discussed the components of an infection control program in the LTCF.These components generally are drawn from regulatory requirements, current nursing home practices, and extrapolations from hospital programs. The limited resources of most LTCFs affect the type and extent of programs developed.Most authors feel that an infection control program should include some form of surveillance for infections, an epidemic control program, education of employees in infection control methods, policy and procedure formation and review, an employee health program, a resident health program, and monitoring of resident care practices. The program also may be involved in quality improvement, patient safety, environmental review, antibiotic monitoring, product review and evaluation, litigation prevention, resident safety, preparedness planning, and reporting of diseases to public health authorities. ## The icp An ICP is an essential component of an effective infection control program and is the person designated by the facility to be responsible for infection control (see, The ICP usually is a staff nurse, a background that is helpful for resident assessment and chart review. The ICP most commonly is a registered nurse. Because of size and staffing limitations, the vast majority of LTCF ICPs have other duties, such as assistant director of nursing, charge nurse, in-service coordinator, employee health, or performance improvement. The number of LTCF beds justifying a full-time ICP is unknown and usually depends on the acuity level of residents and the level of care provided. A LTCF with more than 250 to 300 beds may need a fulltime ICP. The LTCF ICP, like the hospital ICP, requires specific training in infection control; well-defined support from administration; and the ability to interact tactfully with personnel, physicians, and residents. APIC and the Community and Hospital Infection Control Association-Canada (CHICA-Canada) have developed professional and practice standards for infection control and epidemiology that address education including qualifications and professional development for the ICP.These standards may not represent the current education and qualifications of ICPs in many LTCFs, but they serve as a benchmark for which LTC ICPs and their facilities can strive. The qualifications include 3 criteria for entering the profession. The ICP: d Has knowledge and experience in areas of resident care practices, microbiology, asepsis, disinfection/ sterilization, adult education, infectious diseases, communication, program administration, and epidemiology; d has a baccalaureate degree (the minimum educational preparation for the role); and d attends a basic infection control training course within the first year of entering the profession. The criteria for professional development include the ICP maintaining current knowledge and skills in the area of infection prevention, control, and epidemiology. The professional development standards include 5 criteria. The ICP: ## The infection control oversight committee The regulatory requirement for a formal LTCF ICC was dropped by OBRA at the federal level, but some states still require them.The ICP should be familiar with state regulations. This committee frequently has been less active than the corresponding ICC in the hospital setting, in part because of decreased physician availability. A small working group (the infection control oversight committee) consisting of the ICP, the administrator, the medical director, and the nursing supervisor or their designee may efficiently make most of the infection control decisions. The ICC functions may be merged with the performance improvement or patient safety programs, but infection control must remain identifiable as a distinct program. Whatever group is selected to oversee the infection control program, it should meet regularly to review infection control data, review policies, and monitor program goals and activities. Written records of meetings should be kept. The LTCF administrative staff should support the ICP with appropriate educational opportunities and resources, including expert consultation in infectious diseases and infection control as needed. The participation of an infectious diseases (ID) physician or other health care professional with training or experience in infection control should be available on at least a consultative basis. Information may be obtained from SHEA (www.shea-online.org or 703-684-1006). The local health department may have useful information, and local ICPs are another valuable source of information, available from the APIC at www.apic.org. ## Educational opportunities for icps ## Surveillance Infection surveillance in the LTCF involves the systematic collection, consolidation, and analysis of data on HAIs. Standardization of surveillance is desirable. To facilitate standardization, resources that include practice guidance for surveillance identifying seven recommended steps are available. These steps are (1) assessing the population, (2) selecting the outcome or process for surveillance, (3) using surveillance definitions, (4) collecting surveillance data, (5) calculating and analyzing infection rates, (6) applying risk stratification methodology, and (7) reporting and using surveillance information.Assessing the population. Infection surveillance may either include all residents in a facility (total house surveillance) or be targeted at specific subpopulations. Although facility-wide surveillance is useful for calculating baseline rates and detecting outbreaks, a more focused analysis could include examination of infection rates in residents who are at risk for certain kinds of infection (such as aspiration pneumonia in residents receiving tube feedings or bloodstream infection among residents with indwelling vascular catheters). Focused surveillance should target infections that are preventable; that occur frequently; and that are associated with significant morbidity, mortality, and cost. Facility-wide surveillance is useful for establishing an infection control ''presence'' in the LTCF and may be required as a part of local or state regulatory programs. To establish baseline infection rates, track progress, determine trends, and detect outbreaks, site-specific rates should be calculated (eg, central line infections per 1000 central line-days). Routine analysis should try to explain the variation in site-specific rates. For example, a change in the rate might be related to a change in the resident population. Focused or highrisk resident surveillance may permit conservation of resources, although in many small institutions whole house surveillance is feasible. Selecting the outcome measures. Traditionally surveillance in the LTCF refers to collection of data on outcome measures such as HAIs that occur within the institution (eg, incidence of UTI or central lineassociated bacteremia). These surveillance data are used primarily to guide control activities, to plan educational programs, and to detect epidemics, but surveillance also may detect infections that require therapeutic action. Process measures (eg, surveillance of infection control practices) should also be part of the infection control and quality improvement programs and may be very helpful in identifying areas for improvement in practice and for monitoring compliance with regulatory aspects of the infection control program. Examples of process measures include observation of hand hygiene compliance, observation of correct catheter care technique, antibiotic utilization studies, timeliness in administering and reading TB skin tests, and administration of hepatitis B immunization to new employees within 10 working days of hire. Using surveillance definitions. Surveillance requires objective, valid definitions of infections. Most hospital surveillance definitions are based on the National Nosocomial Infections Surveillance System (NNIS) criteria,but no such standard exists for long-term care. NNIS (now the National Healthcare Safety Network [NHSN]) definitions depend heavily on laboratory data and recorded clinical observations. In the LTCF, radiology and microbiology data are less available, and written physician notes and nursing assessments in the medical record usually are brief. Timely detection of HAI in the LTCF often depends on recognition of clues to infection by nurses' aides and reporting of these findings to the licensed nursing staff.Positive cultures do not necessarily signify infection. Modified LTCF-specific surveillance criteria were developed by a Canadian consensus conference. These definitions were designed in light of some of the unique limitations of nursing home surveillance mentioned previously. They are used widely, although they have not yet been validated in the field.Collecting surveillance data. Published LTCF surveys have been either incidence or prevalence studies. Prevalence studies detect the number of existing (old and new) cases in a population at a given time, whereas incidence studies find new cases during a defined time period. The latter is preferred because more concurrent information can be collected by an incidence study if data are collected with regularity. The surveillance process consists of collecting data on individual cases and determining whether or not a HAI is present by comparing collected data to standard written definitions (criteria) of infections. One recommended data collection method in the LTCF is ''walking rounds.'' 182 This is a means of collecting concurrent and prospective infection data that are necessary to make infection control decisions. Surveillance should be done on a timely basis, probably at least weekly.During rounds, the ICP may use house reports from nursing staff, chart reviews, laboratory or radiology reports, treatment reviews, antibiotic usage data, and clinical observations as sources of information. Analysis and reporting of surveillance data. Analysis of absolute numbers of infections is misleading; calculation of rates provides the most accurate information. Rates are generally calculated by using 1000 resident-days as the denominator. In the past, average daily census has sometimes been used as the denominator, but resident-days more clearly reflect resident risk. Infection control data, including rates, then need to be displayed and distributed to appropriate committees and personnel (including administration) and used in planning infection control efforts. The data should lead to specific interventions such as education and control programs. To compare rates within a facility or to other facilities, the method of calculation must be identical (including the denominator). Even when calculation methods are consistent, infection rates may differ between facilities because of different definitions of infection or differences in resident risk factors and disease severity, and thus comparisons may not be valid. Comparison of infection rates between facilities, for public reporting or other purposes, requires control of definitions and collection methods, severity adjusting and data validation.The use of a regional data set may allow for more meaningful intrafacility comparison of infection rates.This may also allow for interfacility comparisons of infection rates across a corporation or geographic area.Analysis and reporting of infection data usually are done monthly, quarterly, and annually to detect trends. This process is facilitated by an individual infection report form, samples of which have been published.The statistics used in analysis of data need not be complex. Computerization for sorting and analysis of data may be timesaving for larger programs, and software for use on a personal computer is available. Graphs and charts facilitate presentation and understanding of infection control data and also may be facilitated by computer programs. The commercially available programs may help with analysis of surveillance data, but manual data collection is still usually necessary. The feasibility of routine surveillance in LTCFs has been demonstrated, and data have been used to provide a basis for continuing education.Surveillance needs to be simple and pragmatic, particularly because the LTCF ICP may be able to spend only a few hours per week on infection control activities. ## Outbreak control Outbreak surveillance and control should be considered a high priority for ICPs. The leading causes of LTCF outbreaks are discussed above and listed in. When the number of cases exceeds the normal baseline, an outbreak within the facility should be considered. The ICP is advised, and required by CMS, to monitor resident and staff illnesses, since healthy personnel may acquire and transmit virulent pathogens. For many, the word outbreak means a dramatic clustering of cases of an infectious disease in a geographic area over a relatively short period of time. However, the threshold for declaring an outbreak and initiating control measures may be much lower. For example, we know that influenza may cause explosive outbreaks in nursing homes.Public health officials have, therefore, set low thresholds for identifying an outbreak if influenza is suspected so that outbreak control strategies can be implemented to avoid high attack rates. The CDC recommends defining a nursing home outbreak of influenza as a single laboratory-confirmed case or a sudden increase of acute febrile respiratory illness over the normal background rate.Special outbreak control measures may, therefore, be appropriate if there is evidence of transmission of an epidemiologically important pathogen within the facility rather than waiting for a fully evolved clinical outbreak. For TB, an outbreak investigation should be triggered by a single active case. TB outbreaks are often caused by a single case and may infect large numbers of residents and staff by the airborne route before detection.In addition, a single infection caused by Legionella spp, scabies, Salmonella spp, or other GI pathogens associated with outbreaks should trigger an evaluation. A single case of Legionella spp may signal colonization of the water supply.The approach to investigating an outbreak includes (1) determining that an outbreak has occurred, (2) developing a case definition, (3) case finding, (4) analyzing the outbreak, (5) formulating a hypothesis regarding mechanism of transmission, (6) designating control measures, and (7) evaluating control measures. A CDC SHEA publication is available to guide investigation of outbreaks.Given the fact that influenza and norovirus outbreaks are relatively common, clinical case definitions should be developed in advance and placed in preexisting policies and procedures. To facilitate rapid implementation of control measures, the charge nurses should be empowered by preexisting policies to rapidly isolate and/or cohort infected individuals and to curtail contact between residents and staff on units in an outbreak situation. The LTCF may have difficulty responding to an epidemic with appropriate measures (such as mass vaccination or administration of antivirals during an influenza outbreak) if consent needs to be obtained on short notice from a resident's decision maker or primary physician. One way to circumvent this problem is to develop preexisting policies and procedures approved by the medical staff and to obtain consent for vaccination and outbreak control measures at the time of admission from the resident or their power of attorney/medical decision maker. ## Isolation and precautions: importance and evolution Prevention of transmission of significant pathogens to patients and HCWs is the major goal of isolation within health care systems. There are very limited data on the impact of isolation and infection control precautions, however, on the transmission of pathogens within LTCFs. The high prevalence of risk factors for infection among LTCF residents, the high colonization rate of MDROs in skilled care units, and the frequent reports of LTCF infectious disease outbreaks support the need for appropriate infection control in that setting.A unique infection control challenge for the LTCF is the mobile resident, who may be confused or incontinent and serves as a possible vector for infectious diseases. The presence of MDROs in the LTCF has implications beyond the individual facility. Because residents of LTCFs are hospitalized frequently, they can transfer pathogens between LTCFs and receiving hospitals; transfer of patients colonized with MDROs between hospitals and LTCFs has been well documented.On the other hand, LTCF residents remain in the facility for extended periods of time, and the LTCF is functionally their home. An atmosphere of community is fostered, and residents share common eating and living areas and participate in various activities. Thus, the psychosocial consequences of isolation measures must be carefully balanced against the infection control benefits. Isolation recommendations from the CDC have been available since 1970 but have specifically been targeted towards acute care settings. ICPs in the LTCF have thus been required to adapt these practices to their individual settings. Traditionally, 2 types of systems for implementing barrier precautions in the hospital were promoted. A Category-Specific System listed 7 categories of isolation or precautions based on means of disease transmission: strict isolation, contact isolation, respiratory isolation, TB isolation, enteric precautions, drainage and secretion precautions, and blood and body fluid precautions. Modifications of this approach have been promoted since 1970 with a refined Category-Specific System in the 1983 recommendations.A Disease-Specific System listed all relevant contagious diseases and the recommended barrier method. In general, the Category-Specific System was simpler to use, but the Disease-Specific System consumed fewer resources because precautions were tailored to the specific disease. In the 1983 guideline, blood precautions were expanded to include body fluids.In response to the HIV/AIDS epidemic, the concept of Universal Precautions was introduced to protect HCWs from all bloodborne exposures.These recommendations became adopted by OSHA and have thus been applicable to all health care settings including LTCFs.In this system, all blood and certain body fluids are considered potentially infectious. Education, provision of needle-disposal units, provision of protective equipment (such as gloves, gowns, and protective eye wear), and monitoring compliance were part of Universal Precautions, although it alone was not considered a complete isolation system. CDC isolation guidelines released in 1996 integrated earlier isolation systems by introducing transmissionbased precautions.Standard Precautions replaced Universal Precautions and were to be applied to all patients. Standard Precautions emphasize hand hygiene, gloves (when touching body fluids), masks, eye protection, and gowns (when contamination of clothing is likely), as well as avoidance of needlestick and other sharps injuries. More specific isolation was recommended for patients with documented or suspected contagious pathogens. These include Airborne Precautions (eg, for varicella, measles, and TB), Droplet Precautions (eg, for influenza and other respiratory infections), and Contact Precautions (eg, for MRSA,VRE, and C difficile diarrhea). CDC and HICPAC have recently released 2 infection control guidelines that have application in this regard to LTCFs. The first one released focuses specifically on the management of MDROs in health care settings, and the second is an update to previously recommended general isolation precautions from 1996 guidelines.Respiratory hygiene/cough etiquette and safe injection practices were added as new elements of Standard Precautions. Most LTCFs do not have negative-pressure rooms for Airborne Precautions, and residents with suspected TB should be transferred to facilities where such units exist. ## Isolation and precautions: mdros The majority of the infection control literature on MDROs in the LTCF has focused on MRSA, but these guidelines may also apply if a facility recognizes significant problems with other MDROs such as VRE or antibiotic-resistant, gram-negative bacilli. Barrier precautions are important in preventing cross infection with known resistant microorganisms, but approaches to isolation of LTCF patients colonized or infected with MDROs vary substantially across facilities.Most LTCFs employ at least some type of isolation for MDROs.It was found that 90.5% of facilities accepting patients with MRSA stated that they followed Contact Precautions despite only 39.7% placing them in private rooms.In another survey, most LTCFs in Nebraska were aware of and often screened for MRSA and employed some precautions in dealing with these residents (eg, single room, cohorting, contact isolation, or placing the resident with MDRO in the same room as a low-risk roommate).Another study demonstrated no difference in transmission of MDROs in a skilled care unit between contact isolation precautions and routine glove use.The authors suggested that universal glove use may be preferable to contact isolation because it reduces social isolation for LTCF residents where their health care facility is also their home. Others have suggested a ''modified'' contact isolation protocol as often more appropriate in the LTCF setting.Clearly, additional evidence-based studies defining the specific isolation needs within LTCF are needed. General guidelines for control of MRSA 148 and VRE 206 are published but emphasize hospital settings. These guidelines serve as an appropriate starting point for adapting an LTCF approach. There are many reports of aggressive infection control measures containing MDROs in the hospital setting.However, data in the LTCF are very limited, and implementation of isolation procedures identical to those found in a hospital may result in undesirable social and psychological consequences and functional decline for residents.SHEA position papers on antimicrobial resistance and infection control specifically address the LTCFand discuss prescreening admissions for resistant bacteria, surveillance for resistant bacteria, and endemic resistance. The recent HICPAC isolation guidelines attempt to address some of the specific needs and concerns of the LTCF.The principles in both documents can be adopted for use in the LTCF setting. The MDRO document discusses general control interventions such as administrative support, education of HCWs, surveillance, and judicious use of antimicrobial agents (see Antibiotic stewardship section below) that are applicable in the LTCF setting. LTCFs are encouraged to identify experts who can provide consultation for analyzing surveillance data and devising effective infection control strategies to control MDROs. The development of laboratory protocols for storing bacterial isolates for molecular typing when needed to understand the epidemiology of transmission is recommended. When the LTCF laboratory has contracted with an off-site laboratory, the facility will need to develop an arrangement for storing and testing isolates. The guidelinesrecommend continuing the use of transmission-based isolation precautions. In LTCFs, it is advised to consider the individual resident's clinical situation when deciding whether to implement or modify the use of Contact Precautions in addition to Standard Precautions if colonized or infected with a MDRO. Standard Precautions are sufficient for relatively healthy and independent residents, ensuring that gloves and gowns are used for contact with uncontrolled secretions, pressure ulcers, draining wounds, stool, and ostomy tubes/bags. Contact Precautions are indicated for residents with MDROs who are ill and totally dependent upon HCWs for activities of daily living or whose secretions or drainage cannot be contained. Single rooms for these residents are recommended if available. The cohorting of MDRO residents is acceptable if single rooms are not available. If cohorting is not possible, then placing residents with MDRO with residents who are low risk for acquisition or with anticipated short lengths of stay is advised. While ''low risk for acquisition'' of an MDRO has not been officially defined, one source suggested that it should include residents who are not immunosuppressed; not on antibiotics; and free of open wounds, drains, and indwelling urinary catheters.Case-by-case decisions, as needed, can be made regarding the best precautions to use for each resident with a MDRO. With Contact Precautions, wearing a gown and gloves for all interactions that may involve contact with the resident and their environment is advised, and eye protection is recommended when there is risk of splash or spray of respiratory or other body fluids. Recommendations for minimizing antibiotic resistance also include using appropriate barrier precautions for MDROs, maintaining a line listing of residents infected or colonized with MDROs, and not attempting eradication of MDROs from colonized residents.It is not recommended that the LTCF refuse MRSA or VRE cases but develop an institutional strategy for control of the resistant organisms based on local considerations.In summary, elements of routine MDRO control for the LTCF include monitoring MRSA and VRE culture results, communicating MDRO data to health care providers, including routine communication about MDROs at in-services, assessing compliance with isolation precautions and hand hygiene, monitoring antimicrobial usage, notifying receiving or transmitting facilities of the presence of a MDRO, designating residents previously known to be infected or colonized with MDROs, and instituting adequate environmental cleaning. If a MDRO problem exists in a LTCF and is not controlled with these basic infection control practices, then additional control measures are indicated. These include consultation from experts, intensification of education, increased efforts to control antimicrobial use, active surveillance cultures, pointprevalence culturing of targeted units, intensification of isolation with compliance assessment, and monitoring environmental cleaning. ## Isolation and precautions: bloodborne pathogen issues LTCFs may be asked to provide care for persons with hepatitis C, hepatitis B, HIV, and acquired immunodeficiency syndrome (AIDS), especially for individuals with advanced disease who are too ill to reside at home but do not require acute hospital care. Earlier guidelines for dealing with HIV infection in the health care setting are incorporated widely in hospitals but also apply in the LTCF.The standard approaches to protecting HCWs and other patients from transmission of bloodborne pathogens have essentially not changed since these earlier recommendations. In the current isolation guidelines,Standard Precautions are still promoted as the main method for preventing exposure to blood and body fluids for all patient interactions. These include the routine use of hand hygiene, gloves, gowns, masks, and eye protection, depending upon the anticipated exposures. The guideline also discusses in detail safe work practices to prevent exposures to bloodborne pathogens, including prevention of needlesticks and other sharp-related injuries; prevention of mucous membrane contact; safe injection practices; and precautions during aerosol-generating procedures. Infection control personnel at all LTCFs should carefully review these guidelines and develop a plan for implementation within their facilities. As in hospitals, it is known that needlestick injuries do occur in the LTCF and usually are related to needle recapping.Plans for regular education of all staff and for compliance with OSHA standards should be in place, and LTCFs should ensure the availability to hepatitis B vaccination and postexposure prophylaxis for HIV or hepatitis B for all employees in accordance with the most recent guidelines. ## Hand hygiene Hand hygiene likely remains the most important infection control measure in the LTCF as well as in the hospital. Unfortunately, poor compliance with hand hygiene recommendations has been noted in LTCFs, as in other settings.Health care provider hand contamination is usually transient and amenable to hand hygiene, 215 frequent hand hygiene would be expected to lower LTCF infection rates,and the availability of alcohol-based hand sanitizer dispensers enhances access to hand sanitizing agents. CDC and HICPAC published a comprehensive hand hygiene guideline.Other published guidelines for hand hygiene and choice of antiseptic agents are also applicable.They recommend the use of bar or liquid soap when hands are visibly dirty or contaminated with proteinaceous material or visibly soiled with blood or other body fluids. If hands are not visibly soiled, then the routine use of an alcohol-based hand rub is recommended in the LTCF. Hands should always be decontaminated after the removal of gloves. Hand hygiene with an antiseptic agent or alcohol-based hand rub is recommended before donning sterile gloves for performing invasive procedures such as placement of an intravenous or urinary catheter. Hand hygiene compliance should be monitored by the facility. ## Resident health Resident health programs are recommended for prevention of infections, 7 but comprehensive programs often are lacking in LTCFs.One of the major functions of a resident health program is the immunization of the elderly resident.The elderly are underserved in terms of immunization to tetanus, 222 as well as pneumococcal and influenza vaccines.They should receive pneumococcal vaccine at age 65, when they are relatively immunologically responsive, rather than at age 80 to 85 when entering the LTCF.Standing orders for influenza and pneumococcal vaccination are associated with improved vaccination rates.Residents should receive a TB skin test on admission and undergo chest radiograph if TST positive or symptomatic.Other resident care practices that should be addressed include resident hand hygiene, oral hygiene, prevention of aspiration, skin care, and prevention of UTIs. Clinical trials in LTCFs have reported no decrease in infections with routine vitamin or mineral supplementation.However, optimal care of comorbid illnesses and good nutrition are principles of care irrespective of impact on infections. ## Employee health Published information on infection control in hospital personnel is available.Employee infection prevention considerations in the LTCF are somewhat different than in the hospital, but the published literature and guidelines generally apply to the LTCFs as well as hospitals. Because of congregate living conditions in most LTCFs, there are some notable differences including an increased risk of exposure to residents with herpes zoster, scabies, conjunctivitis, influenza, TB, and viral gastroenteritis. The pediatric LTCF offers additional challenges to the prevention of infection including childhood diseases, such as varicella, measles, mumps, and rubella. Regulations concerning protection of employees from bloodborne pathogens apply to the LTCF.The LTCF should be able to provide timely chemoprophylaxis to employees who may have blood/body fluid exposure to residents known to have HIV.Employee health policies and procedures should address postexposure follow-up or prophylaxis for certain infections, such as hepatitis B, hepatitis C, TB, scabies, and HIV. Primary employee vaccination considerations should include influenza, hepatitis B, tetanus/diphtheria, and pertussis. Varicella, measles, mumps, rubella, and hepatitis A are of greater concern in the pediatric LTCF setting. Influenza vaccine campaigns should require signed declination statements by employees who decline vaccination.Adult vaccination information can be found at http:// www.immunize.org/. Vaccination should include hepatitis B to protect from this bloodborne pathogen. Varicella vaccine is appropriate if an employee is not immune. Hepatitis A vaccine may be appropriate in certain circumstances, especially in behavioral health and developmental disability facilities. Vaccine Information Sheets (VIS) should be given to all adult vaccinees as required by the National Childhood Vaccine Injury Act (42 U.S.C. §300aa-26). Anaphylaxis or any other adverse event requiring medical attention within 30 days after receipt of a vaccine must be reported to the Vaccine Adverse Events Reporting System (VAERS), a requirement of the National Vaccine Injury Compensation Program (www.vaers.org/pdf/vaers_form.pdf). Initial assessment of employees and education in infection control also are important, as is a reasonable sick-leave policy.Ill employees may cause significant outbreaks in the LTCF.Initial screening should include TB, also required by some states.LTCFs are required to prohibit employees with communicable diseases or infected skin lesions from direct contact with residents and to prohibit employees with potentially infectious skin lesions from contact with residents' food.Education. The value of education of the LTCF ICP has long been recognized, and surveys of personnel confirm this need.The importance of ICP education is accentuated by the great turnover in LTCF personnel. While the benefits of ICP training are widely assumed, one study analyzed the effects of a 2-day, intensive basic training program on 266 ICPs.Trainees not only demonstrated an increase in postcourse knowledge but, at 3-and 12-month follow-up, had a significant increase in implementation of key infection control practices. Practices included performance of surveillance, using infection definitions, calculating infection rates, and giving employees and residents TST and influenza vaccine. The role of education in infection prevention in the LTCF extends well beyond the ICP. One of the most important roles of the ICP is education of LTCF personnel in basic infection control principles. It is recommended that the ICP routinely assess the educational needs of staff, residents, and families and develop educational objectives and strategies to meet those needs; collaborate in the development, delivery, and evaluation of educational programs or tools that relate to infection prevention, control, and epidemiology; and continuously evaluate the effectiveness of educational programs and learner outcomes. Education should focus on new personnel and certified nursing assistants.Priority for training should be directed toward orientation, OSHA-mandated programs, problem-oriented teaching, and other programs required by regulations. Surveillance data are an excellent starting point for infection control training, and compliance rounds provide an opportunity for the ICP to provide timely, informal education to personnel. Infection control content should include information on disease transmission, hand hygiene, barrier precautions, and basic hygiene.In addition, all individuals with direct resident care responsibility need education in early problem and symptom recognition. The teaching methods used need to be sensitive to language, cultural background, and educational level. A coordinated, effective educational program will result in improved infection control activities. ## Antibiotic stewardship Antibiotic-resistant bacteria pose a significant hazard in the LTCF, and this resistance has been strongly associated with antibiotic use.Antimicrobials are among the most frequently prescribed medications in the LTCF.Antibiotics are given to approximately 7% to 10% of residents in LTCFs, frequently for lengthy periods of time.A study of 22 LTCFs noted an incidence of antibiotic prescriptions of 2.9 to 13.9 antibiotic courses per 1000 resident-days.Several studies have questioned the appropriateness of this practice.A common problem is the failure to distinguish infection and colonization (such as a positive swab culture of a pressure ulcer or a urine culture showing bacteriuria without signs or symptoms of infection) and the treatment of the colonization with antibiotics. In addition, antibiotics often are prescribed over the telephone in this setting.There also appears to be significant variability in antibiotic prescribing patterns in the LTCF.Several reviews and guidelines for infection control efforts to curb antibiotic resistance in health care settings (including LTCFs) have been published.These guidelines stress the importance of having an ICP trained in infection control and LTCF administrative support and resources for the infection control program.The CDC has published a 12-step program for preventing antimicrobial resistance among LTCF residents that addresses the broad areas of preventing infection (eg, resident vaccination), diagnosis/treatment of infection, using antibiotics wisely, and preventing transmission (www.cdc.gov). A LTCF antibiotic review program is recommendedand is often found in LTCFs.Recent guidelines have addressed the development of antimicrobial stewardship programs in hospitals.Using this guideline as a starting point, LTCFs are encouraged to include antimicrobial stewardship in the LTCF infection control program and discuss appropriate choices for various clinical situations.A recent survey revealed that fewer than one third of LTCFs surveyed had any such antibiotic use protocols in place.Minimum criteria for initiation of antibiotic therapy have been proposed to improve antimicrobial prescribing in LTCFs 252 and may be of assistance in developing antibiotic appropriateness criteria. Approximately two thirds of LTCF professionals identified a clear need for greater education regarding judicious antibiotic use in LTCFs.Education and development of antibiotic guidelines have improved antimicrobial usage in the LTCF setting in several studies.Other aspects of the program Policies and procedures. An important aspect of infection control programs is the development and updating of infection control policies and procedures. Because practices change, they should be reviewed on a scheduled basis. Review of the Bloodborne Pathogens Exposure Control Plan is required to be done annually.Resources are available on the writing of policies and procedures in general 255,256 dietetic service policies, 255 laundry policies, 257 physical therapy policies,and handwashing.Respiratory therapy issues may be relevant to the LTCF, including cleaning of humidifiers, respiratory therapy equipment, suctioning technique, and tracheotomy care.Pharmacy and medication issues include use of multidose medication vials and resident specific creams and ointments. A policy and procedure on hand hygiene are critically important to have available for staff.The policy details specific indications for hand hygiene, including when coming on duty; whenever hands are soiled; after personal use of toilet; after blowing or wiping nose; after contact with resident blood or body secretions; before performing any invasive procedures on a resident; after leaving an isolation room; after handling items such as dressings, bedpans, catheters, or urinals; after removing gloves; before eating; and on completion of duty. The corresponding procedure should list explicit steps in the hand hygiene process. A 15-second handwash is usually recommended.Alcohol-based hand rubs should be made available and used by staff, especially when handwashing facilities are inadequate or inaccessible. Hand hygiene compliance should be monitored.Facility management. Environmental control in the facility is an important consideration. Routine environmental cultures are not cost-effective and do not usually generate information relevant to clinical infections. However, periodic environmental compliance rounds are recommended.Sources are available suggesting specific environmental measures such as dishwasher and laundry cleaning temperatures,although limited data exist. A related area of concern is sterilization, disinfection, and asepsis, including the evaluation of cleaning methods, such as monitoring reuse of disposable equipment. Resources are available.An infection control program should also monitor basic hygiene (eg, respiratory etiquette) and compliance with proper infection control techniques. Staff, residents, and families may all be the source of HAIs if there is a breakdown in basic hygiene. Selection of proper disinfectants and antiseptics requires infection control expertise. Reading the manufacturer's label directions and following the required dilution and contact time instructions are recommended. Infection control input will also be needed on additional and new products that affect infection prevention, such as urinary catheter systems, gloves, and disposable diapers. Quality, efficacy, and cost issues need to be weighed in product selection.Waste management is the important in the LTCF. Medical and biohazardous waste issues are controversial; Environmental Protection Agency (EPA) regulations, OSHA regulations, and CDC recommendations may conflict.Local health department regulations should also be checked. Several resources are available on medical waste issues relevant to the LTCF. 162,Disease reporting. Another important function of the infection control program is disease reporting to public health authorities. State and local health departments will provide a list of reportable diseases and other public health resources. Performance improvement/resident safety. The increased emphasis on quality indicators in health care is becoming evident in LTC. There are important differences in definitions of infection published for LTCF surveillance (see Surveillance section above) and those in the long-term care Minimum Data Set (MDS) manual. This is especially important for UTIs. In addition, CMS provides a Web site called Nursing Home Compare,which posts information to the public on nursing home quality measures, inspections, staffing, and other data for individual LTCFs. For instance, UTI in the CMS MDS requires a physician diagnosis in the chart and a positive urine culture.This definition has been found to be inaccurate compared with standard definitions such as the McGeer definition,which requires a combination of symptoms and signs.A quality assessment and assurance committee is required.Infection control is the prototype quality improvement or performance improvement (PI) program, and many of the techniques used in infection control are directly applicable to PI, such as data collection, data analysis, and intervention.The traditional performance improvement process focuses on adverse events and assesses functions of the system.In the course of performing infection surveillance, there is ample opportunity to monitor compliance with infection control policies and procedures and to provide informal infection control education to address observed problems. Examples of appropriate quality indicators for PI study include resident immunization with influenza and pneumoccoccal vaccines, 272 employee vaccination for influenza,number of employee TSTconversions, and employee hand hygiene compliance. A national focus on patient safety and prevention of adverse events has relevance to the LTC setting as well.Preparedness planning. The ICP will frequently play a key role in LTCF preparedness planning. The planning is currently focused on pandemic influenza but should prepare the LTCF for dealing with a variety of disaster scenarios. Issues to be considered include surge capacity, medication availability and rationing, stockpiling, staff shortages during an influenza pandemic, and communication with public health authorities for planning purposes.It appears that the LTCF ICP will play an important role in preparedness and that about half of LTCFs have a pandemic influenza plan. ## Resources Having appropriate job-related resources is essential to good performance in the role of infection prevention and control. A few resources for the ICP are listed below: ## Recommendations Seefor scoring scheme. Comment: The elements of a program generally include the following: a. Surveillance-Systematic data collection to identify infections in residents b. Outbreak Control-A system for detection, investigation, and control of epidemic infectious diseases in the LTCF c. Isolation-An isolation and precautions system to reduce the risk of transmission of infectious agents d. Policies and procedures-Relevant to infection control (seeComment: Men with incontinence should have voiding managed by a condom catheter rather than indwelling catheter, where possible. Residents with chronic indwelling catheters should have the catheter replaced and a specimen collected immediately prior to initiating antimicrobial therapy for symptomatic infection. 4 A program to minimize the risk of pneumonia in the LTCF should address the following: reducing the potential for aspiration, minimizing atelectasis, and caring for respiratory therapy equipment (Category II). Comment: Pneumonia prevention guidelines are available, and many of the suggested measures are applicable to the LTCF. 5 Policies and procedures should be developed for prevention of infections associated with nasogastric and gastrostomy feeding tubes, including the following: preparation, storage, refrigeration, and administration of feeding solutions and care of percutaneous feeding tube skin sites (Category II). 6 Policies and procedures should be developed for prevention of IV infections, including central lines, if these devices are used (Category IB). Comment: Policies should address indications for IV therapy, the type of dressing used to cover the IV exit site, cannula insertion, site maintenance, and changing fluids or tubing. ## J. resident health program 1 A resident health program should be implemented (Category II). d There should be explicit and accessible documentation of program components in the resident record (Category II). 2 At admission, each resident should have a complete history (including important past and present infectious diseases), immunization status evaluation, and recent physical examination (Category II). 3 All newly admitted residents should receive TB screening unless a physician's statement is obtained that the resident had a past positive TST (Category IA/ IC). Comment: A 2-step booster TST is often recommended in this setting. 4 When new or active TB is suggested by a positive skin-test result, or symptoms are consistent with active TB, a chest radiograph and medical evaluation should be obtained (Category II). 5 Follow-up TST for TB should be performed periodically or after discovery of a new case of TB in a resident or staff member (Category IB). No recommendation on frequency of routine follow-up TSTs for residents. 6 Each resident should receive current vaccinations for tetanus, diphtheria, influenza, pertussis, pneumococcal pneumonia, and any other vaccines recommended by the ACIP (Category IB/IC). 7 Each resident should receive the influenza vaccine annually in the fall, unless medically contraindicated (Category IC). Comment: Facilities should obtain resident consent at admission for yearly influenza vaccination and use standing orders for yearly influenza vaccination. 8 Policies and procedures addressing visitors should be developed to limit introduction of community infections (such as influenza) into the LTCF (Category II). 3 Follow-up skin testing of staff who are TST negative should be performed periodically based on the facility's annual risk assessment or after discovery of a new case of TB in a resident or staff member (Category 1A/IC). ## K. employee health program Comment: The intradermal Mantoux method or licensed blood test should be used. The frequency of testing depends on the regional prevalence of TB; the facility's annual risk assessment; and federal, state, or local regulations. All employees should have current immunizations as recommended for HCWs by the Advisory Committee on Immunization Practices (ACIP), with documentation in the employee record (Category 1A/IC). 5 Employees with blood or body fluid contact should be offered HBV immunization within 10 working days of hire and after training has been completed (Category 1C). Comment: Refusal of this vaccine should be documented, using the OSHA-required Declination Statement for Hepatitis B vaccine. 6 Employees should be offered the influenza vaccine annually (Category 1A/1C). Comment: A vaccine declination statement may be signed by each employee who declines influenza vaccination. 7 Each employee should be taught basic use of personal protective equipment and hand hygiene and to consider blood and all body fluids as potentially infectious (Category 1C). 8 Employees with signs or symptoms of communicable diseases (eg, cough, rash, diarrhea) should not have contact with the residents or their food (Category 1B). 9 All employees should be educated to report any significant infectious illnesses to their supervisor and the staff member responsible for employee health (Category 1B). Comment: Each employee record should include factors affecting immune status (such as steroid therapy, diabetes, HIV infection), history of communicable diseases, illnesses, and incidents such as exposures to contagious diseases, needlesticks, injuries, and accidents. 10 The LTCF should develop protocols for managing employee illnesses and exposures (such as bloodborne pathogens like HIV and hepatitis B and C, as well as TB, scabies, or gastroenteritis) (Category 1B/IC). Comment: An employee absentee policy that discourages the employee from working while ill should be developed. ## L. education 1 Infection control education should be provided at the initiation of employment and regularly thereafter. Training should include all staff, especially those providing direct resident care (Category IC). 2 All programs should be documented with the date, topic, names of attendees, and evaluations (Category IC). Comment: Program topics should be timely and relevant to infection prevention and control. Basic hygiene, hand hygiene, respiratory etiquette, transmission of infectious diseases, occupational health, prevention of TB and bloodborne pathogens, Standard and Transmission-based Precautions, infection control standards, and the susceptibility of residents to infectious diseases are topics that should be included. The ICP may recommend topics. Surveillance data are of interest to staff and may be included as appropriate. The educators should evaluate the educational program and outcomes and use that information to modify future programs. Comment: The LTCF should encourage judicious use of antimicrobials with guidelines based in part on local susceptibility patterns. Antibiotic utilization and appropriateness may be monitored, and these data used for interventions (eg, education, antibiotic restrictions). ## M. policies and procedures 2 The ICP should monitor antibiotic susceptibility results from cultures to detect clinically significant antibiotic-resistant bacteria (such as MRSA or VRE) in the institution. Changes in antibiotic-susceptibility trends should be communicated to appropriate individuals and committees (Category IB). ## O. miscellaneous aspects 1 There should be a system for reporting notifiable diseases to proper public health officials (Category 1C). 2 The infection control program should collaborate with the performance improvement (PI) program, if a formal program exists (Category II). Comment: Infection control is an important component of PI, and the epidemiological techniques used in infection control will assist the PI program. 3 The ICP should be involved with the review and selection of new products that have infection control implications (Category II). 4 The ICP should be involved with LTCF influenza pandemic preparedness planning (Category II). 5 Infection control activities should address relevant resident safety issues (Category II). ## P. regulations 1 The infection control program must be in compliance with federal, state, and local regulations (Category IC). 2 The infection control program should reflect national, evidence-based standards of practice for infection prevention and control (Category IC).	None	http://www.ajicjournal.org/article/S0196655308006044/pdf	None
39b48e9fdbe67bf8428a5b3646e9b9627468b0a8	pubmed	Severe influenza treatment guideline	Severe influenza treatment guideline ## Introduction background and purpose Severe influenza is defined as influenza with a severe symptom or syndrome such as respiratory distress or deceased consciousness or accompanying a severe complication such as encephalopathy or renal failure. In contrast to mild influenza, for which patients recover mostly by ambulatory care, severe influenza requires hospital admission in most cases or intensive treatment in the intensive care unit in some cases. In particular, the elderly, infants, and chronic patients are known to be at high risk for severe influenza because they may have accompanying complications such as exacerbation of an underlying disease, development of pneumonia, and another organ dysfunction or they may die. Therefore, there is an increasing need for an effective treatment method applicable to severe influenza. Severe influenza treatment methods, which have been recently discussed, include high-dose, long-term antiviral therapy, combination antiviral therapy, administration of antibiotics, application of extracorporeal membrane oxygenation (ECMO), administration of a corticosteroid, administration of intravenous immunoglobulin (IVIG), application of plasmapheresis, and administration of a statin. However, no comprehensive, specific expert guideline for these methods is available yet. The Transgovernmental Enterprise for Pandemic Influenza in Korea published in 2012 a guideline for the use of an antiviral agent for seasonal influenza. But the guideline deals with only the use of an antiviral agent, not the various treatment methods which can be applied to severe influenza [bib_ref] Clinical practice guideline for antiviral treatment and chemoprophylaxis of seasonal influenza, Choi [/bib_ref]. Therefore, this guideline was developed by analyzing and evaluating domestic and international literature and guidelines with respect to the various treatment methods so that severe influenza could be effectively treated. ## Scope and subjects The subjects of this guideline are all patients including infants and the elderly. The subject disease is severe seasonal influenza infection. This guideline adapts the general definition of severe influenza from influenza-related severe acute respiratory illness. Quoting the 2010 guideline of the World Health Organization (WHO), severe influenza is defined as follows. Users of this guideline are all general practitioners and medical specialists who treat severe influenza patients. This guideline includes information on not only on antiviral agents but also on antibiotics, ECMO, corticosteroids, IVIG, plasmapheresis, statins, etc. The recommendations included in this guideline could be changed according to future study results. # Method of development ## Constitution of the guideline development committee For the development of this guideline through a multidisciplinary discussion, the guideline development committee was constituted with nine members that included an infectious disease specialist, a pediatrics specialist, and a methodology specialist. ## Derivation of key questions based on guidelines previously developed To define key questions for the treatment guideline, clinical practice guidelines previously developed were first reviewed. The reviewed clinical practice guidelines were those that were published between 2009 and 2013 which included ones written in both English and Korean. The reviewed guidelines were limited to those that were developed by a central or local government or by academic societies. The guidelines were searched for in four databases. [fig_ref] Table 1: Database and search terms for the clinical guideline [/fig_ref] shows the database and key words used in the search. Two of the Development Committee members reviewed the treatment guidelines and selected 23 guidelines appropriate to the scope of this guideline (Appendix 1). To derive the key questions, the key questions included in each guideline were listed, compared, and reviewed. Then, a total of 10 key questions were chosen. ## Determination of the development method After reviewing the 10 key questions, a systematic literature review was performed for the questions which had not been dealt with in previous guidelines or which needed additional searching. Other key questions were reviewed with the evidence and the degree of recommendations provided by the previous guidelines. If necessary, domestic evidence and recent literature were added. ## Literature search Evidence in the guidelines previously developed The quality of the selected treatment guidelines was not evaluated. The newness was verified by determining the year of publication and the year of the basis search. The recommendations for each of the selected key questions provided by the individual guidelines were compared by making a recommendation comparison table for each key question. ## Additional literature search According to the selection of the key questions, an additional literature search was carried out for eight key [fig_ref] Table 2: Number of selected references for each key question [/fig_ref] shows the selected articles for each of the key questions. ## Determination of recommendation grade for recommendations The grade of the recommendations was determined by reviewing the design method of the selected clinical studies. The grade of the recommendations was determined by carefully considering whether the recommendation could be generalized and whether the recommendation could be consistently applied to actual clinical settings. When the domestic basis was not sufficient, the degree was determined by the entire Guideline Development Committee reaching a consensus. The Development Committee used the evidence and recommendation grades of the Infectious Diseases Society of America [fig_ref] Table 3: Recommendation of strength and evidence for recommendations [/fig_ref]. The statement for each recommendation was determined by a specialist panel meeting. Nine specialists participated in the panel meeting and they evaluated the appropriateness of each recommendation on a 1 to 9 point scale (1 point-most inappropriate; 9 points-most appropriate). The panel meeting was held as a face to face meeting. The results and problems were reviewed in the first evaluation. The recommendations were revised and evaluated again in the second evaluation. ## External review and approval The recommendations were reviewed by five specialists and their comments were reflected in the guideline. To collect opinions of the stakeholders, approval was acquired from the Korean Society of Infectious Diseases and the Korean Society for Chemotherapy. ## Antiviral agents ## Key question 1: what is the optimal dose of oseltamivir for the treatment of severe influenza? - Standard-dose oseltamivir is recommended for the treatment of severe influenza (BI). Many studies have been conducted to compare and evaluate the effects of treatment using a standard-and high-dose of antiviral agent with mild influenza infection patients without any complications. However, each study showed clinically and virologically different results [bib_ref] Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized..., Hayden [/bib_ref] [bib_ref] Intravenous peramivir for treatment of inf luenza A and B virus infection..., Kohno [/bib_ref] [bib_ref] Efficacy and safety of oseltamivir in treatment of acute inf luenza: a..., Nicholson [/bib_ref] [bib_ref] Eff icacy and safety of the oral neuraminidase inhibitor oseltamivir in treating..., Treanor [/bib_ref]. Although the data are not sufficient regarding highdose antiviral agent treatment in patients with severe inf luenza, double-dose oseltamivir treatment (two times a day at 150 mg each) has been recommended for the treatment of A/H5N1 avian influenza infection considering the decreased oral absorption rate and the safety data for high-dose administration. However, a large-scale prospective cohort study in China conducted with patients infected by the pandemic influenza A (H1N1) in 2009 (3,066 patients presenting pneumonia) showed that high-dose oseltamivir treatment (> 3.8 mg/ kg per day) did not improve the survival rate compared with the standard-dose treatment [bib_ref] Antiviral therapy and outcomes of patients with pneumonia caused by influenza A..., Yang [/bib_ref]. A multi-institutional, double blind, randomized study conducted in Southeast Asia showed that high-dose oseltamivir treatment (two times a day at 150 mg each) in patients with severe influenza did not have a particular therapeutic advantage over the standard-dose treatment (two times a day, 75 mg each). Specifically, there was no difference in the virus repression effects and in the clinical therapeutic reactions (the period of time requiring mechanical ventilation, the duration of intensive care unit admission, mortality, etc.) on the fifth day after starting the treatment. A recently published study, which was conducted on adult inf luenza inpatients aged 18 or higher in Hong Kong, compared the therapeutic effects of standard-and high-dose oseltamivir treatments [bib_ref] A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with..., Lee [/bib_ref]. In this study, there was no significant difference between the standard-and high-dose groups in the viral RNA detection rate, fever duration, and admission duration on the fifth day after starting the treatments. The study is limited in the sense that severe, critical patients were not included in the study subjects. However, the maximum and minimum blood oseltamivir concentrations were measured in the study, indicating that the administration of the standard-dose oseltamivir treatment, two times a day at 75 mg each, also showed a blood oseltamivir concentration which was about eight to 18 times higher than the 90% inhibitory concentration. Therefore, treatment using oseltamivir with the standard-dose is recommended also for patients with severe influenza infection (BI). It is recommended that the actual dose of oseltamivir according to age, weight, or underlying diseases should follow the Clinical Practice Guideline for Antiviral treatment and Chemoprophylaxis of Seasonal Influenza [bib_ref] Clinical practice guideline for antiviral treatment and chemoprophylaxis of seasonal influenza, Choi [/bib_ref]. Domestic data with regard to treatment with a highdose antiviral agent is very limited. Kim et al. [bib_ref] A case of high dose oseltamivir treatment in an influenza A (H1N1)..., Kim [/bib_ref] reported that an oseltamivir administration at a high dose, which was two times more than the standard dose, showed a clinical improvement in a pediatric severe influenza patient who had a graft-versus-host disease. Kang et al. [bib_ref] Virological clearance rate of high-dose oseltamivir or triple-combination antiviral therapy in complicated..., Kang [/bib_ref] evaluated the therapeutic reactions of high dose oseltamivir treatment in severe adult patients who were infected by the pandemic influenza in 2009 and reported that six out of the eight severe patients with accompanying pneumonia survived and no virus was detected in five out of the six surviving patients on the fifth day after starting the treatment. Although a few important studies may provide a basis for whether to recommend standard-or high-dose oseltamivir treatment for severe influenza infection, additional studies are required in the future. In addition, there are insufficient data to establish a recommendation for a high-dose therapy with intravenous peramivir or a zanamivir inhaler. ## Key question 2: what is the optimal duration of the antiviral treatment for a severe influenza patient? - If the clinical course remains severe or progressive, the duration of the antiviral treatment is recommended to be extended longer than the usual treatment duration (e.g., 5 days for oseltamivir). No clinical studies have evaluated the effectiveness of a longer duration of antiviral treatment for treating severe influenza patients. However, one study showed that hospitalized patients with influenza can shed detectable virus beyond the 5-day period [bib_ref] Duration of inf luenza A virus shedding in hospitalized patients and implications..., Leekha [/bib_ref] and many experts have expressed their opinion that a longer duration of antiviral treatment may be helpful in patients with severe inf luenza. At the time of the H1N1 pandemic in 2009, the WHO influenza antiviral therapy guideline also recommended that the antiviral treatment should be maintained without a break until the virus infection is resolved or there is satisfactory clinical improvement. guideline also stated that a longer use of an antiviral agent may be considered if a severe state continues even after using an antiviral agent for 5 days. Therefore, if the clinical course remains severe or progressive, the duration of the antiviral treatment is recommended to be extended longer than the usual treatment duration (e.g., 5 days for oseltamivir) (BIII). Furthermore, the usual antiviral treatment duration is recommended to follow the Clinical Practice Guideline for Antiviral Treatment and Chemoprophylaxis of Seasonal Influenza [bib_ref] Clinical practice guideline for antiviral treatment and chemoprophylaxis of seasonal influenza, Choi [/bib_ref]. However, if the clinical course remains severe or progressive even after administering an antiviral agent for the usual treatment duration, antiviral drug susceptibility testing will be needed. ## Key question 3: should antiviral combination therapy be used in a severe influenza patient? - Antiviral combination therapy is not generally recommended for the treatment of severe influenza (BII). Data with respect to the combined use of antiviral agents are very limited. Prospective studies that compared the effects of oseltamivir monotherapy, zanamivir monotherapy, and oseltamivir and zanamivir combination therapy with patients who were infected by mild seasonal influenza without any complications in the 2008 to 2009 season showed that the therapeutic effect of the oseltamivir and zanamivir combination treatment was rather lower compared to that of the oseltamivir single treatment and not significantly different from that of the zanamivir single treatment [bib_ref] Oseltamivir-zanamivir bitherapy compared to oseltamivir monotherapy in the treatment of pandemic 2009..., Escuret [/bib_ref] [bib_ref] Efficacy of oseltamivir-zanamivir combination compared to each monotherapy for seasonal influenza: a..., Duval [/bib_ref]. Although the data with respect to a combined use of the antiviral agents in a severe influenza patient are not sufficient, a study showed that the synergic effect of an oseltamivir and amantadine combination therapy could be helpful in a severe patient [bib_ref] Effects of double combinations of amantadine, oseltamivir, and ribavirin on influenza A..., Smee [/bib_ref]. A recent report showed that a triple therapy with oseltamivir, amantadine, and ribavirin, having different active sites, provided not only an in vivo synergic effect on a seasonal influenza virus but also a synergic effect on a seasonal influenza virus presenting resistance to one drug . With regard to the clinical usefulness of such a triple combination therapy, a retrospective study that compared the treatment result of oseltamivir monotherapy with that of oseltamivir, amantadine, and ribavirin combination therapy in severe influenza patients admitted to an intensive care unit during the epidemic period of the pandemic H1N1 in 2009 showed that the 14-day mortality and 90-day mortality were lower in the case of the combination therapy compared to the case of the monotherapy, but the difference was not significant [bib_ref] Triple-combination antiviral drug for pandemic H1N1 influenza virus infection in critically ill..., Kim [/bib_ref]. In another study conducted with H1N1 infected patients who were admitted to an intensive care unit in 2009, a combination of antiviral agents did not show a better survival rate than that of a monotherapy [bib_ref] Evaluation of the antiviral response to zanamivir administered intravenously for treatment of..., Fraaij [/bib_ref]. Therefore, according to the research results available until now, because the combined administration of antiviral agents to a severe influenza patient may not be considered more effective and the indiscriminate application of a combined administration of antiviral agents to all severe influenza patients is not recommended (BII). However, because various combinations of currently available antiviral agents have not been sufficiently evaluated and a number of animal test reports have shown that a combined use of antiviral agents is effective, the recommendation with respect to a combined use of antiviral agents to a severe influenza patient may need to be revised by additional studies in the future. In addition, considering that such a combined therapy does not present many drug side effects, a limited application of a combined use of antiviral agents may be taken into consideration for a severe influenza patient who is suspected to have resistance to an antiviral agent or who does not respond to a conventional treatment. ## Antibiotics key question 4: should an antibiotic be administered to a severe influenza patient? - An antibiotic along with an antiviral agent is recommended to be administered from the beginning of the treatment to a severe influenza patient with accompanying pneumonia (BII). - An antibiotic is recommended to be administered to a patient with severe influenza complicated by acute otitis media or sinusitis (BII). Some studies have shown that the prescription of an antibiotic in acute sore throat patients alleviate the symptom a little and decrease the suppurative complications such as acute otitis media. However, such an effect was more distinctive in a patient group in which throat swabs were positive for Streptococcus [bib_ref] Antibiotics for sore throat, Mar [/bib_ref] , and more side effects were found in a group in which an antibiotic was prescribed for upper respiratory infection [bib_ref] Antibiotics for acute bronchitis, Smucny [/bib_ref] , and there was no difference in the time taken until loss of symptoms between the group in which an antibiotic was immediately administered and the group in which an antibiotic was administered only after a secondary bacterial infection was verified [bib_ref] Delayed antibiotics for respiratory infections, Spurling [/bib_ref]. Considering these results, it is not generally recommended to administer an antibiotic to all influenza patients [bib_ref] Italian evidence-based guidelines for the management of influenza-like syndrome in adults and..., Morciano [/bib_ref]. Therefore, the use of an antibiotic is recommended only in cases where the influenza infection is complicated by pneumonia, acute otitis media, sinusitis, and other infections (BII). ## Key question 5: when an antibiotic is considered for The most frequent and serious complication of influenza is secondary bacterial pneumonia. In cases of influenza complicated by pneumonia, it is difficult to distinguish whether the pneumonia is from an influenza virus or a secondary bacterial infection. However, once the influenza is complicated by pneumonia, a secondary bacterial infection is identified in many of the cases. Many studies were conducted regarding the etiologic bacteria of pneumonia in patients with severe influenza complicated by pneumonia during the 2009 H1N1 pandemic. A study conducted in the United States with 36 dead pediatric patients in 2009 showed that 10 of the 36 subjects (43%) were definitely diagnosed with a secondary bacterial infection microbiologically or pathologically. A study which was conducted later also showed that 17 out of 53 dead pediatric patients (32%) were verified to have had a secondary bacterial infection microbiologically. The bacteria frequently isolated from patients with pneumonia by inf luenza infection included Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes, and Moraxella catarrhalis. Because secondary bacterial pneumonia often accompanies inf luenza, the early use of an antibiotic with an antibacterial activity specific to the bacteria mentioned above is recommended in the cases of patients with influenza complicated by pneumonia. Therefore, according to the Treatment Guideline for Community-acquired Pneumonia, an empiric antibiotic for pneumonia due to influenza infection such as ampicillin/sulbactam, amoxicillin/ clavulanate, third-generation cephalosporins, and respiratory quinolones could be used as the primary drug [bib_ref] Treatment guidelines for community-acquired pneumonia in Korea: an evidence-based approach to appropriate..., Song [/bib_ref]. However, because atypical bacteria such as Mycoplasma and Legionella are not likely to accompany influenza, there could be a low need to use a macrolide in inf luenza patients although it is the primary drug for general community-acquired pneumonia. In the cases of otitis media and sinusitis, antibiotics such as amoxicillin and amoxicillin/clavulanate are used as the primary drug. When the culture test result shows that the bacteria, which has caused a secondary bacterial infection, has resistance to the primary drug or that the clinical condition of the patient is not improved, the used antibiotic should be replaced by another according to the susceptibility test result and the treatment guideline for each infectious disease. In a case where hospital-acquired pneumonia seems to have developed because of a long period of admission for a severe influenza patient, it is recommended to treat that patient with an appropriate antibiotic according to the culture test result from the patient's respiratory sample and to the antibiotic resistance pattern of respiratory pathogens in each institution. ## Extracorporeal membrane oxygen-ation key question 6: should extracorporeal membrane oxygenation be applied to a severe influenza patient? - ECMO is recommended to be applied to an influenza patient presenting continued hypoxia which does not respond to a conventional treatment (BIII). Application of ECMO to a severe influenza patient is a supportive method to acquire time for the patient to recover, rather than a direct treatment of influenza. Thus, ECMO application is one of the rescue therapies which should be considered when a patient is having respiratory failure from influenza who does not respond to a www.kjim.org conventional therapy [bib_ref] Trends in and perspectives on extracorporeal membrane oxygenation for severe adult respiratory..., Sadahiro [/bib_ref] [bib_ref] Recommendations of the Infectious Diseases Work Group (GTEI) of the Spanish Society..., Rodriguez [/bib_ref]. There is no prospective study on the effect of ECMO in a severe influenza patient. Most of the studies are case studies most of which are about the pandemic H1N1 in 2009. Reports have shown different mortality rates of severe influenza in which ECMO was applied between 8% and 75%, but the average mortality rate was 32%, indicating a relatively good effect [bib_ref] Pandemic flu and the sudden demand for ECMO resources: a mature trauma..., Michaels [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation (ECMO) in patients with H1N1 influenza infection: a systematic..., Zangrillo [/bib_ref] [bib_ref] Predicting mortality risk in patients undergoing venovenous ECMO for ARDS due to..., Pappalardo [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation for 2009 influenza A (H1N1) severe respiratory failure in..., Takeda [/bib_ref] [bib_ref] Portable miniaturized extracorporeal membrane oxygenation systems for H1N1-related severe acute respiratory distress..., Roncon-Albuquerque R Jr [/bib_ref] [bib_ref] ry support during the influenza A (H1N1) pandemic flu in Sweden, Brink [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation for critically ill patients with 2009 influenza A (H1N1)-related..., Hou [/bib_ref] [bib_ref] Oseltamivir-resistant 2009 H1N1 inf luenza pneumonia during therapy in a renal transplant..., Shetty [/bib_ref] [bib_ref] Critical care paper review 2012, Sohn [/bib_ref] [bib_ref] pandemic influenza A (H1N1) in critically ill children in, Morgan [/bib_ref] [bib_ref] Extracorporeal lung support in patients with severe respiratory failure secondary to the..., Bonastre [/bib_ref] [bib_ref] Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics..., Lemaitre [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation for 2009 inf luenza A (H1N1) acute respiratory distress..., Beurtheret [/bib_ref] [bib_ref] Extracorporeal membrane oxygenation in severe hypoxemia: time for reappraisal?, Azevedo [/bib_ref] [bib_ref] The application of extracorporeal membrane oxygenation in critically ill patient, Li [/bib_ref] [bib_ref] Severe influenza A (H1N1) 2009 infection: a single centre experience and review..., Van Ierssel [/bib_ref] [bib_ref] H1N1 influenza virus infection and necrotizing pneumonia treated with extracorporeal membrane oxygenation, Ji [/bib_ref] [bib_ref] Early extracorporeal membrane oxygenation in a patient with pandemic influenza (H1N1 2009)..., Lee [/bib_ref]. Therefore, it is recommended to apply ECMO to an influenza patient presenting continued hypoxia which does not respond to a conventional treatment (BIII). Indications and contraindications for consideration or implementation of ECMO are shown in [fig_ref] Table 4: Indication and contraindication of extracorporeal membrane oxygenation for influenza patients with acute... [/fig_ref] [bib_ref] Recommendations of the Infectious Diseases Work Group (GTEI) of the Spanish Society..., Rodriguez [/bib_ref]. ## Steroids key question 7: should a corticosteroid be administered to a severe influenza patient? - Systemic corticosteroid administration should not performed for the treatment of a severe influenza patient (BII). - The exception is that a corticosteroid could be administered for the treatment of a disease for which the therapeutic effect of a steroid has already been proven, such as asthma, COPD, and adrenal insufficiency (BIII). Administration of empirical corticosteroids as a first line or salvage treatment was reported in more than half of the severe patients including acute respiratory distress syndrome during the pandemic influenza in 2009. However, the effect of corticosteroids in a severe influenza patient has not been studied sufficiently and thus, is still controversial. Quispe-Laime et al. [bib_ref] H1N1 influenza A virus-associated acute lung injury: response to combination oseltamivir and..., Quispe-Laime [/bib_ref] suggested the use of a low to moderate dose of a steroid because a corticosteroid may signif icantly improve lung injuries. However, this study result has limitations due to its research design and the small size of the study populations. Kil et al. [bib_ref] Early corticosteroid treatment for severe pneumonia caused by 2009 H1N1 inf luenza..., Kil [/bib_ref] reported that the duration of fever and the duration of oxygen therapy were significantly shorter, and the number of patients whose pneumonia was resolved at the time of discharge was greater in the severe pediatric influenza patient group where a steroid was adminis- tered. Sohn et al.also reported that the administration of a corticosteroid within 48 hours to 37 pediatric patients presenting exacerbating influenza pneumonia resulted in the recovery of all the patients without a sequela. However, these two studies also should be carefully interpreted because the size of the study population was small and the subjects were limited to pediatric patients. There is a considerable number of clinical case series and case reports in which severe patients with encephalopathy or with respiratory complications such as pneumonia improved after the use of a corticosteroid [bib_ref] Corticosteroids do not cause harmful increase of viral load in severe H1N1..., Confalonieri [/bib_ref] [bib_ref] Methylprednisolone infusion for life-threatening H1N1-virus infection, Confalonieri [/bib_ref] [bib_ref] Effects of mild hypothermia and steroid pulse combination therapy on acute encephalopathy..., Ohtsuki [/bib_ref] [bib_ref] A case of acute respiratory distress syndrome associated with pandemic influenza A..., Hibino [/bib_ref] [bib_ref] Case of novel influenza A (H1N1) pneumonia with shrinkage of a pulmonary..., Samejima [/bib_ref] [bib_ref] Case of adult influenza type A virus-associated encephalopathy successfully treated with primary..., Sakurai [/bib_ref] [bib_ref] Non-invasive management of acute respiratory distress syndrome related to Influenza A (H1N1)..., Djibre [/bib_ref] [bib_ref] Virus associated hemophagocytic syndrome accompanied by acute respiratory failure caused by influenza..., Ando [/bib_ref] [bib_ref] Multiphasic acute disseminated encephalomyelitis (ADEM) following influenza type A (swine specific H1N1), Athauda [/bib_ref] [bib_ref] Treatment of critically ill influenza A H1N1 patients in plateau region, Wang [/bib_ref] [bib_ref] Efficacy of plasma exchange and methylprednisolone pulse therapy on inf luenza-associated encephalopathy, Kawashima [/bib_ref] [bib_ref] Combined therapy with hypothermia and anticytokine agents in influenza A encephalopathy, Munakata [/bib_ref] [bib_ref] Steroid-sensitive post-viral inflammatory pneumonitis (PVIP), Roberts [/bib_ref]. However, all the studies that analyzed the effect of corticosteroids during the pandemic H1N1 infection in 2009 showed a negative result. A study conducted by the European Society of Intensive Care Medicine showed that the use of a corticosteroid was not helpful to the treatment of a patient and rather, increased the risk of hospital-acquired pneumonia [bib_ref] Use of early corticosteroid therapy on ICU admission in patients affected by..., Martin-Loeches [/bib_ref]. Mady et al. [bib_ref] Clinical experience with severe 2009 H1N1 influenza in the intensive care unit..., Mady [/bib_ref] conducted a study with patients admitted to an intensive care unit at the time of the pandemic influenza in 2009 and reported that use of a corticosteroid increased the mortality three times. Linko et al. [bib_ref] Corticosteroid therapy in intensive care unit patients with PCR-confirmed inf luenza A..., Linko [/bib_ref] prospectively observed the mortality of patients who were administered a corticosteroid and the patients who were not among the influenza confirmed patients admitted to an intensive care unit during the pandemic influenza in 2009 and reported that there was no significant difference in the mortality between the two groups. Han et al. [bib_ref] Early use of glucocorticoids was a risk factor for critical disease and..., Han [/bib_ref] compared the prognosis of an early corticosteroid administration group in which a steroid was administered within 72 hours after onset of inf luenza symptoms, a delayed administration group, and a nonadministration group and reported that the percentage of patients who progressed to a severe disease and the mortality were higher in the early administration group. Maravi-Poma et al. [bib_ref] Severe 2009 A/H1N1v influenza in pregnant women in Spain, Maravi-Poma [/bib_ref] analyzed the severe influenza treatment results among pregnant women and reported that the mortality tended to be higher in the corticosteroid administration group than in the nonadministration group although the difference was not statistically significant. A study conducted in Japan by al. [bib_ref] Collaborating Study Group on Inf luenza-Associated Encephalopathy in Japan. Treatment of pandemic..., Kawashima [/bib_ref] in which a survey was given to medical doctors who had treated pediatric inf luenza encephalopathy showed that the administration of a corticosteroid did not affect the treatment results. Brun-Buisson et al.analyzed 208 acute respiratory failure patients who had no other indication for corticosteroids other than acute respiratory failure and showed that the administration of a corticosteroid increased the mortality and the risk of hospital-acquired pneumonia, and particularly, early administration within 3 days after mechanical ventilation was correlated with increased mortality. Similar to the results of other studies, a study on viral pneumonia did not show a therapeutic effect for a steroid [bib_ref] Corticosteroid therapy in patients with primary viral pneumonia due to pandemic (H1N1)..., Diaz [/bib_ref]. There has not yet been a well-designed randomized controlled study to evaluate the effect of corticosteroid administration in severe influenza. Some clinical case series and case reports showed that the corticosteroid had a therapeutic effect. On the contrary, prospective cohort studies and retrospective comparative studies, which were conducted with larger study populations, showed that corticosteroid administration did not decrease mortality but rather increased complications. Therefore, in general, systemic corticosteroid administration for treatment of a severe influenza patient is not recommended (BII). The exception is that a corticosteroid could be considered for treatment of a disease for which the therapeutic effect of a corticosteroid has already been proven, such as asthma, COPD, and adrenal insufficiency (BIII). ## Other treatments key question 8: should intravenous immunoglobulin or statin injection or plasmapheresis be implemented for treatment of a severe influenza patient? - There is not sufficient evidence to recommend implementation of IVIG, statin, or plasmapheresis for treatment of a severe influenza patient. No randomized controlled study has been conducted with respect to whether the administration of IVIG may improve the prognosis of a severe inf luenza patient. Only a few case reports are available [bib_ref] Case of adult influenza type A virus-associated encephalopathy successfully treated with primary..., Sakurai [/bib_ref] [bib_ref] A case of acute respiratory distress syndrome associated with novel H1N1 treated..., Chong [/bib_ref] [bib_ref] Pooled human immunoglobulin therapy in critically Ill patients with pandemic 2009 inf..., Gordon [/bib_ref] [bib_ref] An adult case of influenza-associated encephalitis successfully treated with high dose intravenous..., Iwanaga [/bib_ref] [bib_ref] Clinical analysis of children with lymphoma complicated with severe pneumonia due to..., Zhang [/bib_ref]. Therefore, there is not sufficient evidence to recommend the administration of IVIG to a severe influenza patient. However, because all the case reports showed good prognosis after the administration of IVIG, according to the clinician's judgment based on the case reports, the administration of IVIG to a severe influenza patient could be considered. A statin, which is an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, blocks intracellular signal transduction via isoprenoid showing an anti-inflammatory effect, regulating immune response, and inhibiting cell growth. It has been known by many clinical studies that a statin is helpful in a pneumonia patient or sepsis patient because of its anti-inflammatory effect [bib_ref] Hackam DG. Statins and sepsis: multiple modifications at multiple levels, Terblanche [/bib_ref]. Vandermeer et al. [bib_ref] Association between use of statins and mortality among patients hospitalized with laboratory-confirmed..., Vandermeer [/bib_ref] analyzed with COPD patients showed that death by influenza and pneumonia and death by COPD were significantly lower in patients who used a moderate dose of statin (≥ 4 mg/day) [bib_ref] Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins, Frost [/bib_ref]. However, a retrospective case-control study conducted in the UK with the Influenza Clinical Information Network at the time of the pandemic H1N1 in 2009 showed that preadmission statin use did not affect the prognosis [bib_ref] Pre-admission statin use and in-hospital severity of 2009 pandemic influenza A (H1N1)..., Brett [/bib_ref]. A retrospective study conducted in Mexico with a small number of influenza patients admitted to an intensive care unit showed that the survival rate was higher in the cases where a statin was administered (pravastatin 40 mg/day). However, a prospective cohort study conducted in Spain with patients presenting pneumonia showed that any anti-inflammatory therapy did not improve the prognosis [bib_ref] Effect of immunomodulatory therapies in patients with pandemic influenza A (H1N1) 2009..., Viasus [/bib_ref]. Therefore, at present, there is not sufficient evidence to recommend statin use for severe inf luenza patients. However, according to a clinician's judgment based on the anti-inflammatory effect and several small-scale studies, statin use in a severe influenza patient could be considered. There are only a couple of clinical case reports with pediatric patients as the subjects in which plasmapheresis was conducted for the purpose of treating severe influenza in a severe influenza patient, not for the purpose of treating a complication such as thrombotic thrombocytopenic purpura (TTP), hemolytic anemia, Guillain-Barre syndrome, acute renal failure, and rhabdomyolysis. Patel et al. [bib_ref] Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1..., Patel [/bib_ref] reported that three pediatric patients who had been clinically exacerbated despite application of an antiviral agent, mechanical ventilation, ECMO, and vasopressor all recovered because plasmapheresis was performed. Kawashima et al. [bib_ref] Efficacy of plasma exchange and methylprednisolone pulse therapy on inf luenza-associated encephalopathy, Kawashima [/bib_ref] performed plasmapheresis with three pediatric patients presenting inf luenza encephalopathy in parallel with steroid administration or glucose and insulin combined treatment and reported that all the patients had recovered without a sequela. All the clinical case reports showed that plasmapheresis was effective, but the num-ber of subjects was too small and the effect has not been analyzed by a large-scale prospective randomized controlled study. Therefore, at present, there is not sufficient evidence to recommend implementation of plasmapheresis for a severe influenza patient. However, implementation of plasmapheresis could be considered in a case presenting a complication for which plasmapheresis has already been proven as an effective therapeutic method, such as TTP, hemolytic anemia, Guillain-Barre syndrome, acute renal failure, and rhabdomyolysis. # Conclusions limitations This guideline was designed to provide recommendations by searching as many studies as possible with a systematic literature review and by evaluating various therapeutic methods for severe inf luenza. However, there were not many study results which could be used as a basis for the recommendations, and domestic literature was particularly insuff icient. Therefore, this guideline may need to be revised by continuously conducting relevant studies in the future. In addition, when this guideline is applied to the treatment of individual patients, the application range of this guideline may be dependent on the state of each patient. In addition, specialists may have different opinions about the application of this guideline depending on each situation. ## Plan for revision Up-to-date results with respect to the recommendations in this guideline will be periodically reviewed every 3 years. The guideline will be revised if there are new research results which may provide an appropriate basis for the recommendations. This guideline provides the basic treatment principles appropriate to the circumstances in Korea as of November 2013 for the treatment of severe seasonal inf luenza. Therefore, rather than applying the suggestions provided in this guideline to all patients having severe influenza, it is appropriate to determine a treatment method according to the final decision of a physician depending on the clinical situation of individual patients based on this guideline. This guideline can be used individually for diagnosis, treatment, and education, but it should not be used for commercial purposes or for a review on the diagnosis and treatment of severe influenza. ## Conflict of interest To use this guideline for another purpose, an agreement should be acquired by submitting a written request to the Transgovernmental Enterprise for Pandemic Influenza in Korea (TEPIK). [fig] • 1 -: Definition of severe influenza: influenza corresponding to the definition of influenza-like illness (ILI; sudden onset of fever and cough or sore throat) and presenting at least one of the following clinical presentations: www.kjim.org http://dx.doi.org/10.3904/kjim.2014.29.Exacerbation of underlying chronic disease, including asthma, chronic obstructive pulmonary disease (COPD), chronic hepatic or renal insufficiency, diabetes mellitus, or other cardiovascular conditions -Any other influenza-related condition or clinical presentation requiring hospital admission [/fig] [table] Table 1: Database and search terms for the clinical guideline [/table] [table] Table 2: Number of selected references for each key question [/table] [table] Table 3: Recommendation of strength and evidence for recommendations [/table] [table] Table 4: Indication and contraindication of extracorporeal membrane oxygenation for influenza patients with acute respiratory distress syndrome [/table]	None	https://www.kjim.org/upload/kjim-29-1-_132-147.pdf	Background and purpose Severe influenza is defined as influenza with a severe symptom or syndrome such as respiratory distress or deceased consciousness or accompanying a severe complication such as encephalopathy or renal failure. In contrast to mild influenza, for which patients recover mostly by ambulatory care, severe influenza requires hospital admission in most cases or intensive treatment in the intensive care unit in some cases. In particular, the elderly, infants, and chronic patients are known to be at high risk for severe influenza because they may have accompanying complications such as exacerbation of an underlying disease, development of pneumonia, and another organ dysfunction or they may die. Therefore, there is an increasing need for an effective treatment method applicable to severe influenza. Severe influenza treatment methods, which have been recently discussed, include high-dose, long-term antiviral therapy, combination antiviral therapy, administration of antibiotics, application of extracorporeal membrane oxygenation (ECMO), administration of a corticosteroid, administration of intravenous immunoglobulin (IVIG), application of plasmapheresis, and administration of a statin. However, no comprehensive, specific expert guideline for these methods is available yet. The Transgovernmental Enterprise for Pandemic Influenza in Korea published in 2012 a guideline for the use of an antiviral agent for seasonal influenza. But the guideline deals with only the use of an antiviral agent, not the various treatment methods which can be applied to severe influenza [1]. Therefore, this guideline was developed by analyzing and evaluating domestic and international literature and guidelines with respect to the various treatment methods so that severe influenza could be effectively treated.
14a68cc3f40426f5e37240935b910f52e0c4627f	pubmed	Dutch Guideline on Knee Arthroscopy Part 1, the meniscus: a multidisciplinary review by the Dutch Orthopaedic Association	Dutch Guideline on Knee Arthroscopy Part 1, the meniscus: a multidisciplinary review by the Dutch Orthopaedic Association ## Funding and potential conflicts of interest The guideline development was financially supported by the Dutch Orthopaedic Association (NOV), using governmental funding from the Quality Foundation of the Dutch Association of Medical Specialists in the Netherlands. The authors declare that there is no relevant conflict of interest. # Method ## Guideline panel In November 2016, a guideline panel, tasked with revising the guideline, was formed consisting of orthopedic surgeons, a radiologist, a trauma surgeon, a physiotherapist, and a sports medicine specialist. A methodologist from the Knowledge Institute of the Federation of Medical Specialists supported the guideline panel by ensuring proper design and systematic evidence-based development of the guideline using the GRADE methodology, to meet all the criteria of the AGREE instrument. # Methodology and workflow The guideline was developed in agreement with the criteria set by the advisory committee on guideline development of the Federation Medical Specialist in the Netherlands, which are based on the AGREE II instrument. The guideline was developed using an evidence-based approach endorsing the GRADE methodology, and meets 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 . The guideline development process involves a number of phases: a preparatory phase, a development phase, a commentary phase, and an authorization phase. After authorization, the guideline has to be disseminated and implemented. Furthermore, uptake and use must be evaluated. Finally, the guideline must be kept up-to date. Each phase involves a number of practical steps . As a first step in the early preparatory phase, a broad forum discussion was held and all relevant stakeholders were consulted to define and prioritize key issues, which were extensively discussed in the guideline panel. The selected, highpriority issues were translated into carefully formulated clinical questions. These questions defined patient problems, intervention, comparison, and outcomes. Furthermore, the patient out-comes relevant to decision-making were prioritized and minimal clinically important differences were defined. In the development phase, the literature was systematically searched using the databases MEDLINE and Embase. Selection of the relevant literature was based on predefined inclusion and exclusion criteria and was carried out by 1 member of the guideline panel (EvA) in collaboration with the methodologist (BS). 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 1 of 4 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 guideline panel member considering any additional arguments relevant to the clinical question, including patient values, preferences, and resource use (costs, organization of care issues). Evidence synthesis, complementary arguments, and concept recommendations were extensively discussed in the guideline committee. Final recommendations were then formulated. The final recommendations are based on the balance between 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 would 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 weighing all relevant arguments together. This includes the weight of the body of evidence from the systematic literature analysis, and also the weight of all complementary arguments formulated, the so-called considerations. When using the GRADE approach, guideline panels must use judgment in integrating these arguments to make a strong or weak recommendation. Thus, although low quality of the body of evidence from the systematic literature analysis will generally result in a weak recommendation, it does not a priori exclude a strong recommendation, and weak recommendations may also result from high-quality evidence . After reaching consensus from the guideline panel, the concept guideline was subjected to peer review by all the relevant stakeholders: the commentary phase. Amendments were made and agreed upon by the guideline panel, and the final text was presented to the Dutch Orthopedic Association (NOV), the Dutch Society for Radiology (NVvR), the Royal Dutch Society for Physical Therapy (KNGF), the Dutch Sports Medicine Association (VSG), and the Association of Surgeons of the Netherlands (NVvH) for authorization. In this authorization phase, additional amendments were made to the guideline text based on the outcome of a general assembly of the NOV. The guideline was finally approved and officially authorized by the NOV in March 2019. ## Recommendation - Do not perform arthroscopy based on 1 or more meniscus tests without additional information from history, physical examination, and any additional radiological examination. 2. What is the place of imaging techniques such as conventional radiographs, MRI, and ultrasound in the diagnostic process? ## Recommendation - Perform imaging, such as conventional radiographs and/or MRI, before performing an arthroscopy. - Perform an MRI in addition to history and physical examination in patients younger than 50 years, unless there is a high a priori chance of intra-articular injury. In that case an arthroscopy without MRI is indicated (provided conventional radiograph is done). A high a priori chance is defined as: history of a traumatic moment, hydrops, and a locked knee. - Do not routinely perform MRI in patients older than 50 years with knee complaints, but start with an AP and lateral radiograph of the knee, preferably with fixed flexion at 20°. - Be cautious when applying ultrasound in the indication for arthroscopy due to insufficient visibility of (intra)osseous and intra-articular structures of the knee. ## What is the additional value of ct and mri arthrography compared with conventional mri in patients with a meniscus repair after injury? ## Recommendation - Consider (direct) MR arthrography over conventional MRI as additional diagnostics for persistent complaints after an arthroscopic treatment of a meniscal injury. ## Which meniscus injuries should be treated, when and how? ## Recommendation Acute meniscal injury - Perform arthroscopy within 2 weeks of injury when a patient has a locked knee with the most likely cause of a ruptured meniscus. - Always consider meniscal repair or follow a wait-and-see policy. Meniscal injury does not necessarily mean meniscectomy. - Leave the peripheral rim of the meniscus intact. - Always try to repair a meniscal tear in young patients if the tear is in the vascularized part of the meniscus. Here, a stable knee or an unstable knee that is stabilized within 6 weeks is indispensable. Degenerative meniscus injury - Start with nonoperative treatment in degenerative meniscus injury. - Consider treating nonoperatively for at least 3 months in the event of a meniscal tear. ## What is the added value of physiotherapy after arthroscopic meniscus surgery of the knee? ## Recommendation - Do not refer patients with an expected normal recovery to the physiotherapist after a meniscectomy. - Discuss with the patient with a delayed recovery the expected effects of physical therapy. # Discussion The guideline is aimed at providing evidence-based advice to medical specialists and physiotherapists, in order to minimize unwarranted variation in treatment of meniscus injuries and to improve the therapeutic results. The 1st question concerned the values of diagnostic meniscus tests. The execution of meniscus tests is part of the standard physical examination during consultation, in all patients with (non)traumatic knee complaints. Other findings during the physical examination, such as a locked knee, or swelling of the knee, may also support the suspicion of meniscal disease. A locked knee may be a reason to qualify a patient for arthroscopy without prior MRI, provided a conventional weightbearing knee radiograph has been taken to exclude other pathology. Analysis of the literature clearly shows that performing meniscus tests alone, separately or in combination is diagnostically insufficiently accurate. In a combination of both a negative Thessaly and McMurray test, the presence of a meniscal injury is unlikely. Further caution with the use of meniscus tests is appropriate if there is concomitant ligamentous injury such as an anterior cruciate ligament rupture. This further decreases the reliability of the meniscus tests. Additional information from demographic factors, history, physical examination, and possibly additional examination (MRI) has to support the diagnosis before treatment decisions can be made. The 2nd question concerned the place and reliability of imaging of ultrasound compared with MRI techniques in the diagnostic process. Prior to arthroscopy osseous pathology (fracture, neoplasm, and infectious processes such as osteomyelitis) should be excluded by imaging. A general MRI scanning protocol, suitable for the assessment of menisci, ligaments, and cartilage, should consist of scans in different planes: sagittal, coronal, and, where relevant, axial. In the choice of 35 sequences at least a combination of short TE (T1-or PD-weighted images) and T2-weighted images with or without fat suppression should be used. Because there is a learning curve in reading of MR images, experience and training of the reader will increase the accuracy of MRI . Experience of the reader has more influence on accuracy of MRI than field strength of the system . Therefore, reading of the MRI by a (musculoskeletal) radiologist, with adequate training and experience, is essential to achieve the highest accuracy. A limited number of studies, compared with those on MRI, indicate that ultrasound of the knee can be accurate in the assessment of menisci and cruciate ligaments. Transducers used in the aforementioned studies ranged from 5 to 14 MHz. No information is available on the influence of the frequency of transducers on accuracy, but higher frequencies yield higher resolution images, probably increasing accuracy. Cartilage can be evaluated only to a minor extent. Bone and bone marrow cannot be assessed with ultrasound. This seriously limits the diagnostic yield of ultrasonography when compared with MRI. The learning curve for performing musculoskeletal ultrasound is considerable, because not only the interpretation of the obtained images but also eye-hand coordination benefits greatly from training and experience. Therefore, ultrasonography is only a reliable diagnostic tool in the hands of an experienced musculoskeletal ultrasonographer. Advocates of ultrasound point to the fact that availability of ultrasound machines is higher than that of MRI systems. This may be true, but the limiting factor will probably be the availability of adequately trained and experienced ultrasonographers. The disadvantage compared with MRI is that the ultrasonographer has to perform the examination in person to make an adequate report, whereas MRI can be reported by a radiologist independent of moment and location of examination. This facilitates plan-care has changed in recent years. It is now preferable to repair a meniscus and if not possible then to perform an arthroscopic partial meniscectomy. Xu and Zhao (2015) undertook a metaanalysis of the comparison between meniscus repair and a meniscectomy with better outcomes for meniscus repair. There is currently insufficient scientific evidence to determine when and which meniscal lesions should be repaired or removed to obtain optimal outcomes in the short and longer term. However, it seems more prudent to have low-threshold suturing in younger patients with a lateral meniscal injury than to perform a partial meniscectomy because of the long-term results after lateral meniscectomy . The working group considers meniscus tears to be repairable when they are torn close to or separated from the knee joint capsule, or a longitudinal tear in the peripheral part the "so-called red-red zone" where the healing potential is best because of the vascularization, provided that the torn meniscus tissue is of good quality and the knee is stable. This usually concerns traumatic meniscal tears. Spontaneous healing of meniscal injuries has also been extensively described, both in combination with anterior cruciate ligament rupture and with isolated meniscal injuries. The working group is of the opinion that in the case of a peripheral longitudinal tear of the meniscus proven on MRI and no restriction of movement in the knee, a wait-and-see policy can be pursued. Due to the chance of spontaneous healing, overtreatment may result. Recovery after meniscus repair takes longer than partial meniscectomy. No evidence-based post-treatment protocol is available, but it is generally advised to do partial weightbearing for 4 to 6 weeks and limit flexion to 90 degrees. Return to sport level is advised after 3 to 6 months. Postoperative rehabilitation should be discussed explicitly with a top athlete so that a well-considered decision can be made with regard to repair or partial meniscectomy. We recommend a different approach to medial vs. lateral meniscus tears. The younger the patient, the more aggressive the surgeon should be in repair of the lateral meniscus. And in the case of a bucket-handle tear in combination with an anterior cruciate ligament rupture, meniscus repair should be performed in combination with an ACL reconstruction. The second part of the 4th question concerns degenerative menisci, as regards treatment of degenerative meniscal tears. Most studies concerning degenerative meniscus injury used 3 months as the "short-term follow-up." During the first 3 months after surgery and nonoperative treatment, a reduction in complaints was measured and the difference in effect of treatment between the two groups seemed minimal. This minimal difference continued up to 24 months. In case of nonobstructive meniscus complaints, conservative treatment is therefore preferable to surgery for the first 3 months after initiations of complaints. The working group has set the age limit for degenerative meniscal injuries to > 50 years, but this is open to debate. The reason for choosing 50 years was to stay in line with the knee osteoarthritis guideline and the asso-ning. An MRI scan consists of multiple images of predefined thickness and interval in at least two orthogonal planes. This means every orthopedic surgeon or radiologist can identify and locate pathology in the knee based on information visible in these images. Because ultrasound is a dynamic examination and the number of obtained images, orientation, and quality of images is entirely operator-dependent; only the reporter/ultrasonographer can extract all the information from an examination. Others will have to rely on the report. This will diminish the added value of ultrasound in preoperative planning or in giving the patient insight into the pathology. When arthroscopy is warranted, MRI can be used to exclude (oncologic) osseous pathology and radiography is not required. Ultrasound cannot fulfill that role because visualization of osseous structures is insufficient. Additional imaging (radiography) is required. This means that ultrasound cannot be a stand-alone diagnostic tool before arthroscopy. Another disadvantage of ultrasound is the inability to visualize bone marrow changes at all, or cartilage in a sufficient manner. Bone bruising or focal chondral lesions can mimic meniscal pathology and the bone bruise pattern can point to specific trauma mechanisms and associated pathology. And one could also assume the use of ultrasound in obese patients is limited. Compared with MRI, ultrasound therefore lacks in completeness. In our opinion, MRI is the diagnostic imaging of choice in patients younger than 50 years and without history of locking or catching or extension deficit (history of trauma, effusion, and extension deficit) . Ultrasound is not equivalent. The 3rd question involved patients with persistent complaints after repair. MR arthrography may have additional value over conventional MRI, as there is evidence that MR arthrography has a higher accuracy for detecting unhealed or re-ruptured menisci. The cost of the study is likely to be higher due to the use of intra-articular contrast. There will also be a higher risk of complications due to the (minimally) invasive nature. No literature data is available showing which strategy (conventional MRI and possibly additional MR arthrography, MR arthrography alone, or direct second-look arthroscopy) is preferable from the point of view of cost-effectiveness or clinical outcome. CT arthrography is also believed to have higher accuracy for detecting unhealed or torn menisci than with conventional MRI. However, no article was included in our literature search confirming this. De examined CT arthrography in patients with MRI contraindication, but studies comparing different imaging modalities are lacking. Availability, expertise, and local customs also play a role in these considerations. The 4th question addressed the treatment of acute meniscus injury and degenerative meniscal lesions. Concerning acute meniscal injury, the working group is of the opinion that studies more than 8 years old, comparing total meniscectomy with partial meniscectomy, are no longer relevant, because standard ciated radiographic diagnostics. Progressive insight shows that lowering the age of 45 years produces the same results and thus can also be considered. Perhaps in the future the age recommendation will further decrease to 35 years, but more research is needed. The5th question addressed physical therapy. Physical therapy is an intervention that entails hardly any risks or complications. In the Netherlands, the first 20 physiotherapy treatments after surgery are reimbursed by the patient's additional insurance. From the 21st treatment onward, reimbursement from the basic insurance applies up to 12 months after the meniscectomy. If the patient has less than 20 treatments in his additional insurance, he will therefore have to pay for physiotherapy treatments him-or herself. Today's society demands a return to work as soon as possible and physiotherapy may be able to contribute to this. In addition, it is often the wish of the patient to be able to quickly return to the old level, particularly when it comes to sports. In certain professional groups (top athletes, heavy physical work), counseling in postoperative recovery can therefore be useful, also to prevent secondary injuries. For example, it may be useful to monitor a top athlete more frequently in connection with a step-by-step build-up. This group of patients often ignore symptoms because they want to get back into competition quickly or because of pressure from the media, the coach, the team, or the athletes. It is not only the type and treatment of meniscal injury that determines whether the patient should be referred to a physiotherapist, but more whether there is normal or (expected) delayed recovery. In the Royal Dutch Physical Therapists (KNGF) meniscectomy guideline two patient profiles are distinguished. Patient profile 1 concerns patients after partial meniscectomy who require little or no physical therapy because of expected normal recovery. These are usually the younger patients with an acute injury of the meniscus, with a blank history. Physiotherapy is desirable in this group only if there is comorbidity (such as an ACL rupture) or fear of movement. Patient profile 2 are patients with a burdened history of previous knee surgeries, in whom the complaints have arisen after repeated (micro)trauma, causing multiple and recurrent ruptures in the meniscus. This may be a sign of nascent osteoarthritis, but the distinction between meniscus pathology and early stage degenerative knee disease may not be clear. These patients are at high risk of delayed recovery and physical therapy is indicated. Other signs of delayed recovery are insufficient increase in function (mobility, gait pattern) and insufficient increase or even decline in activities and participation. In that case, physical therapy can help improve mobility and gait recovery, and increase strength and neuromuscular control, which may also increase activity and participation. However, as discussed in this guideline, in most cases these patients are no longer even eligible for arthroscopy and therefore should be treated nonoperatively. This guideline was composed for arthroscopic treatment of knee injuries. Here we present our recommendations concerning the meniscus. We should keep in mind that there is a continuum from a traumatic meniscal injury at a younger age to a degenerative meniscal lesion around midlife. We have changed our thoughts from performing partial meniscectomy in the case of meniscal lesions to first considering nonoperative treatment before meniscal repair. If surgery is indicated and meniscal repair is not possible partial meniscectomy should be considered. Spontaneous decrease in pain with meniscus lesions is possible. We should be aware that a degenerative meniscus lesion is one of the first signs of osteoarthritis of the knee. (2) and the pooled specificity 84% (CI 69-92). The positive likelihood ratio (LR+) was 3.2 (CI 1.7-5.9) and the negative likelihood ratio (LR-) was 0.52 (CI 0.34-0.81). In other words, information from McMurray's test contributes only mildly to the probability that the patient in question has a meniscal injury. ## Apley's test In the systematic review of, the Apley's test data was not pooled due to insufficient data. 2 studies included in the review ## Thessaly's test In the systematic review ofthe pooled sensitivity for Thessaly's test at 20° was 75% (CI 53-89) and the pooled specificity 87% (CI 65-96). The positive likelihood ratio (LR+) was 5.6 (CI 1.5-21.0) and the negative likelihood ratio (LR-) was 0.28 (CI 0.11-0.71). The data of the Thessaly test at 5° was not pooled due to insufficient data.reported a sensitivity of 64% (CI 60-68) for medial and/or lateral meniscus tears. The corresponding specificity was 53% (CI 43-63). The reported LR+ and LR-were 1.37 (CI 1.10-1.70) and 0.68 (CI 0.59-0.78). Although the results of Goossens are not in line with the pooled estimates from, we suggest that Thessaly's test contributes only mildly to the probability that a patient has a meniscal injury. ## Joint line tenderness (jlt) test In the systematic review ofthe pooled sensitivity for the JLT test at 20° was 83% (CI 73-90) and the pooled specificity 83% (CI 61-94). The LR+ was 4.0 (CI 2.1-7.5) and LR-was 0.23 (CI 0.12 to 0.44). In other words, information from the JLT test contributes only mildly to the probability that the patient in question has a meniscal injury. also evaluated the combination of the Thessaly test followed by the McMurray test. ## Supplementary data ## Combination of physical tests The combination of tests contributes only mildly to the probability of meniscal injury. Although the sensitivity of a combined negative test score is higher than 70%, this result contributes only mildly to the probability of having a meniscus injury. With other words, not much information is gained after performing the Thessaly test followed by the McMurray test. ## Level of evidence There are 4 levels of evidence: high, moderate, low, and very low. RCTs start with a high level of evidence. McMurray's test: The level of evidence for McMurray's test is moderate, as 1 study used MRI as the reference standard, which consequently was the largest study in the metaanalysis (indirectness). Apley's test: As the results of Apley's test could not be pooled because of insufficient data, the level of evidence could not be evaluated. Thessaly's test (at 20°): The level evidence for Thessaly's test is moderate, as 1 study used MRI as the reference standard, which consequently was the largest study in the metaanalysis (indirectness). ## Joint line tenderness test: The level evidence for the JLT test is moderate, as 1 study used MRI as the reference standard, which consequently was the largest study in the metaanalysis (indirectness). ## Thessaly's test (at 20°) followed by mcmurray's test: the level of evidence is high. Question 2 ## Mri medial meniscal injury In the systematic review of, the pooled sensitivity and specificity of MRI for detection of medical meniscal tears were 0.89 (CI 0.83-0.94) and 0.88 respectively. This means that 11% of patients with meniscal tears could be missed, and 12% of patients could have meniscal tears while the MRI diagnosis was normal. The pooled LR+ was 8.0 ) and the pooled LR-was 0.1 (CI 0.7-0.2). In the systematic review of, the pooled sensitivity and specificity of 3T MRI to diagnose medial meniscal injury were 0.94 (CI 0.91-0.96) and 0.79 (CI 0.75-0.83) respectively. ## Lateral meniscal injury In the systematic review of, the pooled sensitivity and specificity of MRI for detection of lateral meniscal tears were 0.78 (CI 0.66-0.87) and 0.95 (CI 0.91-0.97) respectively. The pooled LR+ was 14.5 and the pooled LR-was 0.2 (CI 0.2-0.4). In the systematic review of, the pooled sensitivity and specificity of 3T MRI to diagnose lateral meniscal injury were 0.81 (CI 0.75-0.85) and 0.87 (CI 0.84-0.89) respectively. ## Knee cartilage lesions In the systematic review of, the pooled sensitivity and specificity of MRI for detection of knee cartilage lesions were 0.75 (CI 0.62-0.84) and 0.94 (CI 0.89-0.97) respectively. The pooled LR+ was 13 (CI 6.5-24) and the pooled LR-was 0.27 . In the systematic review of, no metaanalysis was performed. The sensitivity of MRI for detection of articular cartilage abnormalities among included studies ranged from 0.29 to 0.96 and the specificity ranged from 0.50 to 1.00. ## Ultrasonography (us) ## Meniscal injury The meta-analysis ofshowed a moderate pooled sensitivity of 0.88 (CI 0.84-0.91) and a high specificity of 0.90 (CI 0.86-0.93) of US in diagnosing meniscal injury. This means that 12% of patients with meniscal injury could be missed, and 10% of patients could have meniscal injury while the ultrasonography diagnosis is normal. The pooled LR+ was 7 (CI 4-12) and the LR-was 0.17 (CI 0.10-0.26). There was moderate to high heterogeneity of these values (73% for sensitivity and 61% for specificity). Therefore, a sensitivity analysis was performed by excluding each study. This analysis decreased the heterogeneity, but the results were similar to the overall results. The systematic review ofincluded only 3 studies evaluating the diagnostic accuracy of ultrasound in the diagnosis of meniscal injury and only one study in the diagnosis of ACL injury. The results of these study were not shown, and no meta-analysis was performed. However, all three studies were included in the meta-analysis of. In the systematic review ofthe pooled sensitivity and specificity for diagnosing meniscal injury using US were 0.78 (CI 0.75-0.80) and 0.84 (CI 0.82-0.86) respectively. However, in this pooled analysis the data of 9 studies published before 2006 were also included. The diagnostic per-formance of US was specified for each included study for different meniscal injuries (lateral, medial, total). ## Level of evidence mri and meniscal injury: The level of evidence for diagnosing meniscal injury was downgraded by 1 level because of limitations in the study design (risk of bias, due to patient selection (nonrandomized) and interpretation of MRI). ## Mri and chondral lesions: The level of evidence for diagnosing chondral lesions was downgraded by 2 levels because of limitations in the study design (risk of bias, due to patient selection (nonrandomized) and interpretation of MRI) and inconsistency of results (wide variance of point estimates across studies). Ultrasonography: The level of evidence for diagnosing meniscal injury was not downgraded. ## Question 3 RCTscompared the accuracy of nonenhanced MRI with that of intraarticular contrast-enhanced direct MRI arthrography and intravenous contrast-enhanced indirect MRI arthrography for detection 10 of recurrent meniscal tears. 41 patients previously treated for a meniscal tear were randomized into 3 groups: conventional MRI, indirect arthrography (intravenous contrast), and direct arthrography (intraarticular contrast). All patients underwent a second-look arthroscopy (i.e., the gold standard).investigated the accuracy of conventional MRI, direct MRI arthrography, and indirect MRI arthrography in assessment of possible recurrent or residual meniscal tears. 364 patients were prospectively examined. However, only 94 patients underwent a second-look arthroscopic surgery (i.e., the gold standard). It was unclear why only 94 patients underwent a second-look arthroscopy and whether these patients were a representative (randomized) sample.evaluated the diagnostic value of direct MRI arthrography in detection of re-torn or unhealed menisci that were previously repaired. 24 symptomatic patients were included, all of whom underwent a second-look arthroscopy (i.e., the gold standard). Authors decided to include patients who received an arthroscopy for both diagnostic and therapeutic purposes.assessed the accuracy of conventional MRI and direct MR-arthrography in the diagnosis of meniscal retears as compared with arthroscopy. 100 patients were included. All patients underwent a second-look arthroscopy (i.e., the gold standard). ## Observational studies ## Accuracy All included studies reported data on the accuracy of the arthrography. LR+ and LR-were calculated using the reported sensitivity and specificity. The accuracy of a direct MR arthrography was high in all 4 studies. Results were consistent across all parameters of accuracy. The accuracy of an indirect MR arthroscopy was reported by only 2 studies. 1 studyreported that the accuracy was high (LR+ > 10 and a LR-< 0.1). The accuracy in another studywas somewhat lower, however, and pointed in the same direction. 3 of the 4 included studies evaluated the diagnostic accuracy of the conventional MRI. All 3 studies suggested that the diagnostic accuracy is moderate. Overall, direct MR arthrography seemed to be able to diagnose a recurrent meniscal tear in a patient with complaints after a therapeutic arthroscopy. There was no difference in the results from an RCT or a cohort study. ## Costs None of the included studies reported any data on costs.anddid not report the number of recurrent meniscal tears. Othersfound 71 recurrent meniscal tears; however, it was unclear among how many patients.reported that among 100 patients 94 had a meniscal retear. The results from the last 2 studies cannot be pooled or compared to draw a conclusion. ## Clinical outcome: meniscal retears Level of evidence Accuracy: The level of evidence was downgraded by 2 levels because of risk of bias (in 3 of 4 studies the results of the arthroscopy (i.e., the gold standard) were not interpreted blinded from the imaging results), imprecision (less than 300 patients included in total). Costs: None of the included studies reported data on the costs. Clinical outcome: It was not possible to assess the level of evidence as the results from 2 studies could not be pooled or compared. ## Question 4 ## Patients with (acute) traumatic meniscus injury No studies were included as none of the studies met the selection criteria.in a meta-analysis determined the effects and complications of arthroscopic sur-gery compared with nonoperative management strategies in patients with degenerative knee disease. 13 RCTs were included to inform on effects of knee arthroscopy and 15 studies (12 observational studies and 3 RCTs) provided data on the complications of knee arthroscopy. ## Patients with a degenerative meniscal tear ## Pain Short-term benefits (< 3 months) were reported in 10 RCTs. The pooled difference in change from baseline was on average 5.4 (CI 1.9-8.8). Long-term benefits (1 to 2 years) were reported in 8 RCTs. The pooled difference in change from baseline was on average 3.1 (CI 0.2-6.4). The benefits of arthroscopy in pain scores, both short and long-term, were no different from that of nonoperative treatment. ## Function Short-term data on function was available in 7 studies and long-term data in 6 studies. The mean score difference from baseline in function after 3 months was 4.9 (CI 1.5-8.4) in favor of arthroscopy and after 1 to 2 years 3.2 (CI 0.48-6.8). ## Complications In line with the recommendation, the working group chose to report the outcomes venous thromboembolism (VTE) and infections as potential complications. The difference in proportion of patients with a VTE between arthroscopy versus nonoperative management was 5 per 1,000 patients (CI 2-10). Arthroscopy may have a small risk of VTE. For infections, the difference between arthroscopy versus conservative management was 2 per 1,000 patients (CI 1-4). Arthroscopy may have a very small risk of infection. ## Level of evidence Pain: The level of evidence for the outcome pain (both shortand long-term) was not downgraded. Although risk of bias due to lack of blinding was a concern in most trials, trials with a low risk of bias reported similar results to those in which there were risk of bias concerns. Function: The level of evidence for the outcome function (both short-and long-term) was downgraded by 1 level due to serious risk of bias and borderline imprecision. Complications: The level of evidence for the outcomes VTE and infections were both downgraded by 2 levels due to serious risk of bias and serious inconsistency. There was no evidence of publication bias. measured pain using a visual analogue scale (VAS), which ranged from 0 to 10 (none to most pain). reported that pain was lower in patients who received physical therapy after arthroscopy compared ## Question 5 ## Pain	None	https://www.tandfonline.com/doi/pdf/10.1080/17453674.2020.1850086?needAccess=true	Background and purpose — A guideline committee of medical specialists and a physiotherapist was formed on the initiative of the Dutch Orthopedic Association (NOV) to update the guideline Arthroscopy of the Knee: Indications and Treatment 2010. This next guideline was developed between June 2017 and December 2019. In this Part 1 we focus on the meniscus, in Part 2 on all other aspects of knee arthroscopy. Methods — The guideline was developed in accordance with the criteria of the AGREE instrument (AGREE II: Appraisal of Guidelines for Research and Evaluation II) with support of a professional methodologist from the Dutch Knowledge Institute of Medical Specialists. The scientific literature was searched and systematically analyzed. Conclusions and recommendations were formulated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Recommendations were developed considering the balance of benefits and harms, the type and quality of evidence, the values and preferences of the people involved, and the costs.
345b0908c0a59839b374490913026d2e664d4fd0	pubmed	Headache in children	Headache in children Headache in children 2013Headache in children The Journal of Headache and Pain 1413201310.1186/1129-2377-14-S1-O3O R A L P R E S E N T A T I O N Cite this article as: Prabhakar: Headache in children. One in 30 children who attend primary school have a headache problem which has an impact on the child and family. However, the problem is under recognised and under treated. In children, identifying a primary headache syndrome can be challengining. However, it can be achieved in a focussed consultation undertaking appropriate history and examination. The course aims to cover the common pitfalls and red flags in the diagnosis of primary headache disorders in childhood and treatment startegies.	None	https://thejournalofheadacheandpain.biomedcentral.com/track/pdf/10.1186/1129-2377-14-S1-O3	None
692c457cdb4dc7c7f50b372c9151f1d26fa74a87	pubmed	JPN Guidelines for the management of acute pancreatitis: diagnostic criteria for acute pancreatitis	JPN Guidelines for the management of acute pancreatitis: diagnostic criteria for acute pancreatitis Clinical questions CQ1. Are clinical symptoms and signs useful in diagnosing acute pancreatitis? CQ2. Which pancreatic enzymes should be measured to diagnose acute pancreatitis? CQ3. What is the optimal examination for diagnosing acute pancreatitis? CQ4. Is US effective in diagnosing acute pancreatitis? CQ5. Is MRI effective in diagnosing acute pancreatitis? CQ6. Is CT effective in diagnosing acute pancreatitis? CQ7. Are plain X-ray examinations useful in diagnosing acute pancreatitis? CQ8. Is the etiology of a specific case of acute pancreatitis necessary for its diagnosis? -Ultrasonography (US) is also one of the procedures that should be performed in all patients with suspected acute pancreatitis. -Magnetic resonance imaging (MRI) is one of the most important imaging procedures for diagnosing acute pancreatitis and its intraperitoneal complications. -Computed tomography (CT) is also one of the most important imaging procedures for diagnosing acute pancreatitis and its intraabdominal complications. CT should be performed when a diagnosis of acute pancreatitis cannot be established on the basis of the clinical findings, results of blood and urine tests, or US, or when the etiology of the pancreatitis is unknown. -When acute pancreatitis is suspected, chest and abdominal X-ray examinations should be performed to determine whether any abnormal findings caused by acute pancreatitis are present. -Because the etiology of acute pancreatitis can have a crucial influence on both the treatment policy and severity assessment, it should be evaluated promptly and accurately. It is particularly important to differentiate between gallstone-induced acute pancreatitis, which requires treatment of the biliary system, and alcohol-induced acute pancreatitis, which requires a different form of treatment. Key words Acute pancreatitis · Criteria for diagnosing acute pancreatitis · Laboratory diagnosis · Computed tomography Offprint requests to: M. Koizumi * President, Japanese Society of Emergency Abdominal Medicine; President, Japanese Society of Hepato-Biliary-Pancreatic Surgery; President, Asian-Pacific Hepato-Pancreato-Biliary Association Chairman, Intractable Pancreatic Disease Investigation and Research Group of the Japanese Ministry of Health, Labour, and Welfare * President, Japan Pancreas Society # Abstract The currently used diagnostic criteria for acute pancreatitis in Japan are presentation with at least two of the following three manifestations: (1) acute abdominal pain and tenderness in the upper abdomen; (2) elevated levels of pancreatic enzyme in the blood, urine, or ascitic fluid; and (3) abnormal imaging findings in the pancreas associated with acute pancreatitis. When a diagnosis is made on this basis, other pancreatic diseases and acute abdomen can be ruled out. The purpose of this article is to review the conventional criteria and, in particular, the various methods of diagnosis based on pancreatic enzyme values, with the aim of improving the quality of diagnosis of acute pancreatitis and formulating common internationally agreed criteria. The review considers the following recommendations: -Better even than the total blood amylase level, the blood lipase level is the best pancreatic enzyme for the diagnosis of acute pancreatitis and its differentiation from other diseases. -A pivotal factor in the diagnosis of acute pancreatitis is identifying an increase in pancreatic enzymes in the blood. # Introduction The diagnosis of acute pancreatitis has been based on the clinical manifestations and results of bloodbiochemistry tests, but there are few common criteria that strictly specify the parameters to be used in diagnosis. The criteria currently used to diagnose acute pancreatitis in Japan were originally developed by the Research Group for Intractable Diseases and Refractory Pancreatic Diseases, which was sponsored by the Japanese Ministry of Health and Welfare (now the Japanese Ministry of Health, Labour, and Welfare). The Research Group states that acute pancreatitis should be diagnosed if the patient presents with at least two of the following three criteria: (1) acute abdominal pain and tenderness in the upper abdomen; (2) elevated levels of pancreatic enzymes in blood, urine, or ascitic fluid; and (3) the presence of abnormal imaging findings in the pancreas that are associated with acute pancreatitis. When a diagnosis is made on this basis, other pancreatic diseases and acute abdomen can be ruled out. In Japan, many surgeons and physicians specializing in digestive system diseases and emergency medicine are familiar with abdominal ultrasonography (US) and perform it routinely. Magnetic resonance imaging (MRI) is less popular than X-rays or computed tomography (CT) scanning and is not a routine procedure in emergency examinations for abdominal diseases. The purpose of this article is to review the conventional criteria and, in particular, the various methods of diagnosis based on pancreatic enzyme values, with the aim of improving the quality of the diagnosis of acute pancreatitis and of formulating common, internationally agreed upon criteria. ## Diagnostic criteria ## Clinical symptoms and signs Clinical question (CQ) 1. Are clinical symptoms and signs useful in diagnosing acute pancreatitis? ## It is essential to interview all patients (including those with consciousness disorders or who are in a state of shock), take their medical histories, and perform a physical examination (recommendation a) Abdominal pain, pain radiating to the back, anorexia, fever, nausea and vomiting, and decreased bowel sounds are frequent manifestations of acute pancreatitis (Tables 1 and 2) (Level 4). 1,2 However, these features are not specific to acute pancreatitis, and when a patient presents with these manifestations, acute pancreatitis must be differentiated from other acute abdominal diseases. Acute pancreatitis accounts for 2% to 3% of all acute abdominal diseases (Level 2b, unknown) 3,4 and in a very few patients there is no abdominal pain (Level 2b). 5 tis are 85% to 100% and 84.7% to 99.0% (Level 2a), [bib_ref] Lipase and pancreatic amylase activities in tissues and in patients with hyperamylasemia, Apple [/bib_ref] respectively. The blood lipase value is more sensitive than blood amylase (Levels 2b-4) 11-13 and provides diagnostic capability similar to that of blood P-amylase (Level 2b). [bib_ref] Normal amylase levels in the presentation of acute pancreatitis, Orebaugh [/bib_ref] Blood lipase is considered a valuable diagnostic tool, because abnormally high values persist for longer than abnormal blood amylase levels (Level 2b), [bib_ref] Serum lipase: a better test to diagnose acute alcoholic pancreatitis, Gumaste [/bib_ref] and it is more sensitive in terms of detecting the presence of acute alcohol-induced pancreatitis. The combined use of blood amylase and blood lipase levels (Level 2a) [bib_ref] Lipase and pancreatic amylase activities in tissues and in patients with hyperamylasemia, Apple [/bib_ref] does not facilitate the diagnosis of acute pancreatitis. The above findings lead to the conclusion that the blood lipase level is an important indicator in the diagnosis of acute pancreatitis and that the measurement of the blood lipase level should be given top priority. Measurement of the lipase level is of primary importance when the blood amylase level of a patient suspected of having acute pancreatitis is normal. ## Blood amylase (blood total amylase) ## Cq3. what is the optimal examination for diagnosing acute pancreatitis? ## Identifying an increase in the level of pancreatic enzymes in the blood is a pivotal factor in the diagnosis of acute pancreatitis (recommendation a) When the cutoff blood amylase level is set at the upper limit of normal, it has a sensitivity of 91.7% to 100% and a specificity of 71.6% to 97.6% for the diagnosis of acute pancreatitis. If the cutoff level is set higher, specificity Acute pancreatitis is sometimes manifested by discoloration of the skin, such as Grey Turner's sign (on the lateral abdominal wall), Cullen's sign (around the navel), and Fox's sign (over the lower portion of the inguinal ligament). However, because these signs appear in only 3% (Level 2b) [bib_ref] The incidence and prognosis of body wall ecchymosis in acute pancreatitis, Dickson [/bib_ref] of patients, and because they are also observed in patients with other diseases (Level 4) 7 and are often seen 48 to 72 h after the onset of pancreatitis, their diagnostic significance is low. ## Blood and urine tests ## Blood lipase CQ2. Which pancreatic enzymes should be measured to diagnose acute pancreatitis? ## When making a diagnosis of acute pancreatitis or a differential diagnosis from other diseases, the blood lipase level is the best pancreatic enzyme parameter, even better than the total blood amylase level (recommendation a) Comparisons of measurements of various pancreatic enzymes to detect the presence of acute pancreatitis (Level 2a) [bib_ref] Lipase and pancreatic amylase activities in tissues and in patients with hyperamylasemia, Apple [/bib_ref] have shown that the blood lipase level is almost as sensitive as the total blood amylase level and has better specificity [fig_ref] Table 3: Comparison of diagnostic tests for acute pancreatitis [/fig_ref]. [bib_ref] Evaluating tests for acute pancreatitis, Agarwal [/bib_ref] [bib_ref] Diagnosis of acute pancreatitis: a proposed sequence of biochemical investigations, Thomson [/bib_ref] According to Apple et al., [bib_ref] Lipase and pancreatic amylase activities in tissues and in patients with hyperamylasemia, Apple [/bib_ref] the sensitivity and specificity of blood lipase in the diagnosis of acute pancreati- improves, but sensitivity declines. When the cutoff level is set at 1000 IU/l, specificity improves to 100%, but sensitivity declines to 60.9% (Levels 2a-4;. [bib_ref] Evaluating tests for acute pancreatitis, Agarwal [/bib_ref] [bib_ref] Correlation of serum amylase levels with pancreatic pathology and pancreatitis etiology, Nordestgaard [/bib_ref] [bib_ref] Diagnostic assays in acute pancreatitis. A study of sensitivity and specificity, Steinberg [/bib_ref] [bib_ref] A rapid assay for serum immunoreactive lipase as a screening test for..., Ventrucci [/bib_ref] [bib_ref] Diagnostic value of routine isoamylase assay of hyperamylasemic serum, Koehler [/bib_ref] [bib_ref] Acute pancreatitis and normoamylasemia. Not an uncommon combination, Clavien [/bib_ref] Sensitivity declines because (1) the blood amylase level does not rise as much in many patients with chronic alcoholic pancreatitis with acute exacerbations as it does in patients with acute pancreatitis (Level 2b) 12,20 and (2) since the elevated blood amylase level declines almost immediately and is maintained for a shorter time than are other elevated pancreatic enzyme levels, the level must be measured soon after the onset (Levels 3b-4). [bib_ref] Serum pancreatic enzyme behavior during the course of acute pancreatitis, Ventrucci [/bib_ref] [bib_ref] Hyperlipidemic pancreatitis, Toskes [/bib_ref] The blood amylase level seldom rises in acute pancreatitis caused by hyperlipidemia (Level 3b). [bib_ref] Amylase and lipase in the emergency department evaluation of acute pancreatitis, Vissers [/bib_ref] Because many other diseases besides pancreatitis are associated with hyperamylasemia [fig_ref] Table 6: Conditions associated with elevation of serum amylase [/fig_ref] ; Level 2a), [bib_ref] Lipase and pancreatic amylase activities in tissues and in patients with hyperamylasemia, Apple [/bib_ref] it is necessary to measure extrapancreatic enzymes with high specificity for pancreatitis in order to make a proper differential diagnosis of pancreatitis. If the blood enzyme value and/or imaging findings do not allow for a diagnosis of acute pancreatitis in a patient with ascites, the amylase level in the ascitic fluid may be useful in making the diagnosis. However, it is not usually very useful, because the amylase level in the ascitic fluid sometimes increases in other diseases, including alimentary tract perforation. ## P-amylase (amylase isozyme) The blood P-amylase level is considered useful in the differential diagnosis of hyperamylasemia, and, while one report claimed it could identify 83% of patients (19/ 23) with hyperamylasemia independent of pancreatic disease (Level 4), [bib_ref] Serum amylase isoenzyme alterations in acute abdominal conditions, Swensson [/bib_ref] others suggest a capability of only 20% to 44% (Levels 3b-4). [bib_ref] Diagnostic assays in acute pancreatitis. A study of sensitivity and specificity, Steinberg [/bib_ref] [bib_ref] Acute pancreatitis and normoamylasemia. Not an uncommon combination, Clavien [/bib_ref] There is a report describing the blood P-amylase level as a useful indicator, because the abnormally high level is maintained for longer than are the abnormal blood amylase levels in acute pancreatitis (Levels 3b), [bib_ref] Variations in amylase isoenzymes and lipase during acute pancreatitis, and in other..., Leclerc [/bib_ref] but another report showed that the blood P-amylase level did not improve sensitivity or specificity (Level 2b). [bib_ref] A rapid assay for serum immunoreactive lipase as a screening test for..., Ventrucci [/bib_ref] The diagnostic value of the P-amylase level for acute pancreatitis requires further study. ## Blood elastase-1 and other pancreatic enzymes Clinically measurable extrapancreatic enzymes can be roughly classified into blood and urine amylase, Pamylase (amylase isozyme), and serum lipase, whose enzymatic activity is measured by an enzyme-chemical method; and serum elastase-1, serum trypsin, and serum phospholipase A2 (PLA2), whose antigen levels are measured immunologically. Because the immunological measurements require a lot of time, it is difficult to use them as a routine procedure for the diagnosis of acute pancreatitis. A latex agglutination method has enabled the rapid, convenient measurement of the serum elastase-1 level. Elastase-1 has the advantage of maintaining an abnormally high value for longer than the levels of other pancreatic enzymes (Level 3b), [bib_ref] Diagnostic and prognostic value of serum elastase-1 in acute pancreatitis, Buchler [/bib_ref] [bib_ref] Comparison of elastase-1 with amylase, lipase, and trypsin-like immunoreactivity in the diagnosis..., Flamion [/bib_ref] although the ability to diagnose or assess the severity of acute pancreatitis (Level 2b) [bib_ref] A prospective study of serum pancreatic elastase-1 in the diagnosis and assessment..., Millson [/bib_ref] was not improved by the combined use of the serum elastase-1 and blood amylase levels. Trypsin is a key enzyme present at the onset of acute pancreatitis, but its activity cannot be measured, because it is too rapidly inactivated by protease inhibitors in the blood, and therefore the quantity of the antigen should be measured immunologically. Blood trypsin has high sensitivity for the diagnosis of acute pancreatitis (Level 2b). [bib_ref] Amylase and lipase in the emergency department evaluation of acute pancreatitis, Vissers [/bib_ref] [bib_ref] Role of serum pancreatic enzyme assays in diagnosis of pancreatic disease, Ventrucci [/bib_ref] The blood PLA2 level rises markedly in acute pancreatitis and is correlated with the severity . [bib_ref] Serum phospholipase A2 and pulmonary changes in acute fulminant pancreatitis, Schroder [/bib_ref] [bib_ref] Purification and characterization of human pancreatic phospholipase A2 and development of a..., Nishijima [/bib_ref] Qualitative evaluation of urine trypsinogen-2 with test paper to determine its rate of positiv-ity in acute pancreatitis has shown that it has a diagnostic ability similar to that of lipase, and it is expected to be useful in early diagnosis (Levels 3b-4). [bib_ref] Rapid measurement of urinary trypsinogen-2 as a screening test for acute pancreatitis, Kemppainen [/bib_ref] [bib_ref] Rapid urinary trypsinogen-2 test strip in the diagnosis of acute pancreatitis, Chen [/bib_ref] Imaging examinations ## Ultrasonography (us) CQ4. Is US effective in diagnosing acute pancreatitis? ## Ultrasonography (us) is one of the diagnostic procedures that should be performed first in all patients suspected of having acute pancreatitis (recommendation a) Ultrasonography (US) is capable of identifying pancreatic enlargement and inflammatory changes near the pancreas, and it may be useful in diagnosing acute pancreatitis. Although, in severe cases, visualization of the pancreas and peripancreatic tissue may be impaired by gas in the intestinal tract (Levels 1b-2b), 34,35 the visualization rate is 62% to 90% for the pancreas, 100% for the peripancreatic tissue in the anterior paranephric cavity, 90% in the cavity of the lesser omentum, and 65% in the mesentery [fig_ref] Figure 1: Plain computed tomography [/fig_ref]. [bib_ref] Diagnostic imaging of acute pancreatitis: prospective study using CT and sonography, Silverstein [/bib_ref] [bib_ref] Extrapancreatic spread of acute pancreatitis: new observations with real-time US, Jeffrey [/bib_ref] Ultrasonography may also visualize abnormal findings associated with the etiology and morbidity of acute pancreatitis, such as ascites, gallstones, and cholangiectasis. It is particularly important to check for the presence of cholecholithiasis and cholangiectasis when judging whether endoscopic sphincterotomy for gallstone pancreatitis is required. It is desirable to examine patients repeatedly, using US, even when no gallstones are detected by the initial examination. US is also useful for screening for comorbidities such as aneurysms. ## Magnetic resonance imaging (mri) ## Cq5. is mri effective in diagnosing acute pancreatitis? ## Mri is one of the most important imaging procedures for the diagnosis of acute pancreatitis and its intraabdominal complications (recommendation b) MRI scanning visualizes pancreatic enlargement and the inflammatory changes around the pancreas (Level 2c) [bib_ref] Detection of severe acute pancreatitis by contrast-enhanced magnetic resonance imaging, Piironen [/bib_ref] and can distinguish the intestinal tract from the necrotic part of the pancreas. Gadolinium-DTPA (Gd-DTPA)-enhanced MRI can visualize foci of pancreatic necrosis (Level 2b). [bib_ref] Comparison of MR and CT scanning in severe acute pancreatitis: initial experiences, Saifuddin [/bib_ref] MRI accurately depicts the state of necrosis, the main pancreatic ducts, and the extent of inflammation, and it has more value than CT (Levels 2b-3c). [bib_ref] Visualization of the heterogeneous internal structure of so-called "pancreatic necrosis" by magnetic..., Hirota [/bib_ref] [bib_ref] Computed tomography and magnetic resonance imaging in the assessment of acute pancreatitis, Arvanitakis [/bib_ref] MRI scanning has the advantage of no X-ray exposure. However, because MRI takes much longer than CT scanning and requires the removal of all metal objects (such as respirators and transfusion pumps) before the examination, it is not routinely used to diagnose acute pancreatitis in Japan, where the system for MRI use is not yet adequate. However, magnetic resonance cholangiopancreatography (MRCP) is often required to identify the etiology of acute pancreatitis, such as cholecholithiasis (Level 4) [bib_ref] MR cholangiopancreatography: prospective comparison of a breath-hold 2D projection technique with diagnostic..., Lomas [/bib_ref] and abnormal pancreaticocholedochal junction (abnormal junction of the pancreatobiliary ducts; Level 4). [bib_ref] Pancreatitis: evaluation with MR cholangiopancreatography in children, Hirohashi [/bib_ref] MRI scanning can be performed earlier than CT, because it requires no operation of the duodenal papilla and there is no risk of aggravating acute pancreatitis. Although MRCP is noninvasive, it has the disadvantages of less clear imaging than endoscopic retrograde cholangiopancreatography (ERCP) and impaired visualization due to peripancreatic fluid collection. ## Computed tomography (ct) ## Cq6. is ct effective in diagnosing acute pancreatitis? ## Ct is one of the most important imaging procedures for the diagnosis of acute pancreatitis and its intraabdominal complications. ct should be performed when the diagnosis of acute pancreatitis cannot be established on the basis of the clinical findings and the results of blood and urine tests and us, or when the etiology of the pancreatitis is unknown (recommendation b) CT is unaffected by the adipose tissue in the abdominal wall and inside the abdominal cavity, and it provides clear local images (Level 1b). [bib_ref] Diagnostic imaging of acute pancreatitis: prospective study using CT and sonography, Silverstein [/bib_ref] CT findings useful for the diagnosis of acute pancreatitis include an enlarged pancreas, inflammatory change around the pancreas, fluid collections, uneven density of the pancreatic parenchyma, and traumatic disruption of the pancreas [fig_ref] Figure 1: Plain computed tomography [/fig_ref]. Gas patterns visualized inside and around the pancreas are often due to fistula formation with the intestinal tract and infection by gas-forming anaerobes (Level 1c). [bib_ref] Pancreatic gas: indication of pancreatic fistula, Alexander [/bib_ref] CT scanning allows for the differentiation of acute pancreatitis from other intraabdominal diseases, such as perforation caused by a gastroduodenal ulcer, and it allows the diagnosis of comorbidities in intraabdominal organs and complications of pancreatitis; it is also an important procedure for assessing the severity of Plain X-rays CQ7. Are plain X-ray examinations useful in diagnosing acute pancreatitis? ## When acute pancreatitis is suspected, chest and abdominal x-ray examinations should be performed to check for the presence of any abnormal findings caused by acute pancreatitis (recommendation a) Abdominal X-ray examinations in acute pancreatitis visualize ileus, localized sentinel loop signs in the left upper abdomen, enlarged duodenal loops and gas collections, colon cutoff signs in the right colon, retroperitoneal gas collection, calcified gallstones, and pancreatolithiasis. Chest X-rays visualize pleural effusion, acute respiratory distress syndrome (ARDS), and pneumonia. None of these findings, however, are specific enough to make a diagnosis of acute pancreatitis (level 4). [bib_ref] An evaluation of the roentgen changes in acute pancreatitis: correlation with clinical..., Stein [/bib_ref] X-ray examinations are necessary, however, to evaluate the clinical course of acute pancreatitis and to differentiate acute pancreatitis from other diseases, such as alimentary tract perforation. Search for the etiology CQ8. Is the etiology of a specific case of acute pancreatitis necessary for its diagnosis? ## The etiology of acute pancreatitis may have a crucial impact on treatment policy as well as the severity assessment, and it should be determined promptly and accurately. it is particularly important to differentiate acute gallstone pancreatitis, which requires treatment of the biliary system, from acute alcoholic pancreatitis, which requires a different form of treatment (recommendation a) Abdominal US should be performed immediately with the start of treatment in order to detect the presence of abnormal findings associated with the etiology of acute pancreatitis, such as gallstones or dilated bile ducts. If acute gallstone pancreatitis is accompanied by jaundice, liver disorders, or cholangiectasis, and where cholecholithiasis is suspected, ERCP is required immediately after the onset, but it should be performed only for the purpose of endoscopic treatment, sphincterotomy, and biliary drainage. ERCP should be performed in patients with acute gallstone pancreatitis who are strongly suspected of having gallstones, but only for the purposes of determining etiology and performing endoscopic treatment. ERCP has several risk factors (level 2b). [bib_ref] An evaluation of the roentgen changes in acute pancreatitis: correlation with clinical..., Stein [/bib_ref] Because ERCP may exacerbate the inflammation at the onset of acute pancreatitis, it should be performed only for limited indications. The guidelines of the British Society of Gastroenterology recommend the performance of ERCP in patients with jaundice, liver disorders, or cholangioectasis, and in those who are strongly suspected of having cholecholithiasis and have had repeated attacks of pancreatitis. [bib_ref] Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study, Loperfido [/bib_ref] Patients with repeated attacks of pancreatitis may have anatomical disorders, such as malfusion of the biliary ducts or abnormal junction of the pancreatobiliary ducts, or they may have a tumor or choledocholithiasis. Because such features are difficult to visualize using other procedures, it is recommended that ERCP be performed as a standby procedure to differentiate the etiology of these disorders and complications. [bib_ref] Major early complications from diagnostic and therapeutic ERCP: a prospective multicenter study, Loperfido [/bib_ref] There is a report claiming that endoscopic US (EUS) can identify cholecholithiasis in 77.8% of patients whose etiology has not been identified by blood tests, US, and CT scanning (level 2b).EUS is indicated in any patient with severe acute pancreatitis in whom choledocholithiasis is strongly suspected, but it should be performed only after adequate evaluation of the patient's general condition. ERCP should be performed without delay. Cases in which cholecholithiasis cannot be diagnosed by extracorporeal US are a good indication for EUS, after the attack subsides. [fig] Figure 1: Plain computed tomography (CT) shows enlargement of the pancreatic body and tail and poorly defined margins of the pancreatic body [/fig] [fig] Figure 2: Plain CT shows enlarged pancreas, associated haziness, and increased density of peripancreatic fatFig. 3. Contrast-enhanced CT shows low-density region of the pancreatic tail and fluid in the left anterior pararenal space acute pancreatitis and selecting a treatment plan. CT scanning is especially needed in severe acute pancreatitis, where adequate information cannot be obtained by US because of abdominal pain and the complication of ileus. [/fig] [table] Table 1: Symptoms and signs of acute pancreatitis [/table] [table] Table 2: Symptoms and signs at onset of acute pancreatitis a [/table] [table] Table 3: Comparison of diagnostic tests for acute pancreatitis [/table] [table] Table 4: Sensitivity and specificity of amylase and other pancreatic enzymes Adapted from Thomson et al.10 [/table] [table] Table 6: Conditions associated with elevation of serum amylase [/table]	None	https://link.springer.com/content/pdf/10.1007/s00534-005-1048-2.pdf	None
13c7d2a5b26eea30c7a55cebd01230d85bb75145	pubmed	None	surgical intervention should be performed only in selected cases, such as those with persistent organ complications or severe clinical deterioration despite maximum intensive care; (4) early surgical intervention is not recommended for necrotizing pancreatitis; (5) necrosectomy is recommended as the surgical procedure for infected pancreatic necrosis; (6) simple drainage should be avoided after necrosectomy, and either continuous closed lavage or open drainage should be performed; (7) surgical or percutaneous drainage should be performed for pancreatic abscess; (8) pancreatic abscesses for which clinical findings are not improved by percutaneous drainage should be subjected to surgical drainage immediately; (9) pancreatic pseudocysts that produce symptoms and complications or the diameter of which increases should be drained percutaneously or endoscopically; and (10) pancreatic pseudocysts that do not tend to improve in response to percutaneous drainage or endoscopic drainage should be managed surgically.Clinical questions CQ1. Which procedure will best result in a definite diagnosis of infected pancreatic necrosis? CQ2. What is the indication for surgical intervention in necrotizing pancreatitis? CQ3. How should sterile pancreatic necrosis be managed?AbstractAcute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course to a rapidly progressive, severe illness. The mortality rate of severe acute pancreatitis exceeds 20%, and some patients diagnosed as mild to moderate acute pancreatitis at the onset of the disease may progress to a severe, life-threatening illness within 2-3 days. The Japanese (JPN) guidelines were designed to provide recommendations regarding the management of acute pancreatitis in patients having a diversity of clinical characteristics. This article sets forth the JPN guidelines for the surgical management of acute pancreatitis, excluding gallstone pancreatitis, by incorporating the latest evidence for the surgical management of severe pancreatitis in the Japanese-language version of the evidence-based Guidelines for the Management of Acute Pancreatitis published in 2003. Ten guidelines are proposed: (1) computed tomography-guided or ultrasound-guided fineneedle aspiration for bacteriology should be performed in patients suspected of having infected pancreatic necrosis; (2) infected pancreatic necrosis accompanied by signs of sepsis is an indication for surgical intervention; (3) patients with sterile pancreatic necrosis should be managed conservatively, and CQ4. What is the optimal timing for surgical intervention? CQ5. What is the optimal surgical procedure for infected pancreatic necrosis? CQ6. What is the optimal drainage procedure after necrosectomy? CQ7. How should pancreatic abscess be managed? CQ8. What is the indication for surgical drainage in pancreatic abscess? CQ9. What are the indications for drainage treatment in pancreatic pseudocysts? CQ10. What is the indication for surgical intervention in pancreatic pseudocysts? # Introduction Research on the pathophysiology of acute pancreatitis has progressed dramatically during the past 20 years. As the number of randomized controlled studies (RCTs, mainly done in the United States and Europe) on the management of severe acute pancreatitis has increased, evidence-based management has come to be demanded. Several guidelines and recommendations for acute pancreatitis have been published in recent years, [bib_ref] IAP guidelines for the surgical management of acute pancreatitis, Uhl [/bib_ref] [bib_ref] Guiding the reluctant. A primer on guidelines in general and pancreatitis in..., Bradley [/bib_ref] [bib_ref] Management of the critically ill patient with severe acute pancreatitis, Nathens [/bib_ref] [bib_ref] Evidence-based clinical guidelines for acute pancreatitis: proposal, Mayumi [/bib_ref] and three institutions in Japan -the Japanese Society for Abdominal Emergency Medicine, the Japan Pancreas Society, and the Research Group for Intractable Diseases and Refractory Pancreatic Diseases, which is sponsored by the Japanese Ministry of Health, Labour and Welfare -collaborated to publish the Japanese-language version of the evidence-based Guidelines for the Management of Acute Pancreatitis in 2003. This paper sets forth the JPN guidelines for the surgical management of acute pancreatitis, which incorporate the latest evidence for the surgical management of severe pancreatitis and are based on the Japaneselanguage version of the guidelines. The surgical management of gallstone pancreatitis is included in the JPN guidelines for the treatment of gallstone-associated acute pancreatitis. ## Clinical course of acute pancreatitis The majority of acute pancreatitis cases (around 80%) are mild and self-limiting, and the patients spontaneously recover within 4-5 days after onset. Mild cases have a mortality rate of 1% or less and rarely require intensive care or surgical management. [bib_ref] IAP guidelines for the surgical management of acute pancreatitis, Uhl [/bib_ref] However, severe acute pancreatitis develops in 10%-20% of cases and part of the pancreas and surrounding tissue becomes necrotic. Severe cases are associated with local complications such as major organ failure, pancreatic necrosis, pancreatic abscess, and pancreatic pseudocysts and are generally classified into two stages. [bib_ref] Modern phase-specific management of acute pancreatitis, Werner [/bib_ref] The first stage of severe acute pancreatitis, the period within 2 weeks after the onset of the disease, is characterized by the systemic inflammatory response syndrome (SIRS), and pancreatic necrosis develops in parallel with that within the first 4 days after onset. The second stage begins 2 or 3 weeks after onset with the development of infectious pancreatic complications such as infected pancreatic necrosis (bacterial infection of the pancreatic necrosis) and pancreatic abscess. Infection of pancreatic necrosis is a major prognostic risk factor in severe pancreatitis, and sepsis-related multiple organ failure is the main life-threatening complication with a mortality rate of 20%-50%. ## Necrotizing pancreatitis Clinical Question (CQ) 1. Which procedure will best result in a definite diagnosis of infected pancreatic necrosis? ## Computed tomography (ct)-guided or ultrasound (us)-guided fine-needle aspiration for bacteriology should be performed in patients suspected of having infected pancreatic necrosis (recommendation a) Acute pancreatitis is classified morphologically into edematous pancreatitis and necrotizing pancreatitis. Edematous pancreatitis accounts for 80%-85% of cases of acute pancreatitis, and most of them are self-limiting and do not require special treatment. The mortality rate for necrotizing pancreatitis, which accounts for 15%-20% of cases, is 30%-40%. [bib_ref] Prognostic factors in sterile pancreatic necrosis, Karimgani [/bib_ref] The mortality rate for infected pancreatic necrosis is high -40% on average, [bib_ref] Pancreatic infection complicating acute pancreatitis, Widdison [/bib_ref] and some studies report rates of more than 70%. [bib_ref] Incidence of necrotizing pancreatitis and factors related to mortality, Allardyce [/bib_ref] In contrast, the mortality rate of sterile pancreatic necrosis with no bacterial infection has been reported as being 0%-11%. [bib_ref] A prospective longitudinal study of observation versus surgical intervention in the management..., Bradley [/bib_ref] [bib_ref] Early surgical debridement of symptomatic pancreatic necrosis is beneficial irrespective of infection, Rattner [/bib_ref] Findings suggest that infected pancreatic necrosis presents with a worsening of clinical manifestations and hematological data, a blood culture with positive bacterial results, and a positive result on the endotoxin test of blood and gas in and around the pancreas on a CT scan. However, these findings are merely indirect evidence of infection in general. CT-or US-guided fine-needle aspiration for bacteriology of pancreatic or peripancreatic necrosis has been established as an accurate, safe, and reliable technique for identifying infected necrosis. Its accuracy is high, at 89.4%-100% (Level 2b), [bib_ref] CT-guided aspiration of suspected pancreatic infection: bacteriology and clinical outcome, Banks [/bib_ref] [bib_ref] Role of ultrasonographically guided fine-needle aspiration cytology in the diagnosis of infected..., Rau [/bib_ref] and it is safe if the correct puncture route is chosen and complications such as intestinal injury do not result (Level 2b). ## Indications for surgery ## Cq2. what is the indication for surgical intervention in necrotizing pancreatitis? ## Infected pancreatic necrosis accompanied by signs of sepsis is an indication for surgical intervention (recommendation b) It is generally agreed that necrotizing pancreatitis with proven infected necrosis is an indication for surgical intervention (Level 5). [bib_ref] IAP guidelines for the surgical management of acute pancreatitis, Uhl [/bib_ref] [bib_ref] Indications for surgery in severe acute pancreatitis, Mcfadden [/bib_ref] [bib_ref] The current management of acute pancreatitis, Ranson [/bib_ref] It is rarely managed conservatively without surgical intervention. ## Cq3. how should sterile pancreatic necrosis be managed? ## Patients with sterile pancreatic necrosis should be managed conservatively and undergo surgical intervention only in selected cases, such as those with persistent organ complications or severe clinical deterioration despite maximum intensive care (recommendation b) Whether sterile pancreatic necrosis is an indication for surgical intervention remains a matter of controversy. Patients often recover from sterile pancreatic necrosis in response to conservative nonsurgical management (Levels 2c-3b). 9,15-17 However, many reports state that failure of acute pancreatitis to improve in response to optimal therapy in an intensive care unit should be an indication for surgical intervention, irrespective of whether the patient has an infection (Levels 2c-3b). [bib_ref] Surgical management of severe pancreatitis including sterile necrosis, Hartwig [/bib_ref] [bib_ref] Early surgical debridement of symptomatic pancreatic necrosis is beneficial irrespective of infection, Rattner [/bib_ref] [bib_ref] Debridement and closed packing for the treatment of necrotizing pancreatitis, Fernandez-Del Castillo [/bib_ref] [bib_ref] Necrosectomy and postoperative local lavage in necrotizing pancreatitis, Beger [/bib_ref] [bib_ref] Improved survival in acute necrotizing pancreatitis despite limiting the indications for surgical..., Foitzik [/bib_ref] However, these reports have differing views about the length of time that conservative management should be applied before surgical intervention is considered, with the period ranging from 3-5 days to more than 5 weeks. A review 23 examining this issue has indicated that although it is difficult to recommend an exact duration, at least 3-4 weeks of conservative management is desirable. However, there are no comparative studies to justify such a conclusion. ## Timing of surgery ## Cq4. what is the optimal timing for surgical intervention? ## Unless there are specific indications, early surgery is not recommended for necrotizing pancreatitis (recommendation d) In the past, early surgical intervention was recommended for severe acute pancreatitis, which is often accompanied by major organ failure, beginning in the early stage after onset. However, the high mortality rate of up to 65% casts doubt on the benefits of early surgical intervention. A retrospective study on the timing of surgery for severe pancreatitis 24 revealed a mortality rate in patients treated by delayed surgery of 12%, which is significantly lower than the 39% rate for those who underwent early surgery; thus, surgical intervention should be delayed as long as possible in severe pancreatitis. The only RCT [bib_ref] Early versus late necrosectomy in severe necrotizing pancreatitis, Mier [/bib_ref] comparing early surgery (pancreatic resection/debridement within 72 h of onset) and delayed surgery (the same procedure 11 days after onset) yielded mortality rates of 56% and 27%, respectively. Although the difference between the rates was significant, the trial was terminated because of the very high mortality rate for the patients who underwent early surgery. The above findings indicate that surgical intervention (necrosectomy) for severe acute pancreatitis patients should be deferred as long as possible (3-4 weeks after the onset). [bib_ref] IAP guidelines for the surgical management of acute pancreatitis, Uhl [/bib_ref] [bib_ref] Management of the critically ill patient with severe acute pancreatitis, Nathens [/bib_ref] The reason for this is that the border between normal and necrotic pancreatic tissue becomes more distinct with time, and this may minimize intraoperative hemorrhage and avoid unnecessary removal of normal pancreas. However, a questionnaire survey of physicians specializing in hepatobiliary pancreatic diseases in Europe that asked about surgical intervention for severe pancreatitis showed no consensus regarding the timing of surgery. [bib_ref] European survey of surgical strategies for the management of severe acute pancreatitis, King [/bib_ref] Surgical procedures CQ5. What is the optimal surgical procedure for infected pancreatic necrosis? ## Necrosectomy is recommended as the optimal surgical procedure for infected pancreatic necrosis (recommendation a) Surgical procedures employed to treat severe acute pancreatitis in the past included mobilization and drainage of the pancreatic bed and extended pancreatic resection. Drainage of the pancreatic bed was widely used in Japan as a standard surgical procedure in the 1980s through the early 1990s. However, it is no longer used because maximal therapy in an intensive care unit has become the principal procedure for managing severe acute pancreatitis and the advances in imaging modalities have provided objective evidence that the necrotic tissue cannot be removed by a simple drainage procedure. On the other hand, the extended pancreatic resection that was the major procedure used mainly in European countries from the 1970s through the 1980s has been increasingly avoided in view of the high incidence of postoperative complications, the failure to improve the overall life-saving rate (Level 1b-3b), [bib_ref] Pancreatic resection versus peritoneal lavation for acute fulminant pancreatitis. A randomized prospective..., Kivilaakso [/bib_ref] [bib_ref] Pancreatic resection versus peritoneal lavage in acute necrotizing pancreatitis. A prospective randomized..., Schroder [/bib_ref] and the lowered quality of life in surviving patients because of the development of abnormal glucose tolerance. [bib_ref] Pancreatic resection versus peritoneal lavation for acute fulminant pancreatitis. A randomized prospective..., Kivilaakso [/bib_ref] Necrosectomy, or debridement of necrotic tissue, including necrotic pancreatic tissue and peripancreatic fat necrosis, is currently used as the key procedure for necrotizing pancreatitis, and no other surgical procedure produces a better outcome (Level 2c). [bib_ref] Necrosectomy and postoperative local lavage in necrotizing pancreatitis, Beger [/bib_ref] [bib_ref] Management of infected pancreatic necrosis by open drainage, Bradley [/bib_ref] Drainage procedures after necrosectomy CQ6. What is the optimal drainage procedure after necrosectomy? ## Simple drainage (recommendation d) should be avoided as the drainage procedure after necrosectomy, and either continuous closed lavage or open drainage (planned necrosectomy) (recommendation b) should be performed instead. the choice between these two procedures can be made at the time based on the surgical findings and/or surgeon's experience Necrosectomy for necrotizing pancreatitis is designed to remove as much necrotic pancreatic tissue as possible. However, because complete debridement is difficult as a result of hemorrhage and because the outcome depends on how thoroughly the remaining necrotic tissue is removed, [bib_ref] Management of infected pancreatic necrosis by open drainage, Bradley [/bib_ref] the simple (conventional) drainage performed in the past should be avoided. The drainage procedures used to remove the necrotic foci after necrosectomy can be mainly classified as (1) conventional drainage, (2) continuous closed lavage, and (3) open drainage. Conventional drainage is simple drainage through an indwelling drainage tube. Continuous closed lavage consists of continuous local irrigation with 6-8 l/day physiological saline through an indwelling double-lumen tube and is continued until no discharge of necrotic tissue is observed. [bib_ref] Necrosectomy and postoperative local lavage in necrotizing pancreatitis, Beger [/bib_ref] Open drainage is direct drainage through the open wound in the abdominal wall achieved by packing the retroperitoneal space and lesser sac with gauze after necrosectomy, and the same procedure is repeated as scheduled (every 2-3 days) until necrotic tissue is no longer observed. [bib_ref] Management of infected pancreatic necrosis by open drainage, Bradley [/bib_ref] Discussion of the comparative advantages of various drainage procedures has continued for more than 20 years, and two reviews based on systematic literature searches have been published. The first review (Level 2a), [bib_ref] Surgical strategies in the treatment of pancreatic necrosis and infection, D'egidio [/bib_ref] published in 1991, analyzed relevant articles published during the 1980s and revealed that the mortality rate of patients with infected pancreatic necrosis treated by conventional drainage, continuous closed lavage, and open drainage was 42%, 18%, and 21%, respectively, and that the outcome of the conventional drainage group was significantly poorer (P < 0.05). The other review (Level 2a), [bib_ref] Surgical treatment strategy for acute necrotizing pancreatitis, Isaji [/bib_ref] which analyzed articles published in the 1990s, revealed that the mortality rate of the patients with infected pancreatic necrosis treated using the above methods was 23.3%, 10.5%, and 28.3%, respectively. When the analysis was limited to articles dealing with severe cases [an average APACHE II (AP-II) score of 17 or more], the mortality rate was 45.8%, 6.3%, and 23.5%, respectively [fig_ref] Table 1: Systematic review of the outcomes of three major drainage procedures after necrosectomy... [/fig_ref]. Both reviews show that patients treated by continuous closed lavage had the best outcome. However, because of extreme inconsistency between the results of two papers 34,45 on continuous closed lavage, both of which were included in the latter systematic review and were reported by the same author at almost the same time, the reliability of the data is highly questionable. In another paper on continuous closed lavage, [bib_ref] Pancreatic necrosis: results of necrosectomy, packing, and ultimate closure over drains, Branum [/bib_ref] approximately half of the patients underwent repeat laparotomy/debridement 12 or 13 times, and thus the results reported in that paper cannot be considered a pure reflection of the effect of continuous closed lavage. There is a planned necrosectomy/debridement procedure in which necrosectomy is repeated by temporarily closing the abdominal wound to avoid the excessive invasiveness of open drainage (Level 2c). [bib_ref] Treatment of severe intra-abdominal sepsis and/ or necrotic foci by an "open-abdomen"..., Garcia-Sabrido [/bib_ref] A recent review compared continuous closed lavage, planned necrosectomy (zipper technique), and open drainage. [bib_ref] Outcome of open necrosectomy in acute pancreatitis, Bassi [/bib_ref] The report stated that the mortality rate in necrotizing pancreatitis patients treated by continuous closed lavage, zipper technique, and open drainage was 19%, 24%, and 20.1%, respectively, and that the differences between the groups were not significant. The closed lavage group had a lower incidence of fistula formation (pancreatic fistula and intestinal fistula) and postoperative hemorrhage, but a higher rate of repeat operation, whereas the zipper technique and open drainage were characterized by a higher incidence of fistula formation and postoperative hemorrhage, but a lower rate of repeat operation. It is difficult to conclude from currently available evidence whether continuous closed lavage or open drainage (or the zipper technique) is better, and in recent years one of these drainage techniques has been chosen freely by surgeons according to the extent of infected necrotic tissue. Continuous closed lavage is chosen when necrotic tissue is localized around the pancreas, and open drainage is recommended if the necrotic area has spread from the root of the mesocolon to the right and/or left paracolic gutter. [bib_ref] Surgical therapy of severe acute pancreatitis: a flexible approach gives excellent results, Kasperk [/bib_ref] Recently, less-invasive procedures have been preferred. Because the pancreas is a retroperitoneal organ, necrosectomy alone by a retroperitoneal approach is performed with simultaneous local lavage (Level 2c). [bib_ref] Retroperitoneal laparostomy: a surgical treatment of pancreatic abscesses after an acute necrotizing..., Van Vyve [/bib_ref] [bib_ref] Direct retroperitoneal open drainage via a long posterior oblique incision for infected..., Morise [/bib_ref] The benefits of this procedure are: (1) peritonitis can be prevented because the abdominal cavity is not entered and infecting organisms are not disseminated into the peritoneal cavity, (2) oral intake can be resumed shortly after the operation, (3) the risk of intestinal fistula formation is low, and (4) the incidence of wound infection and abdominal wall incisional hernia is minimized. The disadvantages are associated with the approach being near the head of the pancreas. It is difficult to reach the posterior surface of the duodenum by a retroperitoneal approach from the right side, and an aggressive procedure involves the risk of massive bleeding as a result of damage to the duodenal wall and portal veins. Moreover, new less-invasive procedures such as percutaneous necrosectomy (Level 2c) [bib_ref] Percutaneous necrosectomy and sinus tract endoscopy in the management of infected pancreatic..., Carter [/bib_ref] [bib_ref] Minimally invasive retroperitoneal pancreatic necrosectomy, Connora [/bib_ref] [bib_ref] Laparoscopic necrosectomy for acute necrotizing pancreatitis, Pamoukian [/bib_ref] and endoscopic transgastric necrosectomy [bib_ref] Retroperitoneal endoscopic debridement for infected peripancreatic necrosis, Seifert [/bib_ref] have been tried and yielded favorable results. Proper evaluation of these new management procedures will require the collection of data from additional cases and follow-up examinations. Pancreatic abscess CQ7. How should pancreatic abscess be managed? CQ8. What is the indication for surgical drainage in pancreatic abscess? ## Surgical or percutaneous drainage should be performed for pancreatic abscess (recommendation b). if the clinical findings of pancreatic abscess are not improved by percutaneous drainage, surgical drainage should be performed immediately (recommendation a) Pancreatic abscess is an indication for surgical intervention, just as for infected pancreatic necrosis. Pus collection is the main lesion in most pancreatic abscess patients, and it has been recently reported (Level 3b) 55,56 that 78%-86% of patients can be managed by percutaneous drainage alone. If a safe puncture route is assured by imaging guidance, this procedure may be the first choice as an aggressive treatment for pancreatic abscess. However, it should be noted that the favorable results reported for this treatment have all been based on retrospective studies, and some of the cases were not pancreatic abscess cases. For example, when severe cases with a Ranson score of 5 or more (Level 2b) [bib_ref] The efficacy of palliative and definitive percutaneous versus surgical drainage of pancreatic..., Lang [/bib_ref] and cases having multiple abscesses (Level 4) 58 were included in the study, the one-stage healing rates of percutaneous drainage declined to 30%-47%. When no improvement in clinical findings is observed after percutaneous drainage, surgical drainage should be performed immediately instead of monitoring the clinical course. 59 ## Pancreatic pseudocysts ## Cq9. what are the indications for drainage treatment in pancreatic pseudocysts? ## Pancreatic pseudocysts that give rise to symptoms and complications or the diameter of which increases should be treated by drainage (recommendation a) Generally agreed indications for drainage treatment of pancreatic pseudocysts include (1) accompaniment by symptoms, such as abdominal pain; (2) complication by infection or bleeding; (3) increase in size during the observation period; (4) a diameter of 6 cm or more; and (5) no tendency to decrease in size during at least 6 weeks of observation. There are no reports opposing indications (1) to (3), but because pseudocysts of 6 cm or larger in diameter may spontaneously resolve after a long follow-up period of 6 weeks or more, (4) and (5), known as "6 cm-6 week criteria," are not absolute indications for drainage . [bib_ref] The natural history of pancreatic pseudocysts documented by computed tomography, Yeo [/bib_ref] [bib_ref] Selected management of pancreatic pseudocysts: operative versus expectant management, Vitas [/bib_ref] CQ10. What is the indication for surgical intervention in pancreatic pseudocysts? ## Pancreatic pseudocysts that do not tend to improve in response to percutaneous drainage or endoscopic drainage should be managed surgically (recommendation a) The drainage procedures for pancreatic pseudocysts include percutaneous, endoscopic, and surgical drainage (mainly cystoenteric anastomosis). Percutaneous drainage, which is the least invasive and has a cure rate of 80%-100%, is considered a promising alternative to surgical drainage (Levels 2c-3c). [bib_ref] Percutaneous drainage of pancreatic pseudocysts: a prospective study, D'egidio [/bib_ref] [bib_ref] Percutaneous catheter drainage compared with internal drainage in the management of pancreatic..., Adams [/bib_ref] However, some reports have suggested that in a few cases pseudocysts only temporarily resolve after percutaneous drainage (Level 3b), [bib_ref] Long-term results of percutaneous catheter drainage of pancreatic pseudocysts, Criado [/bib_ref] whereas other reports have indicated that the complete cure rate as a result of surgical drainage is better than that using other drainage procedures (Level 3b). [bib_ref] Percutaneous drainage of pancreatic pseudocysts is associated with a higher failure rate..., Heider [/bib_ref] [bib_ref] Pancreatic pseudocysts following acute pancreatitis: risk factors influencing therapeutic outcomes, Soliani [/bib_ref] One prospective controlled study (Level 2b) 57 yielded a one-stage cure rate using percutaneous drainage and surgical drainage of 77% (20/26) and 73% (18/26), respectively, with no significant differences between them. Because it has been reported that the average duration of catheterization for percutaneous drainage is 16-42 days in cases that respond (Levels 2c-3b), 62,63 surgical drainage, such as cystoenteric anastomosis, should be performed if there is no tendency toward improvement even after this duration. When deciding whether the disease is an indication for percutaneous drainage, it is critical to identify the morphology of the pancreatic duct and its relationship to the pancreatic cyst. Percutaneous drainage has been found to be effective in cases in which the pancreatic duct has normal morphology and in which the pancreatic duct is stenosed but does not communicate with the cyst. [bib_ref] Main pancreatic ductal anatomy can direct choice of modality for treating pancreatic..., Nealon [/bib_ref] There is a report 68 that percutaneous drainage is often ineffective for pancreatic pseudocysts complicated by splenic parenchymal involvement, but that distal pancreatectomy and splenectomy are effective. Endoscopic management may be indicated in some cases of pancreatic pseudocyst. Transintestinal drainage, such as by transgastric and transduodenal drainage (Level 4), and transpapillary drainage (Level 4), indicated, but transgastric drainage should be performed only when compression of the intestinal wall by a cyst can be confirmed endoscopically. It has been suggested that guidance by endoscopic ultrasonography may enhance the safety of drainage procedures (Level 4). [bib_ref] Endoscopic ultrasound-guided one-step transmural drainage of cystic abdominal lesions with a large-channel..., Seifert [/bib_ref] Transpapillary drainage can be used in cases in which there is communication between the cysts and pancreatic ducts but a transintestinal approach cannot be used. Major complications of endoscopic management include bleeding, infection, and perforation, but there have been no reliable reports comparing effectiveness and safety with that of surgical management. [table] Table 1: Systematic review of the outcomes of three major drainage procedures after necrosectomy for infected pancreatic necrosis Necrosectomy with conventional drainage Necrosectomy with continuous closed lavage Necrosectomy with open drainage Reference n AP-II Deaths Reference n AP-II Deaths Reference n AP-II Deaths [/table]	None	None	None
7177ec0de4321f9648cdf4d2bbfcc9e48559e60c	pubmed	Prenatal Diagnosis and Genetic Screening: Community and Service Implications	Prenatal Diagnosis and Genetic Screening: Community and Service Implications # Introduction Everyone is at risk for having abnormal offspring. In fact, at some time in their reproductive life about half the world's women conceive a pregnancy with a chromosomal abnormality. However, most such pregnancies end in a spontaneous abortion and until recently many infants born with serious abnormalities died, often undiagnosed, in early childhood. The purpose of this report is to demonstrate how advances in medical research have created new opportunities in preventive medicine. Most infants with congenital malformations and chromosomal disorders are born to healthy young women with no identifiable risk factor. There is no evidence that such 'sporadic' disorders can be prevented, and neither diagnosis nor intervention is possible before pregnancy is established. Therefore the only means of detecting the disorders is by populationscreening during pregnancy using methods that are safe, simple and cheap. By contrast, 2 to 3% of all couples are at high and recurrent risk of having a child with an inherited disorder. It is becoming increasingly possible to detect these couples by biochemical or DNA tests. Screening for carriers of inherited diseases should whenever possible be offered before pregnancy so that couples at risk can choose from the full range of options available. The objectives of prenatal diagnosis are: To allow the widest possible range of informed choice to women and couples at risk of having children with an abnormality. To provide reassurance and reduce the level of anxiety associated with reproduction. To allow couples at risk to embark on having a family knowing that they may avoid the birth of seriously affected children through selective abortion. To ensure optimal treatment of affected infants through early diagnosis. [fig_ref] Table 1: Approximate annual incidence of births of infants with congenital and genetically determined... [/fig_ref] gives a very general classification of the disorders under consideration in the report, and indicates their relative frequency. Some of the commoner inherited disorders are listed in [fig_ref] Table 2: Incidence of some severe inherited diseases and their approximate carrier frequency in... [/fig_ref]. Almost everyone carries one or more recessively inherited genetic defects and about 3% of couples have a high and recurrent risk of bearing a child with a specific inherited disorder. The fact that about 4,000 such 'single gene disorders' are listed in McKusick's Mendelian inheritance in man shows on the one hand the collective frequency, and on the other the diversity and individual infrequency of these conditions. People who carry inherited diseases require time both to come to terms with their carrier status and to make informed decisions. It is therefore important, whenever possible, to identify carriers before pregnancy. There is an important planning difference between risks that can be identified before pregnancy and those that can be detected only during the course of pregnancy. So far, our improved understanding of the molecular basis for single gene defects has proved much more valuable for diagnosis than for treatment. Intrauterine treatment of the affected fetus is of limited value, though intrauterine diagnosis may allow more effective treatment of the newborn child. Neonatal diagnosis allows a few well defined disorders to be treated satisfactorily, and many congenital malformations can be corrected surgically, but the remainder of these disorders result in either death in infancy or prolonged chronic illness with premature death in adolescence or adult life. There seems little prospect of radical change in this general picture. Prenatal diagnosis services must operate at two levels. At one level are specialist clinical genetics and fetal medicine services, which must be supported on another level by genetics services in the community. The community service involves population screening delivered through the primary health care system and obstetric and other hospital services. In both specialist and com-munity-based services it is important to distinguish between pre-pregnancy and pregnancy screening. Equitable delivery of these services requires that they be integrated into all levels of the maternal and child health system. Their multidisciplinary implications mean that explicit planning and organisation as well as funding are now essential. 2. Scope of prenatal diagnosis Although it will never be possible to identify everyone at risk, with present technology the potential exists for a great reduction in births of infants with severe congenital and genetically determined disorders. Prenatal diagnosis involves an invasion of many seemingly normal pregnancies in the search for uncommon abnormalities, and so must be practised to the highest possible standard. The following important recent developments extend the range of prenatal diagnosis, sometimes increase its speed and often allow tests to be performed earlier in pregnancy: i The rapid development of obstetric ultrasound has greatly increased the feasibility of directly detecting congenital malformations and has made possible improved fetal sampling methods. ii The introduction of chorionic villus sampling (CVS) allows genetic diagnosis in the first trimester of pregnancy, thus increasing the acceptability, and in some cases the speed, of prenatal diagnosis. iii The development of molecular genetics means that: an increasing range of inherited disorders can be detected in fetal cells, including chorionic material; improved carrier diagnosis is possible in families at risk; -conditions in which the genetic abnormality is still unknown are open to diagnosis. However, the usefulness to the community of these new diagnostic methods depends on: -the extent to which the population is informed, so that individuals and couples can request testing, and pregnancies at risk can be identified; -the level of popular demand for prenatal diagnosis; adequate service provision. Because of the possibility of error or unexpected natural variation, both screening and prenatal diagnosis must be practised to the highest possible standard according to the following general principles: i The methods used must be capable of giving a clear result with a minimum of false positives and negatives, and their safety should be defined. ii Staff must be suitably trained and must work within a professional code of practice. iii In case of the slightest doubt, the diagnosis should, as far as possible, be confirmed by an independent approach. iv Prenatal diagnoses should, whenever possible, be confirmed in aborted fetuses, and in babies born following diagnosis. The services of an expert in fetal pathology are essential. v Results should be subjected to regular audit, with particular emphasis on false positives and false negatives. National and regional monitoring should be established. ^ The genetic, obstetric and laboratory aspects of prenatal diagnosis are closely related and optimal results require close collaboration. Ideally, the obstetric scanning and sampling procedures, counselling, and laboratory analysis should be practised side-by-side in the same institution. vii Women with a continuing pregnancy in which a fetal abnormality has been diagnosed require expert support from the neonatologist and neonatal surgeon. In addition to being safe, simple and cheap, screening methods should be reliable. They should have a high detection rate (a high proportion of affected individuals should yield a positive result) and a low false-positive rate (few unaffected individuals should yield a positive result). Whenever possible, screening should be carried out before pregnancy. Assuming continuing progress in methods of prenatal diagnosis, the birth prevalence of dominant and Xhnked severe disorders might be reduced by up to 50%, while population screening for carriers of comnion recessively inherited disorders may drastically reduce the birth prevalence of affected infants. Prenatal diagnosis is now possible in the first trimester of pregnancy (before the 12th week of gestation) by chorionic villus sampling (CVS). This increases the importance of identifying mothers at risk prior to pregnancy or very early in pregnancy. More infor-mation on the shortand long-term risks of CVS is awaited from randomised controlled comparisons with amniocentesis, now under way. ## Future developments in prenatal diagnosis Technical innovations of many kinds are continually broadening the scope of prenatal diagnosis with important service implications. Particularly important are the development of DNA technology, progress in obstetric ultrasound, and improved possibilities for screening for Down's syndrome in pregnancy. Although the precise techniques that will eventually be used are still uncertain, the implications in terms of medical training, community education and service provision for prenatal diagnosis and genetic screening are already obvious. It is now essential for health care planners to participate in these developments. In view of the rate of progress, it is unwise to wait until the details of the laboratory methods have been settled before making the decision to set up the service. Workers and laboratories should be supported, and rapid evaluation and development of methods and flexibility in their application should be promoted. Improved undergraduate and postgraduate medical education in genetic methods, and technical training of medical and non-medical staff, are equally important. ## Ethnic minorities In England at present about 5.5% of the population and 9% of births are in ethnic groups with specific genetic risks. People of Jewish origin are at increased risk of carrying Tay-Sachs disease, and many ethnic groups originating outside northern Europe are at high risk of the haemoglobin disorders. It is cheap and easy to detect carriers of these disorders, and prenatal diagnosis, which is freely available at several national centres, is in high demand from informed couples at risk. The haemoglobin disorders in particular provide a good model of screening at the community level for inherited disease. The fact that the haemoglobin disorders affect particular ethnic minorities is often thought to be a useful 'primary screen', but in reality is a major difficulty. There has been considerable resistance to the requirement to develop a selective approach to the groups at risk, partly because of anxiety about attracting attention to ethnic minorities and fear that focusing on their genetic problems will be considered racist. But such fears cause real racial discrimination when they result in failure to provide a necessary medical service. Approaches to the haemoglobin disorders have been local initiatives. There has been much wasteful duplication of effort, and though a consensus view on the best approaches can be developed only by pooling experience, information is still not integrated at a regional or national level. In particular, the education-Journal of the Royal College of Physicians of London Vol. 23 No. 4 October 1989 2] y al component of a community approach and the production of educational aids cannot be organised effectively on a district basis. These problems lead to failure to inform, misinformation, anxiety, waste of resources and unnecessary duplication of testing. The requirements for an adequate screening programme for haemoglobin disorders include the recognition of specialist centres which should have associated ethnic genetic counsellors to act as a focus for a community service. The DoH has now issued haemoglobinopathy cards to be given to people who have been screened. Though the information provided is still inadequate, it is to be hoped that this is the first step in better central recognition of this problem, which would include advice to regions on funding for special services. Among ethnic minorities, many older mothers are not being counselled because it is assumed that they will not want karyotyping, and because of language difficulties. British Pakistanis have a strong tradition of consanguineous marriage. It would be inappropriate to try to interfere with this custom on genetic grounds. However, as a group, British Pakistanis do have special genetic counselling needs. ## Genetic counselling and education Couples at risk for bearing an abnormal child, and pregnant women who discover they are carrying an abnormal fetus, have to choose among several options and must live with the decision for the rest of their lives. They need information and support through the process of genetic counselling. Three core ethical principles are recognised for genetic counselling: i The autonomy of the individual or the couple. ii Their right to full and complete information. iii The preservation of the highest standard of confidentiality. Although counselling should be non-directive, this does not mean simply telling people the facts and leaving them to make their own decision. Counselling is a special skill that depends on training and the ability to communicate, and involves actively helping couples to reach decisions in the context of their unique medical, moral and social situation. To meet the requirement for autonomy, it is essential to communicate the diagnosis and the implied risks effectively. Because genetic disease is diverse and in some cases unpredictable, and the language, culture and social level of those counselled covers such a wide range, communication can represent a major challenge. Couples at high risk for having children with inherited diseases rarely see separation and finding another partner an acceptable alternative to having their own (genetic) children. If they modify their reproductive behaviour, prenatal diagnosis is most often their method of choice. Such couples need information and the support of a trained genetic counsellor who should possess good communication skills. ## Genetic counselling and education Now that genetic screening and prenatal diagnosis are accepted components of medical practice, audit is essential for their effective service delivery. Although audit is still very underdeveloped, such audit as exists points to inadequate delivery of existing services. Some data are collected and recorded, but usually not on a regular basis. Data collection should be organised on a regional and national level in order to monitor the impact of prenatal diagnosis. It is particularly necessary to develop ways of monitoring the impact of routine ultrasound scanning. There is a strong medical and socio-economic case for rational planning and adequate funding of prenatal diagnosis services but most existing economic analyses of such services are highly unsatisfactory, and underestimate their true benefits. The economic dilemma of modern medicine arises partially from the fact that many medical advances improve the survival of people with chronic disabilities, and so lead to increasing service needs. Largely because of this, in the absence of prevention, the cost of treating patients with the inherited diseases listed in ?' 'Effectiveness score' is a rough indicator of the effectiveness of treatment in controlling the disease. 1 = completely effective; 5 = ineffective. The score indicates that when treatment is effective, costs can be high and tend to rise because of improved patient survival. When there is no effective treatment, as for Huntington's chorea, costs to the NHS can be modest and are not expected to increase with time, unless a more effective treatment is found. [fig_ref] Table 3: Estimated minimum annual cost to the NHS in the UK of treating... [/fig_ref] will double in the next 20-30 years. Unlike many other branches of medicine, medical genetics has a built-in means through genetic counselling and prenatal diagnosis for limiting its own expansion. i For many couples, the relatively small cost of a prenatal diagnosis represents the price of a healthy child, since without prenatal diagnosis they might not dare to undertake a pregnancy. ii A proportion of couples at risk (25% in the case of X-linked and recessively inherited diseases) find the pregnancy is affected. Most of those at risk for severe disease choose to terminate the pregnancy, and soon undertake another in the hope of replacing the aborted fetus with a healthy one. iii If the costs of the whole programme are aggregated, it is cheaper to screen and counsel the whole population than it is to treat affected children who would otherwise be born to unprepared couples. iv When prospective carrier screening is possible, a primary-health-care-based policy of community information, screening and counselling provides by far the best medical service to the groups at risk and also leads to the greatest short-and long-term savings. v Most analyses agree that screening and prenatal diagnosis programmes are wanted by the population and offer major financial advantages. The investment required is relatively modest and will conserve NHS resources for other uses. ## '? organisation of services There is now a national network of clinical geneticists and a clinical genetics unit in most NHS regions. Most are associated with an academic centre, but few have adequate staff or counselling or diagnostic resources, and very few bring together all the relevant services on one site. In addition, prenatal diagnosis services are falling short of their potential because of conspicuous inadequacies of medical education and community information, absence of educational aids, and inadequate counselling associated with screening and prenatal diagnosis. Monitoring of the impact of prenatal diagnosis is almost non-existent. To improve the situation, planning is needed at national, regional and district levels. Policy formulation, development and distribution of education materials, and service monitoring should be organised at a national level. Each region should develop an organisation, involving genetics and fetal medicine centres, neonatologists and paediatric pathologists, obstetric and paediatric consultants, primary care physicians, community physicians, health workers involved in family planning, health visitors, midwives, nurses and experts in health education and community medicine. A designated coordinator (who may often but not always be a clinical geneticist) should be responsible for bringing these People together on a regional basis to improve delivery of both specialist and community genetics services. For the prenatal diagnostic service to be delivered effectively, the regional organisation must be reflected at the district level and involve general practitioners, maternal and child health workers and antenatal clinics. ## Ethical aspects of prenatal diagnosis The central ethical obligations of prenatal diagnosis are those of good medicine. Bad science, sloppy medicine, insensitive communication and misinformation can cause at least as much harm as failure to enunciate ethical principles or minor deviation from them. The choice of option and outcome following prenatal diagnosis should be made by informed couples; they are the best judges of what should be done. The same objective situation may lead to different decisions by different couples or individuals, depending on their attitudes and beliefs?particularly those of the mother. But their decision will also depend on the advice available to them, in terms of both its scientific quality and the manner in which it is given. Prenatal diagnosis should be undertaken within the general principles of informed consent, including the possibility that, after testing, the question of terminating the pregnancy may have to be faced. Women must therefore have the right to refuse testing, even at a fairly preliminary stage, and must understand the implications of their decision. While prenatal tests should not be pressed upon anyone, they should be made available, even to women who are completely opposed to abortion, since testing may provide welcome reassurance, or an informed choice to care for a child with a known handicap, or allow the option of abortion to be reconsidered on the basis of known facts. Though it is important to consider financial costs and benefits in order to ensure that these services are made available, couples should never be pressed to choose termination of an affected pregnancy on grounds of cost. Any decision should arise exclusively from the moral perceptions of the couple themselves. A doctor does not have the right to deprive pregnant women of the possibility of prenatal diagnosis because of his or her own opposition to abortion. If, in conscience, a doctor cannot offer information and access to the service, it is obligatory to refer the woman or the couple to someone who will do so. Counselling should be non-directive. Information, not direction, is given in such a way as to help the parents to make the decision that is right for them. The counsellor should as far as possible be ethically neutral, and the long-term ethical presuppositions must be those of the parents. The most likely outcome of prenatal testing is reassurance, requiring no further choices. If, however, the tests suggest that a handicapped child is likely, the degree of likelihood should be explained, and also the extent of the burden which the child and family may have to carry The ethical case has already been made for carrying out genetic counselling prior to marriage or pregnancy, when possible. should be made with the relevant professional bodies to develop the genetic component of the training curriculum and to organise updating courses for existing practitioners. 6. Because of the large numbers involved, and the relative simplicity of some issues in large-scale screening programmes, genetic information and counselling must be provided at the community level. The ideal professionals to provide information and counselling would be specially trained health visitors and midwives, who are already the point of first and most frequent contact with mother and child. The suggestion is consistent with current proposals to train nurse specialists, who in this case would act as reference and training resources for MCH workers in general. 7. Specialist genetic counsellors already work with clinical geneticists and with specialists in particular disorders. Equivalent specialist counsellors should be attached to each obstetric unit practising pre-natal diagnosis. It is urgent to define a career structure for such specialist counsellors, who may have differing professional backgrounds, and carry out a wide range of activities. 8. a Policy formulation, defining a career structure for genetic counsellors, development and distribution of educational materials and service monitoring, should be organised at national level. b Each region needs to develop an organisation for ensuring delivery of genetic screening and prenatal diagnosis. This organisation should include clinical genetics and fetal medicine centres, neonatologists and paediatric pathologists, obstetric and paediatric consultants, primary care physicians, community physicians, health workers involved in family planning, health visitors, midwives, nurses, and experts in health education and community medicine, c For the service to be delivered effectively, the regional organisation must have roots at the district level, in the antenatal clinics and among general practitioners and other maternal and child health workers. 9. Because of their multidisciplinary nature, prenatal diagnosis services should be under the overall supervision of designated district and regional coordinators who may often, but not always, be clinical geneticists. The co-ordinator's responsibility should be to ensure that the services are provided to the recommended standard and co-ordinated and monitored throughout each region. 10. Though monitoring should be organised on a regional basis, a national centre is needed to develop appropriate methods, co-ordinate information nationally, and stimulate equal service delivery throughout the country. 11. Face-to-face counselling and written information are complementary rather than alternative sources of information for an educated population; one should not be given without the other. Information packages need to be directed to schools, young couples and pregnant women, and individuals with defined genetic risks. Because of the wide range and different levels of educational resources needed to cover the spectrum of potential abnormalities, a National Genetic Health Education Unit is needed to generate, store and disseminate information. 12. These proposals should be implemented through working groups and supported by the DoH. This is a very abbreviated summary of the full report which is available from the Royal College of Physicians, price ?10.00. [table] Table 1: Approximate annual incidence of births of infants with congenital and genetically determined disorders in the UK (Total annual births about 700,000). Journal of the Royal College of Physicians of London Vol. 23 No. 4 October 1989 [/table] [table] Table 2: Incidence of some severe inherited diseases and their approximate carrier frequency in the UK Approximately equal to the incidence of disease; ie few, and mostly relatives of patients About twice the incidence of the disease; ie relatively few, and most are female relatives of patients [/table] [table] Table 3: Estimated minimum annual cost to the NHS in the UK of treating patients with selected inherited disease, and projected future figures if there were no prevention [/table]	None	None	Everyone is at risk for having abnormal offspring. In fact, at some time in their reproductive life about half the world's women conceive a pregnancy with a chromosomal abnormality. However, most such pregnancies end in a spontaneous abortion and until recently many infants born with serious abnormalities died, often undiagnosed, in early childhood. The purpose of this report is to demonstrate how advances in medical research have created new opportunities in preventive medicine. Most infants with congenital malformations and chromosomal disorders are born to healthy young
e79a4e04ebdcc671d100e12102659b7e24f26c4c	pubmed	COVID-19 guidance for triage of operations for thoracic malignancies: A consensus statement from Thoracic Surgery Outcomes Research Network	COVID-19 guidance for triage of operations for thoracic malignancies: A consensus statement from Thoracic Surgery Outcomes Research Network # Abstract The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted, forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies as the impact of COVID-19 evolves as each hospital. (J Thorac Cardiovasc Surg 2020;160:601-5) Thoracic Surgery Outcomes Research Network. ## Central message The extraordinary demands of managing the COVID-19 pandemic has disrupted the world's ability to care for patients with thoracic malignancies. As a hospital's COVID-19 population increases and hospital resources are depleted, the ability to provide surgical care is progressively restricted-forcing surgeons to prioritize among their cancer populations. Representatives from multiple cancer, surgical, and research organizations have come together to provide a guide for triaging patients with thoracic malignancies, as the impact of COVID-19 evolves at each hospital. [fig_ref] TABLE 1: Guidance for the triage of patients with thoracic malignancies Phase I Few... [/fig_ref] patients. In response, many hospitals have abruptly reduced or eliminated elective operations. As the COVID-19 burden on a hospital increases, procedures that improve survival may similarly have to be reduced or eliminated (ie, semielective, urgent, and perhaps some emergent operations). For some cancer patients, surgery may be delayed for months or even years without negative consequences. In other scenarios, however, failure to perform an indicated cancer surgery in a timely fashion may have long-term implications on a patient's survivorship or significant permanent deficits in their quality of life. Therefore, cancer patients and the oncology teams that treat them are likely to face difficult decisions between suboptimal management strategies. Thoracic oncology decisions are further complicated by the fact most of the patients with lung, esophageal, and other thoracic malignancies would be considered to be a high-risk group for poor outcomes with COVID-19 (advanced age, emphysema, and heart disease). Further, the indicated therapeutic procedures can both impair lung function (ie, lung isolation, removal of lung tissue) and expose clinical teams to aerosolized viral load (bronchoscopy, double-lumen endotracheal tube placement, airway surgery, laparoscopy and possibly lung surgery particularly with parenchymal lung leaks). We have assembled a document to offer guidance intended to facilitate these difficult decisions when caring for patients with thoracic malignancies during the COVID-19 pandemic [fig_ref] TABLE 1: Guidance for the triage of patients with thoracic malignancies Phase I Few... [/fig_ref]. [bib_ref] Effects of delayed surgical resection on shortterm and long-term outcomes in clinical..., Samson [/bib_ref] [bib_ref] Defining the ideal time interval between planned induction therapy and surgery for..., Samson [/bib_ref] [bib_ref] Delay in diagnostic workup and treatment of esophageal cancer, Grotenhuis [/bib_ref] [bib_ref] Does the timing of esophagectomy after chemoradiation affect outcome?, Kim [/bib_ref] [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] [bib_ref] A systematic review and meta-analysis of stereotactic body radiation therapy for colorectal..., Cao [/bib_ref] [bib_ref] Lobectomy versus stereotactic body radiotherapy in healthy patients with stage I lung..., Rosen [/bib_ref] [bib_ref] Survival of primary stereotactic body radiation therapy compared with surgery for operable..., Khorfan [/bib_ref] [bib_ref] Surveillance versus esophagectomy in esophageal cancer patients with a clinical complete response..., Semenkovich [/bib_ref] [bib_ref] Cincinnati Research in Outcomes and Safety in Surgery (CROSS) Group. Outcome of..., Levinsky [/bib_ref] ## Assumptions Much of the impact, timeline, duration, risks, and ultimate recovery from the COVID-19 pandemic remain unknown. In an effort to give context to this triage guide, several assumptions have been made: The risk of nosocomial infection (patients and clinicians infected while in hospital) [bib_ref] COVID-19: towards controlling of a pandemic, Bedford [/bib_ref] [bib_ref] Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia, Li [/bib_ref] [bib_ref] China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease..., Guan [/bib_ref] [bib_ref] Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington..., Arentz [/bib_ref] [bib_ref] Minimise nosocomial spread of 2019-nCoV when treating acute respiratory failure, Cabrini [/bib_ref] and competition for resources (surgical and medical patients) will increase in proportion to the prevalence of hospitalized COVID-19 patients. The duration of restriction on elective surgery will last approximately 3 months. Each facility's progression through the phases of care restriction will be variable, but surgeons should be prepared for rapid changes in hospital status (ie, consider what eligible operations could or should be performed as soon as possible). Surgical leadership are provided with daily updates regarding a hospital's COVID-19 population and resource status. ## Process of priority status determination for individual patients There are nuances to each patient's management approach, such as proceeding with surgery, delaying surgery, or pursuing alternative treatment, that will impact risk tolerance for both patient and surgeon. Ideally, when traditional cancer treatment is not logistically feasible, a patient's care plan will be made with input from a group of clinicians with expertise in thoracic malignancies, such as a case conference or tumor board. We encourage the use of this multidisciplinary strategy as guidance as appropriate for each individual hospital or clinic setting. Several considerations may cause a group's consensus approach to differ from what is proposed in [fig_ref] TABLE 1: Guidance for the triage of patients with thoracic malignancies Phase I Few... [/fig_ref] : The risk of delay may not be specifically captured by the outlined descriptors (ie, tumor may have aggressive growth kinetics or histology). Resource limitations (clinicians, supplies, facilities) affecting surgical, medical and radiation oncology departments may pose heterogeneous restrictions from hospital to hospital. Clinicians will need to keep in mind the important concept of social distancing in modifying management to limit the number of visits to the hospital for any reason. In addition, because the duration of surgical volume restriction is unknown (3 months is presumed), patients who are delayed or deferred should be tracked (ie, a patient registry or database). Considerations for the database should include the following: Indication if reassessment during the period of delay could influence care plan (ie, follow-up computed tomographic scan). This should be extremely selective, because access to imaging will likely be increasingly restricted with increased COVID-19 prevalence. An indication of case priority (ie, first group, second group, third group) for rescheduling when restrictions are lifted to best care for patients whose survival may be most impacted by additional delay. Alternative treatment strategies used in lieu of surgical resection (ie, systemic chemotherapy, stereotactic body radiotherapy, or other ablative strategies, palliative stent placement, etc) should also be tracked. ## Disclaimers This guidance document is meant to serve patients based on estimates of risk for average patients (in terms of tumor behavior, patient health, hospital resource availability) associated with each strategy. These should not be considered rigid guidelines. This guide is not intended to supplant clinical judgment or the development of consensus regarding institutional approaches to cancer treatment. There is a great deal of uncertainty around this evolving pandemic and information may change rapidly. Critical portions of the transition are not addressed. In reality, there is likely to be a Phase "1a," "1b," "1c," where only fraction of the priority cancer patients may have access to surgery. Clinicians may have to further restrict of surgery, likely across specialties (ie, colon cancer, breast, hepatobiliary) based on the perceived magnitude of risk of delay and over shorter time periods (ie, impact of 8-week delay, then 4 weeks, etc). Preoperative evaluation is likely to be impacted (ie, pulmonary function testing), and preoperative screening for COVID-19 is evolving (survey for symptoms, temperature assessment, possible selected testing for COVID-19 where available). It is possible that the strategies outlined in this document could be replaced as our understanding of unique challenges that COVID-19 poses within each country, state, and health care environment evolves. This document is not intended as a guide for other clinical scenarios, epidemics, or pandemics. ## Shared decision making and transparency Transparency regarding the potential risks of deferring or proceeding with an operation remains a priority. Surgeons should discuss these decisions individually with their patients. Multidisciplinary teams are encouraged to develop alternative treatment strategies if surgical resection is declined or infeasible. ## Origins of consensus statement This initiative is an extension of the American College of Surgeons and Commission on Cancer (CoC) effort to provide guidance for surgeons to make difficult triaging decisions in the face of progressively limited access to operating rooms, and there may be some slight differences in this document compared with the CoC-published documents. A partnership was formed between the CoC (Tim Mullett, Larry Shulman, Linda Martin, and Matt Facktor), the Thoracic Surgery Outcomes Research Network (ThORN, a research collective of board-certified general thoracic surgeons), and leaders from the American College of Surgeons (Heidi Nelson, Valerie Rusch, and Douglas Wood), and reviewed by leadership from The Society of Thoracic Surgeons and the American Association of Thoracic Surgery (David Jones and Shaf Keshavjee). The limited data were discussed in an open exchange, and the resulting guide is best characterized as being based on "expert opinion" in terms of strength of evidence. The authors recognize that multiple resources are becoming available to triage all types of surgical treatment. We intentionally avoided language that is currently being used to structure guidance based on procedures (ie, tiers) or patient status [fig_ref] TABLE 1: Guidance for the triage of patients with thoracic malignancies Phase I Few... [/fig_ref] defines 3 phases of hospital status based on (A) the prevalence of COVID-19 patients within the hospital, (B) availability of hospital resources, and (C) the rate of change (in terms of increasing prevalence of infections and resource depletion). Because there are unique considerations for individual patients, each phase is accompanied by a "compass statement" that is meant to give additional direction to navigate volume restriction based on perceived risk to patients and hospital staff. For each phase, surgeons should operate for recommended scenarios (first column) but also for recommended scenarios from all higher phases (ie, appropriate operations during Phase II, include first column under both Phase II or Phase III). There are very limited data to inform many key decisions. The data and references in this section are meant to serve as an estimate of effect size, using the largest data sets available. They are not complete and, therefore, should not be used as definitive data but are only suggestive of the magnitude of effect. ICU, Intensive care unit; PPE, personal protective equipment; EBUS, endobronchial ultrasound; VATS, video-assisted thoracoscopic surgery. A study from the National Cancer Database suggests that the interval between diagnosis and surgery (ie, time-to-treat) for stage I lung greater than 8 weeks is associated a reduction in 5-year survival (54.8% vs 48.7%, P>.001). 1 For stage III lung cancer patients, a delay of greater than 3 months between neoadjuvant therapy and surgery was associated with shorter median survival (33.2 months vs 39.8 months, P ¼ .03). [bib_ref] Defining the ideal time interval between planned induction therapy and surgery for..., Samson [/bib_ref] Smaller institutional studies have not revealed a clear association between the diagnosis-to-treatment interval and long-term outcomes in patients with esophageal cancer. [bib_ref] Delay in diagnostic workup and treatment of esophageal cancer, Grotenhuis [/bib_ref] A delay of greater than 8 weeks between neoadjuvant therapy and surgery for esophageal cancer is not associated with decrement in long-term survival. [bib_ref] Does the timing of esophagectomy after chemoradiation affect outcome?, Kim [/bib_ref] yAvailability of alternative treatments may vary across health systems and over time. The decision to pursue alternative treatment must balance risk of deferring alternative treatment (chemotherapy and radiotherapy) with risk of exposure of both patients and staff to COVID-19 infection. In Phase I, alternative treatments predominately considered in patients felt to be harmed by delay are listed (ie, the first column of table). zAt the time of writing, the risk of death with COVID-19 infection is felt to be higher among patients receiving chemotherapy, but the data are incredibly limited (18 cancer patients in China). [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] xAlthough the accuracy of the clinical staging examination may be enhanced by invasive staging procedures, the magnitude of survival benefit from superior staging may be considered by some to be modest. In the setting of strained resources and potential exposure risk to clinical staff from staging procedures (bronchoscopy and mediastinoscopy), treating a patient based exclusively on a noninvasive staging evaluation (ie, imaging alone) is reasonable. kThese procedures are currently felt to be associated with a particularly high potential to disseminate COVID-19. They should be done selectively and ideally in patients who have been screened for active COVID-19 infection. {There are incomplete data comparing surgery to stereotactic ablative radiotherapy for early-stage lung cancer in patients eligible for surgery. Observational data, which is likely biased with patients who were not surgical candidates, suggests a modest survival advantage of surgery (5%-15% higher 5-year survival). 6-8 #Among presumably highly selected patients, salvage resection has been associated with reasonable survivorship after definitive nonsurgical therapy for esophageal cancer, particularly if the patient has had a good response by imaging. 9,10 *Recommended for patients in whom a delay would likely compromise survival (ie, first column from Phase I section). (ie, emergent, urgent, and semiurgent) to avoid confusion, and have instead organized recommendations based on the conditions that exist within each hospital ("phases"). ## Final thought There are times when the right decision becomes easier-as the impact of the decision evaporates. This is one of those times. We hope that this document facilitates the timely execution of what are sure to be increasingly difficult decisions. [table] TABLE 1: Guidance for the triage of patients with thoracic malignancies Phase I Few COVID 19 patients in hospital Hospital resources intact (eg, ICU beds, ventilators, clinicians, PPE) COVID-19 trajectory not in rapid escalation phase Compass Statement: Surgery restricted to patients whose survivorship is likely to be compromised by surgical delay of 3 months Compass Statement: Surgery restricted to patients likely to have survivorship compromised if surgery not performed within the next few days Compass Statement: Surgery restricted to patients likely to have survivorship compromised if surgery not performed within next few hours [/table]	None	http://www.jtcvs.org/article/S0022522320307443/pdf	None
8269d6be72d53393ff7a13bc261ee0e3e9e16442	pubmed	Palliative and supportive care in head and neck cancer: United Kingdom National Multidisciplinary Guidelines	Palliative and supportive care in 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. It provides recommendations on the assessments and interventions for this group of patients receiving palliative and supportive care. # Introduction Palliative care aims to improve the quality of life (QoL) of patients and their carers facing the problems associated with life threatening illness. This can be achieved by the prevention and relief of suffering, ensuring comfort and dignity, by means of early identification, assessment and management of pain and other, physical, psychosocial and spiritual issues. Patients with head and neck cancer are a group in whom both specialist palliative and supportive care is especially appropriate whether the treatment intent is curative or not, since the disease and its treatments result in a huge burden of morbidity: short and long to a taking over of care. Support provided will need to accommodate any communication impediment. In turn, specialist palliative care practitioners need to be aware of when and how to use palliative interventions such as surgery, radiotherapy (RT) and chemotherapy. All this is best achieved by a high level of integration of servicesteam working, including the primary care teamand excellent communication, with the 'key worker' (usually a specialist nurse) at the centre. ## Approaches Palliative care takes a holistic approach, addressing physical, psychological, social and spiritual needs of the patient, their carers and family (Box I). Interventions which may be appropriate to palliative care include oncological and surgical approaches, drug management, psychological support, Allied Health Professional (AHP) input and complementary therapies. This paper focuses on medical and surgical interventions for physical symptoms, but these should be addressed as part of a wider holistic and multidisciplinary approach, which includes concern with psychosocial and spiritual issues. Whilst the distinctions between physical and psychosocial symptoms should not be overstated, different interventions will dominate in each category. Drugs, anticancer treatments such as RT, surgery and procedures will dominate in the first category, whilst counselling, honest communication, support groups and complementary therapies will be preferred in the second. This distinction is not clear-cut, however; counselling and honest communication are important parts of pain relief, whilst drugs have a role in the management of symptoms such as anxiety and depression. A well-developed multidisciplinary approach, coupled with an open-minded approach to intervention, is therefore essential. It is the role of the MDT team to discuss treatment options in all patients. This includes decisions on who should be treated and what is untreatable disease. This is a complex issue and although broad guidelines can be applied each case should be assessed individually. Radical treatment in advanced or recurrent head and neck cancer may be futile and result in poorer QoL, therefore important decisions need to be made at presentation about which treatment pathway to take. The alternative where there is a low chance of cure is a palliative pathway. Palliative treatments include surgical and non-surgical interventions with the intention of slowing disease growth and symptom control, and extending life with focus purely on symptom control. Effective decision making in the palliative setting is important. The patient and family should adequately understand the diagnosis and prognosis, especially if the trajectory changes due to intervention or disease progression. It should be made clear that symptoms will be identified and treated and patients should be asked if there are any new goals for their treatment since cure is not possible. In other words, the team should not convey a sense of hopelessness simply because the goal is not indefinite survival. Hope can be maintained within the context of the patient's own goals whether they are: - physicalrelief of symptoms - psychologicalfear of distress, suffocation, bleeding or uncontrollable pain at the end of life - Socialdesire to witness a family event, celebrate a birthday or make a trip. Symptoms should be actively sought and treated in a proactive manner, and it should not be assumed or conveyed that any new symptom is as uncontrollable as the tumour itself. Treatment options should be discussed for the new symptom including those that may not extend life. Although patient choice is central to the treatment options taken, the treating clinician should make recommendations to guide treatment and share the burden of difficult decisions. - All core team members should have training in advanced communication skills (G) ## Symptom control Surgical palliation Incurable end-stage head and neck cancer leads to distressing symptoms. Patients may remain active and selfcaring while trying to cope with problems of pain, swallowing, breathing and bleeding. Palliative surgery may be indicated in such cases. Little high-level evidence is available to confirm the surgical benefit; however, descriptive studies support its use in selected cases. Surgery can reduce primary tumour bulk, reduce pain and bleeding, improve swallowing, nutrition and improve and airway (see below). Debulking surgery for advanced neck disease can achieve symptom control, but major resections only rarely offer levels of benefit, which justify the extent of surgical morbidity. Newer endovascular techniques, including embolisation and vessel stenting, may offer symptom control for bleeding related to major vascular erosion, and these interventions can be considered in patients at high risk of erosion of major vessels. Acute haemorrhage from carotid 'blow-out' (erosion of the carotid vessels) is a distressing end of life event. Whilst occasional success can be achieved with swift surgical intervention, many patients succumb rapidly. In these cases, attempts to reduce the flow of blood with direct pressure while administering appropriate rapid acting sedatives (e.g. benzodiazepines) should be made. Constant verbal support to the patient is a key to help handle anxiety. Do not leave the patient's side. If surgical intervention is considered inappropriate careful discussion and measured information giving to the patient (if they wish to participate) or family members and carers is essential. This should include the anticipated clinical scenario and an acceptable plan of care should be devised to manage these circumstances. This may include the use of dark towels, anticipatory prescribing, and may influence preferred place of care. ## Recommendations - Palliative surgery should be considered in selected cases (R) - For control of bleeding endovascular stenting or embolisation should be considered (R) ## Non-surgical palliation Radiotherapy. Debate continues around the optimal dosage regimen for palliative RT. Low-level evidence exists for the use of hypofractionation schedules and short course RT. Other protocols such as those described by the Radiation Therapy Oncology Group have also demonstrated benefit. Symptom control can be achieved in up to 80 per cent of selected patients with particular response in terms of pain control. No high-level evidence exists to support one protocol over another, but case series report benefit. Re-irradiation may be offered but may be associated with severe radiation toxicity. A systematic review of RT for painful bone metastases reports benefit in up to 50 per cent of patients. [bib_ref] Bisphosphonates for the relief of pain secondary to bone metastases, Wong [/bib_ref] There is evidence to support the use of bisphosphonates to aid pain control of bone pain as an additional step once RT and conventional pharmacology has been used. The role of the new monoclonal drugs including RANKligand inhibitors (e.g. denosumab) has yet to be elucidated. Chemotherapy. This includes the use of platinum-based agents, 5-fluorouracil and methotrexate, either as monotherapy or in combination with RT and demonstrates benefit in symptom control and QoL measures, but may increase toxicity and hence side effects from the treatment. Careful consideration of the balance between benefit and harm must be made on an individual patient basis. Non-platinum-based agents are reported as conferring symptom control in the selected cases. Future modalities. Future research will include the role of taxanes, e.g. paclitaxel, monoclonal antibodies e.g. cetuximab, newer chemotherapeutic agents, photodynamic therapy and interstitial laser therapy. Descriptive series report some symptom controls using these modalities but without any evidence of improved survival. ## Recommendations - Hypofractionated or short-course RT should be considered for local pain control and for painful bony metastases (R) - Bisphosphonates can be considered for bone pain following RT (R) Palliation of dysphagia Forty per cent of patients with head and neck cancer suffer from dysphagia. This is due to: [formula] - mechanical obstruction - functional obstruction - drug induced side effects - fistula - pain. [/formula] Assessment of the swallow is essential in palliative head and neck patients. It is important to establish whether oral intake is possible and whether it is safe. Aspiration is not H COCKS, K AH SEE, M CAPEL et al. ## S200 uncommon and may be silent in up to 40 per cent of patients, thus the bedside assessment is of limited value. Functional endoscopic evaluation of swallowing (FEES) is straightforward, easily repeatable, portable and can give good information on the aetiology of aspiration as well as feedback to the patient on trials of preventative manoeuvres. It can also be useful in the assessment of ability to deal with different textures and complements information obtained from videofluoroscopy. Aspiration does not inevitably mean no oral intake. A degree of aspiration may be well tolerated and methods taught to clear the airway after swallowing can be implemented. Similarly certain textures may be better tolerated and the use of thickened fluids can help maintain oral intake. It is important to take into account the patient's wishes and the patient may make an informed choice to continue to swallow despite the potential and real risk of aspiration pneumonia. Quality of life is absolute. In patients who are unable to swallow, the use of an enteral route via nasogastric tube (NGT) or gastrostomy allows for hydration, nutrition and medication. The type of tube used depends largely on ability to pass an NGT or fashion a gastrostomy, perceived duration of use and patient choice. If enteral nutrition via NGT is likely to extend beyond two to three weeks then gastrostomy should be considered and discussed with the patient. There exists no clear guidance on when or if it is acceptable to withdraw nutritional support. Patient and family wishes are crucial in this decision process and full consultation is imperative. Conventional treatments can be helpful in the palliation of swallowing. Surgical debulking either with or without the laser or debrider and RT may help reduce bulk in a hypopharyngeal tumour, dilatation can help in stricture formation and this can be surgical or radiologically guided. Stenting may play a role but often head and neck tumours are too high to accommodate a stent comfortably and without impacting on other functions. ## Recommendations - All palliative patients should have a FEES assessment of swallow to assess for risk of aspiration (G) - Establishment of enteral feeding must be considered early in patients who are unable to maintain their intake orally (G) ## Palliation of the airway Where there is airway compromise it is common practice to consider a tracheostomy. However, it may be possible to avoid tracheostomy in some cases if the consideration is given to surgical debulking techniques. This is dependent on local expertise and equipment. [bib_ref] Interventions for noisy breathing in patients near to death, Wee [/bib_ref] Sometimes avoiding surgical intervention is the most appropriate course of action, for example, a patient with a tracheal tumour that has been repeatedly debulked, and has received palliative RT, is not a candidate for stenting. There will come a time when the airway compromise will be life threatening. A tracheostomy may not be an option in this instance. In such instances opioids for dyspnoea in addition to palliative sedation and reduction of secretions can support a patient in a terminal event. These situations are difficult and information should be imparted to the patient sensitively. In the situation where the patient wants to fully discuss the anticipated scenario a sense of control can be restored to them by discussing what interventions can be undertaken pharmacologically to avoid any distress. If the patient does not want to participate in the discussion this should be documented and discussed with family and/or carers. This situation may influence the preferred place of care. To have the patient and the family prepared for the event is paramount. They must know what will be in place to prevent the dyspnoea and anxiety associated with such a situation and the patient must be comfortable to the end. If a tracheostomy is indicated local protocols should exist or be developed to help the patient, the family and community staff manage tracheostomy wound care along with maintenance of a clean secure tube. Heat moisture exchange and voicing attachments may be used to aid patient communication. ## Pain Pain is very common, affecting most patients at any stage. It may be disease or treatment related, either acute and/or immediate or persistent and/or lifelong. Pain occurring after a long, pain free interval is likely to be recurrent disease. Assessment must take account of the presence of 'total pain' i.e. physical, spiritual, psychological and social elements. The three major pain types are all encounteredsomatic, visceral and, particularly difficult, neuropathic. Analgesic use is best based on the World Health Organization (WHO) 'pain ladder' (Box II) with three steps of increasing potency, and used depending on pain severity and response. The severity of the pain dictates the strength of the analgesic and the pathophysiology dictates the adjuvant used. ## Box ii who pain ladder Paracetamol ± non-steroidal anti-inflammatory drug ± adjuvant Weak opioid (codeine or tramadol) + step 1 drugs Strong opioid replacing the weak + step 1 drugs The choice of formulation depends on whether the patient can swallow, is vomiting, or has a nasogastric (NG) or gastrostomy tube in situ. Somatic pain. Morphine remains the first choice strong opioid, other than perhaps in renal impairment when an alternative is preferred. It is initiated by titrating immediate release morphine oral solution or tablet (e.g. Oramorph™ solution or Sevredol™ tablet). Once responsiveness and dosage are known, then sustained release preparations are used, with immediate release doses for breakthrough at a sixth of the 24 hour sustained release dosage. If the patient can swallow, then sustained release tablets (e.g. MST Continus™) or capsules (e.g. Zomorph™) can be used. If a tube is in place then a morphine suspension (e.g. MST suspension™) or opened capsules (e.g. Zomorph™) can be used. If this is not feasible, usually because of vomiting, then a subcutaneous (SC) infusion of morphine or diamorphine can be used, with SC doses for breakthrough. Diamorphine is preferred since it is more soluble and can be used in much smaller volumes. Transdermal preparations of fentanyl have theoretical and practical attractions for stable background pain as an alternative, particularly if there is morphine intolerance (e.g. sedation and dysphoria) or there is renal failure. For breakthrough pain, oral opioids can still be used. Alternatively, new preparations of buccal, sublingual or intranasal fentanyl may have a role in specific situations, with supervision of a specialist service. Oxycodone can be an alternative to morphine where there is intolerance, particularly dysphoria; there is an immediate release solution and injection, but there is only a tablet form of sustained release oral preparation, limiting its use where swallowing is compromised. Hydromorphone is not useful orally where swallowing is impossible, both immediate and sustained release being capsules, but it may be injected. Methadone in liquid form can be very useful, being rapid in onset and long acting because of its half-life; it is best used by specialists as it can accumulate. Neuropathic pain. This is very common both as a presenting feature of the disease and a result of treatment, particularly radiation. The drugs used can be referred to as adjuvants. - A tricyclic antidepressant, most usually amitriptyline is available as tablet and liquid. - Anticonvulsants such as gabapentin and pregabalin are the most used, available only as tablets or capsules unless through special arrangements with a pharmacy. Gabapentin can be opened and administered via the gastrostomy tube. - Carbamazepine is an alternative and is available both as tablet, liquid and even suppositories. Sodium valproate is also available as a liquid preparation. First line would be either antidepressant or anticonvulsant titrated to maximum dose tolerated (usually added to a conventional analgesic): second line would be to use both. Some advocate corticosteroids (e.g. dexamethasone 8-16 mg daily) as first line for acute neuropathic pain where there is felt to be a significant inflammatory component. Appetite stimulation limits use if dysphagia is a concomitant feature. It is not for chronic or predictably long-term pain. Clonazepam is occasionally useful. Methadone and ketamine are useful, but only in specialist settings. Visceral pain. Treatment depends on the cause, titrating analgesics and using the pain ladder. If the pain is poorly sensitive to opioids, adjuvants should be considered early, for example pain due to metastatic disease in the liver or nerve compression may be eased with Dexamethasone (4-8 mg daily). Judicious use of all these drugs is best achieved by seeking advice from the specialist palliative care service whenever there is concern. Interventional pain techniques can be very effective where systemic treatments fail or if the patient is intolerant of the significant doses of combination analgesics. Mucosal pain. This can be due to treatment, infection or tumour. Treatment of infection such as candida or herpes is essential. Useful additional topical agents include sulcralfate, benzydamine, chlorhexidine, steroids and topical local anaesthetics such as lignocaine preparations. Coating measures including bioadherent oral gel may be preferred by the individual patient. ## Recommendations - Pain relief should be based on the WHO pain ladder (R) - Specialist pain management service involvement should be considered early for those with refractory pain (G) ## Nausea and vomiting The approach must take an account of the large number of patients who are enterally fed. Even with this there is often a need for injectable anti-emeticssubcutaneous (SC) boluses or continuous infusions, at least until initial control is established. Enteral feeding poses its own challenge, and prokinetic drugs such as metoclopramide (tablet, oral solution or injection) or domperidone (tablet, suspension or suppository) may be needed to ensure best function. Otherwise the approach is similar to that in general use. Remember the practical issue of providing a large bowl, tissues and water for the patient and be prepared to rehydrate using IV or SC fluids if appropriate. ## Constipation Constipation develops in half of patients who are terminally ill with cancer admitted to a hospice. In addition, it is common during treatment in many patients. This is due to dehydration, reduced physical activity and the use of constipating drugs, particularly opioids and anticholinergic medication. Laxatives should be initiated once opioid medication is prescribed. Hypercalcaemia and hypothyroidism are other causes, which may be overlooked. The principle of treatment is avoidance and early recognition. Enquiry should be made on patient contact. Laxative agents include stimulants such as bisacodyl and senna and softeners such as lactulose, magnesium hydroxide and docusate. Polyethylene glycol preparations including movicol and laxido are commonly used. These should be used prophylactically. If constipation develops it can lead to nausea and vomiting and in the severe situation pseudobstruction. If rectal examination reveals hard stool then the use of suppositories and enemas can be helpful. Ultimately, a manual evacuation may be necessary. ## Recommendation - Constipation should be avoided by the judicious use of prophylactic laxatives and the correction of systemic causes such as dehydration, hypercalcaemia and hypothyroidism (G) ## Confusion and agitation It is important to distinguish anxiety (unsettled, frightened, panic) from confusion, particularly delirium. Confusion is common, affecting up to 75 per cent of cancer patients at some stage. Many head and neck patients have a history of heavy alcohol (and tobacco) consumption, predisposing them to the effects of withdrawal, and given that cancer is more commonly seen in old age; then cognitive impairment is not uncommon. Benzodiazepines are the mainstay of pharmacological treatment of anxiety. Diazepam can be given orally, via a tube in liquid form, or by injection intravenously. Lorazepam can be swallowed or a tablet dissolved sublingually. If injections and/or infusions are needed, midazolam is preferred, as it can be given subcutaneously (most common route) or intravenously when almost immediate effect is needed. The key limiting factor, however, is rapidly developing tolerance; benzodiazepines are useful for short-term management of episodes of anxiety, but are limited where anxiety is pre-existing and established. Delirium as a cause of confusion can be related to a number of organic causesinfection, dehydration, metabolic disturbance, respiratory failure, urinary retention, constipation, brain metastases, etc. Administered drugs are common causes, particularly opioids and drug withdrawal (see above). While treatment has to be aimed at the cause, symptom management is required in the short term. While benzodiazepines have a role, indeed a specific indication in drug withdrawal, most often delirium is better managed using haloperidol (as tablet, liquid or injection, including SC) or levomepromazine (as tablet or injection) where sedation is needed in managing paranoia etc. In some cases, particularly for irreversible agitation or delirium in a dying patient, benzodiazepines and antipsychotics need to be combined and are often administered using a syringe driver. ## Recommendation - Organic causes of confusion should be identified and corrected where appropriate, failing this, treatment with benzodiazepines or antipsychotics should be considered (G) ## Secretions Although xerostomia is common in these patients, excess secretions and/or the inability to swallow or otherwise clear secretions is often troublesome. Physically the use of suction either by carer or the patient is often helpful. There are three widely used antimuscarinic drugs. - Hyoscine hydrobomide (scopolamine) is available as a transdermal patch, oral or sublingual tablet and is commonly used; however, it has central as well as peripheral actions and (unpredictable) sedation and/or confusion can result. - Hyoscine butylbromide, which is not central nervous system active, but equally effective peripherally, and is arguably the drug of choice. It is available as a tablet, though often ineffective by that route; hence SC use may be preferred. - Glycopyrronium, which is similarly peripherally active, and is most often given subcutaneously. A liquid form can be prepared but efficacy is unpredictable. - Excess secretions at the end of life are treated similarly, but the evidence in a Cochrane review suggests they are of very limited benefit. Established practice accepts SC preparations of anticholinergic medication are available for use to support this end of life phase. Timely management is a key here; if secretions develop, then regular or continuous antisecretory drugs should be started as soon as practical, rather than relying on PRN drugs. ## Steroids As with other cancers, corticosteroids are widely used. Dexamethasoneis the most used, because of its potency, relative lack of mineralocorticoid properties, and wide range of formulations (water soluble tablets, solution, and injection, SC or intravenous). [bib_ref] A prospective study of the use of steroids on a palliative care..., Hardy [/bib_ref] Dexamethasone 1 mg = Prednisolone 7.5 mg Long-term use also requires that attention be paid to bone mineral density, and bisphosphonates, and calcium and/or vitamin D supplements are indicated. i.e. to increase the dose when there is intercurrent illness or other stressor; and the need to reduce very gradually if used for more than three to four weeksincluding at the end of life. Some advise that steroids given for poor appetite or fatigue can be discontinued then. This puts the patient at risk of steroid insufficiency, an unnecessary symptom burden even at that stage, and dexamethasone can be given in small volumes subcutaneously once daily, as part of end of life care if appropriate. ## Spinal metastases The incidence of spinal metastases in head and neck squamous cell carcinoma is reported to be less than 2 per cent; however, it is more common in thyroid cancer (2-13 per cent). The most important factor in determining outcome is neurological status prior to treatment. Due to the devastating neurological sequelae of spinal cord or cauda equina compression early recognition (Box III) and action is essential and consideration that symptoms may be suggestive of spinal metastatic disease is the first step.Neurological symptoms and signs should be assessed and a magnetic resonance imaging of the whole spine obtained. This is an oncological emergency and steroids should be commenced while investigations or admission are arranged. Treatment depends on findings and includes steroids, surgical stabilisation and RT. Clear guidelines on diagnosis and management have been published by National Institute for Health and Care Excellence (NICE) and the readers should familiarise themselves with these. 7 ## Recommendation - Patients with symptoms suggestive of spinal metastases or metastatic cord compression must be managed in accordance with the NICE guidance (R) Care of the dying Care of the dying is an important part of good palliative care. Dying patients may have significant and rapidly changing symptoms, together with a recognition that no further active intervention is appropriate. For these reasons, timely assessment, regular review and confident symptom control are essential. In addition, this is an important time for loved ones; as noted by Dame Cicely Saunders, 'How people die remains in the memories of those who live on'. Ongoing sensitive and honest communication, coupled with sensible and proactive decision-making are therefore essential. [bib_ref] A framework for making advance decisions on resuscitation, Regnard [/bib_ref] Reversible causes for a patient's deterioration should be considered and may be acted upon depending upon earlier discussions, clinical acumen and based on the best interests of the patient. The physical changes preceding death generally include decreasing mobility, decreasing level of consciousness and interaction, minimal intake, progressing to no oral intake, decreasing urine output, haemodynamic deterioration and changes in respiratory pattern. Recognising death is imminent, the doctor may lead multiprofessional decision making and communication ensuring the patient (if appropriate) and families or carers understand the expected trajectory. The patient's values and preferences should be upheld where possible, these may include rapid discharge to enable the patient to die in the place of their choice, or enable their family to stay with them if in in-patient settings. Any religious, spiritual or cultural preferences should be identified. The Liverpool Care Pathway (LCP) was a protocol developed at the Marie Curie Institute Liverpool, and in use in the UK between 1997 and 2014. Concerns about the use of the pathway were raised in the press, and a subsequent government review was undertaken. Whilst recognising both good and bad outcomes arising from the use of the pathway, the ultimate recommendation of the review body was that the LCP be withdrawn. Current approach is based on this framework but using a more individualised and tailored care plan. Such plans are currently subject to local variation but can be used in all care settings including patient homes. National guidance is being developed following consultation. A key role of the doctor is to recognise that death is imminent, and, as recommended in the government review, the patient's senior clinician has a vital role in this decision in the MDT. Recognition of dying should prompt a thorough review of all care and interventions, with unnecessary medication being stopped, and essential medication continued, usually by SC infusions and boluses. In the head and neck patient, the frequent presence of NG and gastrostomy tubes allows continued use of some medications which would otherwise be impossible to administer. It is important to highlight that recognising dying does not automatically lead to discontinuing any such interventions; only that their role in improving symptoms should be assessed. Whilst nutrition is usually inappropriate in dying patients neither SC nor intravenous fluid is necessarily ruled outalthough the benefits can be, indeed often are very limited. Enteral tubes provide a further option for those patients. Sensitive discussion with the patient (if appropriate) and family or carers should be initiated to dispel any concerns held and agree a plan appropriate to the individual which may require modification depending upon the timescale and symptoms observed. A further vital aspect of end of life care, recognised both in the LCP and the review, is the need for regular multiprofessional assessment, and the possibility that patients may improve, for whatever reason, and hence the management plan be changed. Whilst an individualised approach is vital for dying patients, certain symptoms are common enough to warrant 'anticipatory prescribing'. The four major symptoms for which this is appropriate are: - pain - nausea and vomiting - agitation - excess secretions. The choice of drugs used is left to individual units and must be individualised further for some patients. For most purposes: - analgesiadiamorphine or morphine - anti-emetichaloperidol or levomepromazine - agitationmidazolam and/or levomepromazine or haloperidol - antisecretoryhyoscine, either butyl or hydrobromide. The right to life Freedom from inhuman or degrading treatment The right to privacy Freedom of expression and to be informed Freedom from discrimination When considering palliative and end of life care, one specific area for consideration is that of CPR. Ultimately, any decisions made around CPR should be undertaken in advance. In the event of a cardiac arrest, and where no such decisions have been made in advance, the default position is to perform CPR. In some cases, even in patients with incurable disease, this is appropriate. In the dying patient, however, or in cases where the chances of CPR succeeding are remote, then CPR adds no benefit to patient care. In such cases, a 'Do not attempt cardiopulmonary resuscitation' (DNACPR) order should be completed. There exists a number of issues regarding DNACPR decisions, outlined in national guidance issued by the British Medical Association (BMA), Royal College of Nursing (RCN) and Resuscitation Council (RC), and recently examined in a Court of Appeal Judgement. Two key points stand outthe decision-making around CPR, and the discussion around such decisions. The current BMA, RCN and RC guidance is summarised here, but may be subject to review in the coming months. Decisions around CPR Where a cardiac arrest is a significant possibility, where CPR has a reasonable chance of success, and where no advance decisions have been made with respect to resuscitation, then CPR should be attempted. Examples of such cases include acute reversible illnesses or treatable arrhythmias. Similarly, if a cardiac arrest is unlikely, then CPR should be attempted if it occurs. Examples here include the otherwise healthy person admitted with a relatively minor illness or an out-of-hospital arrest in public. A presumption of patient consent exists here, and it is not relevant to discuss in advance unless requested (and in such a case, patient wish should be respected). Whilst this is applicable to many hospital patients, it is less relevant to palliative care patients, in whom life-threatening events are more likely, and CPR is less likely to succeed. At the other extreme, where a patient is dying and no reversible causes for their condition exist, then CPR is inappropriate. In this context, cardiac arrest may be viewed as the final event in the process of natural death. Nevertheless, whilst the clinical decision may be clear, serious consideration needs to be given to discussion with the patient and family; this is covered in the section 'Discussing CPR decisions', below. In many cases, including in palliative care, the benefits and burdens of CPR are less clear-cut. For example, in a patient with an ultimately palliative diagnosis but who is otherwise active and well, there is a small chance that CPR in the event of a cardiac arrest may succeed. It is beyond the remit of this work to outline factors that count for and against this. In such cases, the preferences of patients (or those delegated to make decisions on their behalf) are pivotal. ## Discussing cpr decisions As outlined above, discussing CPR decisions is not relevant in a large proportion of hospital patients, as presumption of consent exists. This section is concerned with those cases where cardiac arrest is a realistic possibility. Where CPR would not succeed. In cases where it has been determined clinically that CPR has no realistic chance of success, the decision rests with the medical team. Any discussion revolves around sensitively informing the patient (and/or any person delegated to be involved in such discussions) of the decision that has been made. Difficulties here arise where the patient or delegated person objects to the decision. In such cases, seeking a second opinion is good practice. It is usually possible to work through such disagreements with time and sensitive communication. In some such cases, the cited guidance allows for DNACPR decisions not to be discussed with the patient or their delegated decision-maker. This applies to situations where the treating team have strong reason to believe that such discussions will cause significant distress or where the patient has asked not to be involved in such discussions. Citing risk of distress should not be undertaken lightly; any such judgement should be carefully documented and backed up with evidencesuch decisions have been challenged in court. It is important to reinforce that the clarity of the decision is not a factor in considering whether to discuss a DNACPR order. Even where CPR has no chance of success, serious consideration should still be given to discussion. Unclear benefits/burdens: a person with capacity. A competent patient can decline CPR and a DNACPR document can be completed based solely on this decision, provided the clinician completing the document is satisfied that the patient has capacity for the decision and understands it. Whilst a competent patient may decline CPR, they may not insist on receiving CPR in the event that they suffer a cardiac arrest, if it is deemed that CPR would not succeed. Where there is a possibility of success, eliciting and respecting the patient's wish is crucial. Such discussions should be handled sensitively, and the patient given the opportunity to consider the discussion and invite family members/carers to support them. There are further subtleties to these decisions, but such discussion is outside the remit of this work. Examples include a patient refusing discussion, or a patient delegating a decision to healthcare professionals. Current professional guidance is helpful in working through these situations.Unclear benefits/burdens: a person with recent loss of capacity. If the patient has recently lost capacity for such decisions, some questions need to be asked: - Have they previously discussed and agreed to a DNACPR? - Have they made some other form of advanced decision to refuse treatment/living will? - Have they been party to 'Advance Care Planning'? - If so, are the circumstances those previously envisaged? It could then be seen as reasonable to let this inform the current decision. It is also important to know whether the patient, when competent, appointed someone with lasting power of attorney under the terms of the Mental Capacity Act, 2005in which case this person should be approached, bearing in mind that they, no more than the patient, can insist on treatment, only decline itsee above. Unclear benefits/burdens: a person with longstanding loss of capacity. If the patient has a longstanding loss of capacity, then the decision is left to the doctor(s) and other members of the team to act in the patient's best interest, in accordance with the provisions of the Mental Capacity Act. Where available, family, next of kin and carers can be asked if they are aware of any opinions expressed previously by the patient, etc.again noting that they cannot actually make the decision, only inform the process. In situations where the patient is alone then under the Mental Capacity Act one must involve Independent Mental Capacity Advocate to contribute to the decision-making process. ## Further considerations It is not possible to cover all eventualities for these decisions, and professional guidance exists and should be followed. Two further issues warrant discussion, however; managing unresolved disagreements and transfer to the home environment. Despite the emotive nature of the subject and complexity of decisions, it is usually possible to work through DNACPR decisions to the agreement of the patient, their loved ones and the clinical team. As described above, a second opinion can be helpful in resolving a disagreement. Occasionally no agreement can be reached between doctor, the team, the patient and those close to the patient. In extreme cases, particularly where the patient lacks capacity, legal advice may be required and consideration given to more formal measures such as the involvement of the Court of Protection. A further point to highlight is the transfer of DNACPR decisions to the home environment. In such context, the patient and their family/carers are responsible for the documentation and, as such, are able to ignore or withhold it if they wish. For this reason, clear communication and agreement in advance are vital. ## Recommendations - Cardiopulmonary resuscitation is inappropriate in the palliative dying patient (R) - 'Do not attempt cardiopulmonary resuscitation' orders should be completed and discussed with the patient and/or the family unless good reasons exist not to do so where appropriate. This is absolutely necessary when a patient's care is to be managed at home (G) ## Key points - Palliative care takes an holistic approach addressing physical,psychological, social and spiritual needs of the patient,their carers and family - Symptoms should be actively sought and treated in a pro active manner by the multidisciplinary team - Pain is very common, affecting most patients at some point and maybe disease or treatment related. - Constipation develops in half of patients who are terminally ill with cancer admitted to hospice - Confusion can affect up to 75% of cancer patients at some stage. - Spinal metastases should be considered where there is new or progressive back pain and investigated pro actively - A key role of the doctor is to recognise when death is imminent and should prompt a through review of all care and interventions with unnecessary medication being stopped.	None	https://www.cambridge.org/core/services/aop-cambridge-core/content/view/543AF37F96D5A88E8123EA86320F792F/S0022215116000633a.pdf/div-class-title-palliative-and-supportive-care-in-head-and-neck-cancer-united-kingdom-national-multidisciplinary-guidelines-div.pdf	Abstract This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. It provides recommendations on the assessments and interventions for this group of patients receiving palliative and supportive care. Recommendations • Palliative and supportive care must be multidisciplinary. (G) • All core team members should have training in advanced communication skills. (G) • Palliative surgery should be considered in selected cases. (R) • Hypofractionated or short course radiotherapy should be considered for local pain control and for painful bony metastases. (R) • All palliative patients should have a functional endoscopic evaluation of swallowing (FEES) assessment of swallow to assess for risk of aspiration. (G) • Pain relief should be based on the World Health Organization pain ladder. (R) • Specialist pain management service involvement should be considered early for those with refractory pain. (G) • Constipation should be avoided by the judicious use of prophylactic laxatives and the correction of systemic causes such as dehydration, hypercalcaemia and hypothyroidism. (G) • Organic causes of confusion should be identified and corrected where appropriate, failing this, treatment with benzodiazepines or antipsychotics should be considered. (G) • Patients with symptoms suggestive of spinal metastases or metastatic cord compression must be managed in accordance with the National Institute for Health and Care Excellence guidance. (R) • Cardiopulmonary resuscitation is inappropriate in the palliative dying patient. (R) • ‘Do not attempt cardiopulmonary resuscitation’ orders should be completed and discussed with the patient and/or the family unless good reasons exist not to do so where appropriate. This is absolutely necessary when a patient's care is to be managed at home. (G)
e1147e4effbca660812657ffb32b8f6c8fae5b22	pubmed	Diabetes and Employment	Diabetes and Employment ## I. evaluating individuals with diabetes for EMPLOYMENT -It was once common practice to restrict individuals with diabetes from certain jobs or classes of employment solely because of the diagnosis of diabetes or the use of insulin, without regard to an individual's abilities or circumstances. Such "blanket bans" are medically inappropriate and ignore the many advancements in diabetes management that range from the types of medi-cations used to the tools used to administer them and to monitor blood glucose levels. Employment decisions should not be based on generalizations or stereotypes regarding the effects of diabetes. The impact of diabetes and its management varies widely among individuals. Therefore, a proper assessment of individual candidates for employment or current employees must take this variability into account. In addition, federal and state laws require employers to make decisions that are based on assessment of the circumstances and capabilities of the individual with diabetes for the particular job in question (2,3). Application of blanket policies to individuals with diabetes results in people with diabetes being denied employment for which they are well qualified and fully capable of performing effectively and safely. It should be noted that, as a result of amendments to the Americans with Disabilities Act, which became effective on 1 January 2009, all persons with diabetes are considered to have a "disability" within the meaning of that law. This is because, among other reasons, diabetes constitutes a substantial limitation on endocrine system functioning-the Act was amended to extend its coverage to persons with a substantial limitation in, among other things, a major bodily function, such as the endocrine system. Therefore, persons with diabetes are protected from discrimination in employment and other areas. The amendments overturned a series of Supreme Court decisions that had severely narrowed who was covered by the law and resulted in many people with diabetes and other chronic illnesses being denied protection from discrimination. This section provides an overview of the factors relevant to a medically appropriate indi-vidualized assessment of the candidate or employee with diabetes. ## Role of diabetes health care professionals When questions arise about the medical fitness of a person with diabetes for a particular job, a health care professional with expertise in treating diabetes should perform an individualized assessment. The involvement of the diabetes health care professional should occur before any adverse employment decision, such as failure to hire or promote or termination. A health professional who is familiar with the person with diabetes and who has expertise in treating diabetes is best able to perform such an assessment. In some situations and in complex cases, an endocrinologist or a physician who specializes in treating diabetes or its complications is the best qualified health professional to assume this responsibility (4). The individual's treating physician is generally the health care professional with the best knowledge of an individual's diabetes. Thus, even when the employer utilizes its own physician to perform the evaluation, the opinions of the treating physician and other health care professionals with clinical expertise in diabetes should be sought out and carefully considered. In situations where there is disagreement between the opinion of the employee's treating physician and that of the employer's physician, the evaluation should be handed over to an independent health care professional with significant clinical expertise in diabetes. ## Individual assessment A medical evaluation of an individual with diabetes may occur only in limited circumstances (3). Employers may not inquire about an individual's health status-directly or indirectly and regardless of the type of job-before making a job offer, but may require a medical examination or make a medical inquiry once an offer of employment has been extended and before the individual begins the job. The job offer may be conditioned on the results of the medical inquiry or examination. An employer may withdraw an offer from an applicant with diabetes only if it becomes clear that he or she cannot do the essential functions of the job or would pose a direct threat (i.e., a significant risk of substantial harm) to health or safety and such threat could not be eliminated with an accommodation (a workplace change that enables a worker with a disability to safely and effectively perform job duties). Another situation in which a medical evaluation is permissible is when a problem potentially related to the employee's diabetes arises on the job and such problem could affect job performance and/or safety. In this situation, a physician may be asked to evaluate the employee's fitness to remain on the job and/or his or her ability to safely perform the job. [formula] - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - [/formula] Employers also may obtain medical information about an employee when the employee has requested an accomodation and his or her disability or need for accommodation is not obvious. An employer should not rely on a medical evaluation to deny an employment opportunity to an individual with diabetes unless it is conducted by a health care professional with expertise in diabetes and based on sufficient and appropriate medical data. The information sought and assessed must be properly limited to data relevant to the individual's diabetes and job performance (3). The data needed will vary depending on the type of job and the reason for the evaluation, but an evaluation should never be made based only on one piece of data, such as a single blood glucose result or A1C result. Since diabetes is a chronic disease in which health status and management requirements naturally change over time, it is inappropriate-and medically unnecessary-for examiners to collect all past laboratory values or information regarding office visits whether or not related to diabetes. Only medical information relevant to evaluating an individual's current capacity for safe performance of the particular job at issue should be collected. For example, in some circumstances a review of an individual's hypoglycemia history may be relevant to the evaluation and should be collected. Information about the individual's diabetes management (such as the current treatment regimen, medications, and blood glucose logs), job duties, and work environment are all relevant factors to be considered. Only health care professionals tasked with such evaluations should have access to employee medical information, and this information must be kept separate from personnel records (3). Such guidelines and protocols can be useful tools in making decisions about individual candidates or employees if they are used in an objective way and based on the latest scientific knowledge about diabetes and its management. These protocols should be regularly reevaluated and updated to reflect changes in diabetes knowledge and evidence and should be developed and reviewed by health care professionals with significant experience in diabetes and its treatment. Individuals who do not meet the standards set forth in such protocols should be given the opportunity to demonstrate exceptional circumstances that would justify deviating from the guidelines. Such guidelines or protocols are not absolute criteria but rather the framework for a thorough individualized assessment. ## Screening guidelines ## Recommendations ## Safety concerns The first step in evaluating safety concerns is to determine whether the concerns are reasonable in light of the job duties the individual must perform. For most types of employment (such as jobs in an office, retail, or food service environment) there is no reason to believe that the individual's diabetes will put employees or the public at risk. In other types of employment (such as jobs where the individual must carry a firearm or operate dangerous machinery) the safety concern is whether the employee will become suddenly disoriented or incapacitated. Such episodes, which are usually due to severely low blood glucose (hypoglycemia), occur only in people receiving certain treatments such as insulin or secretagogues such as sulfonylureas and even then occur infrequently. Workplace accommodations can be made that are minimal yet effective in helping the individual to manage his or her diabetes on the job and avoid severe hypoglycemia. ## Hypoglycemia Hypoglycemia is defined as a blood glucose level Ͻ70 mg/dl. It is a potential side effect of some diabetes treatments, including insulin and sulfonlyureas. It can usually be effectively selft r e a t e d b y i n g e s t i o n o f g l u c o s e (carbohydrate) and is not often associated with loss of consciousness or a seizure. Severe hypoglycemia, requiring the assistance of another person, is a medical emergency. Symptoms of severe hypogly-cemia may include confusion or, rarely, seizure or loss of consciousness. Most individuals with diabetes never experience an episode of severe hypoglycemia because either they are not on medication that causes it or they recognize the early warning signs and can quickly self-treat the problem by drinking or eating. Also, with self-monitoring of blood glucose levels, most people with diabetes can manage their condition in such a manner that there is minimal risk of incapacitation from hypoglycemia because mildly low glucose levels can be easily detected and treated. A single episode of severe hypoglycemia should not per se disqualify an individual from employment. Rather, an appropriate evaluation should be undertaken by a health care professional with expertise in diabetes to determine the cause of the low blood glucose, the circumstances of the episode, whether it was an isolated incident, whether adjustment to the insulin regimen may mitigate this risk, and the likelihood of such an episode happening again. Some episodes of severe hypoglycemia can be explained and corrected with the assistance of a diabetes health care professional. However, recurrent episodes of severe hypoglycemia may indicate that an individual may in fact not be able to safely perform a job, particularly jobs or tasks involving significant risk of harm to employees or the public, especially when these episodes cannot be explained. The person's medical history and details of any history of severe hypoglycemia should be examined closely to determine whether it is likely that such episodes will recur on the job. In all cases, job duties should be carefully examined to determine whether there are ways to minimize the risk of severe hypoglycemia (such as adjustment of the insulin regimen or providing additional breaks to check blood glucose levels). ## Hyperglycemia In contrast to hypoglycemia, high blood glucose levels (hyperglycemia) can cause long-term complications over years or decades but does not normally lead to any adverse effect on job performance. The symptoms of hyperglycemia generally develop over hours or days and do not occur suddenly. Therefore, hyperglycemia does not pose an immediate risk of sudden incapacitation. While over years or decades, high blood glucose may cause long-term complications to the nerves (neuropa-thy), eyes (retinopathy), kidneys (nephropathy), or heart, not all individuals with diabetes develop these long-term complications. Such complications become relevant in employment decisions only when they are established and interfere with the performance of the actual job being considered. Evaluations should not be based on speculation as to what might occur in the future. Job evaluations should take high blood glucose levels into account only if they have already caused long-term complications such as visual impairment that interfere with performance of the specific job. ## Aspects of a safety assessment When an individual with diabetes is assessed for safety risk there are several aspects that must be considered. Blood glucose test results. A single blood glucose test result only gives information about an individual's blood glucose level at one particular point in time. Because blood glucose levels fluctuate throughout the day (this is also true for people without diabetes), one test result is of no use in assessing the overall health of a person with diabetes. The results of a series of self-monitored blood glucose measurements over a period of time, however, can give valuable information about an individual's diabetes health. Blood glucose records should be assessed by a health care professional with expertise in diabetes. History of severe hypoglycemia. Often, a key factor in assessing employment safety and risk is documentation of incidents of severe hypoglycemia. An individual who has managed his or her diabetes over an extended period of time without experiencing severe hypoglycemia is unlikely to experience this condition in the future. Conversely, multiple incidents of severe hypoglycemia may in some situations be disqualifying for high-risk occupations. However, the circumstances of each incident should be examined, as some incidents can be explained due to changes in insulin dosage, illness, or other factors and thus will be unlikely to recur or have already been addressed by the individual through changes to his or her diabetes treatment regimen or education. Hypoglycemia unawareness. Some individuals over time lose the ability to recognize the early warning signs of hypoglycemia. These individuals are at increased risk for a sudden episode of severe hypoglycemia. Some of these individuals may be able to lessen this risk with careful changes to their diabetes management regimen (for example, more frequent blood glucose testing or frequent meals). Presence of diabetes-related complications. Chronic complications that may result from long-term diabetes involve the blood vessels and nerves. These complications may involve nerve (neuropathy), eye (retinopathy), kidney (nephropathy), and heart disease. In turn, these problems can lead to amputation, blindness or other vision problems, including vision loss, kidney failure, stroke, or heart attack. As these complications could potentially affect job performance and safety, such complications should be evaluated by a specialist in the specific area related to the complication. If complications are not present, their possible future development should not be addressed, both bec a u s e o f l a w s p r o h i b i t i n g s u c h consideration and because with medical monitoring and therapies, long-term complications can now often be avoided or delayed. Thus, many people with diabetes never develop any of these complications, and those that do generally develop them over a period of years. ## Inappropriate assessments The following tools and terms do not accurately reflect the current state of diabetes treatment and should be avoided in an assessment of whether an individual with diabetes is able to safely and effectively perform a particular job. Urine glucose tests. Urine glucose results are no longer considered to be an appropriate and accurate methodology for assessing diabetes control. Before the mid-1970s, urine glucose tests were the best available method of monitoring blood glucose levels. However, the urine test is not a reliable or accurate indicator of blood glucose levels and is a poor measure of the individual's current health status. Blood glucose monitoring is a more accurate and timely means to measure glycemic control. Urine glucose tests should never be used to evaluate the employability of a person with diabetes. A1C and estimated average glucose (eAG). Hemoglobin A1C (A1C) test results reflect average glycemia over several months and correlate with mean plasma glucose levels (4). An eAG is directly related to A1C and also provides an individual with an estimate of average blood glucose over a period of time, but it uses the same values and units that are observed when using a glucose meter or re-cording a fasting glucose value on a lab report [bib_ref] Translating the A1C assay into estimated average glucose values, Nathan [/bib_ref]. A1C/eAG values provide health care providers with important information about the effectiveness of an individual's treatment regimen (4) but are often misused in assessing whether an individual can safely perform a job. Because they identify only averages and not whether the person had severe extreme blood glucose readings, A1C/eAG results are of no value in predicting short-term complications of diabetes and thus have no use in evaluating individuals in employment situations. The American Diabetes Association recommends that in most patients A1C levels be kept below 7% (4), or eAG below 154 mg/dl. This recommendation sets a target in order to lessen the chances of long-term complications of high blood glucose levels but does not provide useful information on whether the individual is at significant risk for hypoglycemia or suboptimal job performance and is not a measure of "compliance" with therapy. An A1C or eAG cut off score is not medically justified in employment evaluations and should never be a determinative factor in employment. "Uncontrolled" or "brittle" diabetes. Sometimes an individual's diabetes is described as "uncontrolled," "poorly controlled," or "brittle." These terms are not well defined and are not relevant to job evaluations. As such, giving an opinion on the level of "control" an individual has over diabetes is not the same as assessing whether that individual is qualified to perform a particular job and can do so safely. Such an individual assessment is the only relevant evaluation. ## Recommendations ## Iii. accommodating employees with DIABETES -Individuals with diabetes may need certain changes or accommodations on the job in order to perform their work responsibilities effectively and safely. Federal and state laws require the provision of "reasonable accommodations" to help an employee with diabetes to perform the essential functions of the job (3). Additional laws provide for leave for an employee to deal with his or her medical needs or those of a family member. Although there are some typical accommodations that many people with diabetes use, the need for accommodations must be assessed on an individualized basis (2). ## Accommodating daily diabetes management needs Many of the accommodations that employees with diabetes need on a day-today basis are those that allow them to manage their diabetes in the workplace as they would elsewhere. They are usually simple accommodations, can be provided without any cost to the employer, and should cause little or no disruption in the workplace. Most employers are required to provide accommodations unless those accommodations would create an undue burden. Some accommodations that may be needed include the following. Testing blood glucose. Breaks may be needed to allow an individual to test blood glucose levels when needed. Such checks only take minutes to complete. Some individuals use continuous glucose monitors but will still need an opportunity to check blood glucose with a meter. Blood glucose can be checked wherever the employee is without putting other employees at risk, and employers should not limit where employees with diabetes are permitted to manage their diabetes. Some employees may prefer to have a private location for testing or other diabetes care tasks that should be provided whenever feasible. Administering insulin. Employees may need short breaks during the workday to administer insulin when it is needed. Insulin can be safely administered wherever the employee happens to be. The employee may also need a place to store insulin and other supplies if work conditions (such as extreme temperatures) prevent the supplies from being carried on the person (10). Food and drink. Employees may need access to food and/or beverages during the workday. This is particularly important in the event that the employee needs to quickly respond to low blood glucose levels or maintain hydration if glucose levels are high. Employees should be permitted to consume food or beverages as needed at their desk or work station (except in an extremely rare situation in which this would pose a hazard and create a safety issue, and if this is the case, an alternative site should be provided). Leave. Employees may need leave or a flexible work schedule to accommodate medical appointments or other diabetes care needs. Occasionally, employees may need to miss work due to unanticipated events (severe hypoglycemic episode) or illness. Work schedules. Certain types of work schedules, such as rotating or split shifts, can make it especially difficult for some i n d i v i d u a l s t o m a n a g e d i a b e t e s effectively. ## Accommodating complications of diabetes In addition to accommodating the day-today management of diabetes in the workplace, for some individuals it is also necessary to seek modifications for longterm diabetes-related complications. Such people can remain productive employees if appropriate accommodations are implemented. For example, an employee with diabetic retinopathy or other vision impairments may benefit from using a big screen computer or other visual aids, while an employee with nerve pain may benefit from reduced walking distances or having the ability to sit down on the job. Individuals with kidney problems may need to have flexibility to take time off work for dialysis treatment. It is impossible to provide an exhaustive list of potential accommodations. The key message in accommodating an employee with diabetes is to ensure that ac-commodations are tailored to the individual and effective in helping the individual perform his or her job. Input from health care professionals who specialize in the particular complication, or from vocational rehabilitation specialists or organizations, may help identify appropriate accommodations. ## Recommendations - Individuals with diabetes may need accommodations on the job in order to perform their work responsibilities effectively and safely; these include accommodating daily diabetes needs and, when present, the complications of diabetes. All such accommodations must be tailored to the individual and effective in helping the individual perform his or her job. (E) CONCLUSION -Individuals with diabetes can and do serve as highly productive members of the workforce. While not every individual with diabetes will be qualified for, nor can perform, every available job, reasonable accommodations can readily be made that allow the vast majority of people with diabetes to effectively perform the vast majority of jobs. The therapies for, and effects of, diabetes vary greatly from person to person, so employers must consider each person's capacities and needs on an individual basis. People with diabetes should always be evaluated individually with the assistance of experienced diabetes health care professionals. The requirements of the specific job and the individual's ability to perform that job, with or without reasonable accommodations, always need to be considered. [fig] Revised: Fall 2009. DOI: 10.2337/dc10-S082 © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. org/licenses/by-nc-nd/3.0/ for details. [/fig]	None	https://diabetesjournals.org/care/article-pdf/33/Supplement_1/S82/473669/zdc10110000s82.pdf	Questions are sometimes raised by employers about the safety and effectiveness of individuals with diabetes in a given job. When such questions are legitimately raised, a person with diabetes should be individually assessed to determine whether or not that person can safely and effectively perform the particular duties of the job in question. This document provides a general set of guidelines for evaluating individuals with diabetes for employment, including how an assessment should be performed and what changes (accommodations) in the workplace may be needed for an individual with diabetes.
c47321ce309cb53ed8cda6f2a1224f2dd64340c3	pubmed	Follow-up for pregnant women during the COVID-19 pandemic: French national authority for health recommendations	Follow-up for pregnant women during the COVID-19 pandemic: French national authority for health recommendations Introduction: In the context of the stage 3 SARS-Cov-2 epidemic situation, it is necessary to put forward a method of rapid response for an HAS position statement in order to answer to the requests from the French Ministry of Solidarity and Health, healthcare professionals and/or health system users' associations concerning follow-up of pregnant women during the COVID-19 outbreak. Methods: A simplified 7-step process that favours HAS collaboration with experts (healthcare professionals, health system users' associations, scientific societies etc.), the restrictive selection of available evidence and the use of digital means of communication. A short and specific dissemination format, which can be quickly updated in view of the changes in available data has been chosen. # Introduction On 14th March 2020, France entered stage 3 of the COVID-19 epidemic outbreak. In a letter dated 27th March 2020, the French General Health Directorate (Direction Générale de la Santé -DGS) referred the matter to the French National Authority for Health (Haute Autorité de Santé; HAS), with a view to drawing up general recommendations designed to ensure continuity of care for pregnant women during lockdown and travel restrictions. Given the very limited data available, the French High Council for Public Health (Haut Conseil de Santé Publique À HCSP) considered pregnant women in the third trimester of pregnancy to be at risk of developing a severe form of COVID-19. The extension of lockdown and the role and workload of healthcare professionals, lead to re-interviewing organizations for the follow-up of pregnant women in terms of prevention and care. These rapid responses focus on the follow-up of pregnant women during lockdown and management of cases of suspected and/or confirmed pregnant womenwith COVID-19. They should be adapted according to the geographical particularities of the epidemic outbreak and access to local resources. These rapid responses are based on the knowledge available at the time of publication and are subject to change as new information becomes available. # Methods In the context of the stage 3 SARS-Cov-2 epidemic situation, it is necessary to put forward a method of rapid response for an HAS position statement in order to answer to the requests from the French Ministry of Solidarity and Health, healthcare professionals and/or health system users' associations. A simplified 7-step process that favours HAS collaboration with experts (healthcare professionals, health system users' associations, scientific societies etc.), the restrictive selection of available evidence and the use of digital means of communication. A short and specific dissemination format, which can be quickly updated in view of changes in available data has been chosen. Step 1) Selection of requests and identification of issues requiring a rapid response by the President of the HAS College. Step 2) Data selection and analysis by the HAS teams in close collaboration with experts named by the National Professional Councils (Conseils Nationaux Professionnels -CNP) and French scientific societies. Data selection was restricted to the best levels of evidence and in descending order: French health agencies' recommendations Recommendations of French and International scientific societies WHO guidelines Recommendations from international health agencies (NICE, INESS, etc.) Literature reviews and recent 2019 and 2020 scientific literature with rapid critical analysis Step 3) Drafting of provisional rapid responses by a select working group: HAS team, previously appointed experts and patient associations Step 4) Review and consultation / information of stakeholders. This step includes a panel of designated healthcare professionals as well as representatives of the French institutions (Direction Générale de la Santé, Direction générale de l'offre de soins, HCSP). These reviews are carried out electronically and allow a response within a short time frame. Step 5) Finalization of the rapid responses by the previously appointed working group. Available online at ScienceDirect www.sciencedirect.com Step 6) Validation and dissemination of the rapid responses by the HAS. The texts are then published in a short format on the website of the HAS, scientific societies and associations involved. A warning is included in the text: "These recommendations, drawn up on the basis of the knowledge available at the date of their publication, are subject to change and are likely to be updated in the light of new available data". The experts' ties of interest are analysed by the HAS ethics officer and the legal department, on the basis of the information available in the "DPI-HEALTH and TRANSPARENCY-HEALTH" databases and are provided to the members of the HAS College for their information Step 7) Regular update of the rapid responses taking into account the developments in the scientific literature and the recommendations from the scientific societies. This document was drawn up jointly by the HAS and experts appointed by the Collège National des Gynécologues et Obstétriciens Français (CNGOF), the Collège National des Sages-femmes de France (CNSF), the Collège de la Médecine Générale (CMG), the Société Française de Néonatalogie (SFN), the Société française de pédiatrie (SFP), the Fédération Française des Réseaux de Santé en Périnatalité (FFRSP), the Association Française de Pédiatrie Ambulatoire (AFPA). The rapid responses were reviewed by the Collectif Interassociatif Autour de la Naissance (CIANE). ## Recommendations ## Monitoring of pregnant women during the pandemic With the aim of reducing the health risk for pregnant women and restricting their movements during lockdown, at the same time as the workload of healthcare professionals, while making pregnancy monitoring safer, there appears to be a consensus as to the need to take the following measures (to be adapted individually according to the clinical, psychological and social situation of each woman) . An initial consultation, (1st or 2nd month) with a midwife, an obstetrician-gynaecologist, a medical gynaecologist or a general practitioner is recommended. This consultation must include medical follow-up, information on the prevention of neural tube closure anomalies (folic acid), prevention advice, support, answers to the woman's or couple's questions, and information. Remote consultation is possible: refer to the COVID-19 rapid response sheet -"Teleconsultation and Telecare" by the HASIf the pregnancy is unwanted: refer to the COVID-19 rapid response sheet "Voluntary termination of pregnancy" by the HASand the French Ministry of Solidarity and Health's recommendation. Consultations by an obstetrician, medical gynaecologist, midwife or general practitioner must include medical follow-up, prevention advice, support, provide answers to the woman's or couple's questions, and information. All women should still attend the three ultrasound consultations as part of pregnancy follow-up Ultrasound should be combined with the follow-up consultation as far as possible. If this is not possible, the ultrasound and the consultation will be carried out in two separate, face-to-face sessions, while ensuring the patient does not have to travel to a significant extent to do so. In the first trimester, between week 11 and 14 of amenorrhea, and based on the results of the second pregnancy consultation in the third month (physical examination, screening, declaration of pregnancy, presumed date of delivery), this consultation must be used to establish the type of care according to the level of risk, and to determine whether the patient should be referred for either hospital or ambulatory care follow-up. In the second trimester, between week 20 and 25 of amenorrhea, based on the results of the 5th month consultation In the third trimester, between week 30 and 35 of amenorrhea, based on the results of the 7th month/8th month consultation. In the case of multiple and high-risk pregnancies it is recommended to keep the monthly or twice-monthly ultrasound monitoring at most and to adapt monitoring according to the clinical situation and the progression of the epidemic. The availability of ultrasound scans in ambulatory care is impacted by the COVID-19 epidemic (a survey conducted by the French College of Fetal Ultrasound reveals that between 10 and 15 % of practices are believed to be closed). It thus appears essential that all stakeholders, doctors (obstetricians, medical gynaecologists, radiologists, general practitioners trained in foetal ultrasound) and midwives in ambulatory care maintain their consultation appointments for screening ultrasounds. The International Society of Ultrasound in Obstetrics and Gynaecology (ISUOG) offers three options for performing ultrasound examinations outside of routine examinations, depending on the urgency of the clinical situation: "to be done without delay"; "to be safely deferred"; "to delay during lockdown". Follow-up for pregnant women during the COVID-19 pandemic: recommendations. Rapid Response #1: Pregnant women in the 3rd trimester of pregnancy are considered to be at significant risk of developing a severe form of COVID-19. Lockdown and barrier measures must be followed and reinforced. Rapid Response #2: Comply with lockdown measures for all pregnant women. Rapid Response #3: Structure the follow-up of pregnancies around the three obstetrical ultrasounds. Rapid Response #4: Follow-up on women with low obstetric risk in ambulatory care as far as possible. Rapid Response #5: A woman's psychological and emotional state should be closely monitored by healthcare professionals during all follow-up consultations, early prenatal assessments and all prenatal classes. Rapid Response #6: Offer psychological support, preferably remotely, if the need is identified by the healthcare professional or if it is requested by the patient. Rapid Response #7: Offer follow-up by remote consultation or face-to-face depending on the obstetric risk and the development of the clinical situation, but also depending on the woman's social and psychological situation and the domestic violence risk. Rapid Response #8: Adapt monitoring of high-risk pregnancies, while ensuring closer monitoring of associated co-morbidities and the risk of severe forms of COVID-19. Rapid Response #9: Ensure closer follow-up of pregnancies suspected or diagnosed COVID-19, with priority to remote consultation. Rapid Response #10: Maintain prenatal classes by remote consultation or by combining them with other consultations lasting a sufficient amount of time and prepare women for birth and early discharge from the maternity unit. Rapid Response #11: Modulate the organization of follow-up of pregnant women according to the geographical particularities of the epidemic and access to local resources. ## Promote intermediate consultations (4th and 6th month) by remote consultation For women at low obstetrical risk: by remote consultation. For women at high obstetrical or psycho-social risk: evaluate beforehand, by telephone contact, the relevance of maintaining the 4th and 6th month face-to-face consultations. ## Third trimester consultation organization Consolidate the 7th (with ultrasound) and 8th month visits (by scheduling them at the end of month 7/start of month 8) or maintain both visits based on the obstetrical risk assessment. They are to be carried out face-to-face, at the practice or at the hospital. Conduct the 9th month consultation in person. Carry out the anaesthesia consultation by telephone and send a questionnaire by e-mail first. The American College of Obstetricians and Gynecologists (ACOG) recommends reducing the number of consultations to the necessary minimum (without specifying) and adapting the follow-up of pregnant women individually by relying on the local care community (general practitioners, midwives). The Royal College of Obstetricians and Gynaecologists (RCOG) recommends promoting remote consultations to ensure social distancing and organizing face-to-face consultations based on pregnancy screening, to monitor risks during pregnancy. A review of the literature also recommends minimal follow-up of pregnant women at low obstetric risk during the epidemic period, by spacing out visits, and remote consultation for visits at 6 and 7/8 months [bib_ref] Considerations for obstetric care during the COVID-19 pandemic, Dotters-Katz [/bib_ref]. Additional remote consultations are also recommended for women at risk (high blood pressure, diabetes, depression). Follow-up of women at low obstetrical risk should be carried out in ambulatory care as far as possible Depending on access to local resources and throughout pregnancy follow-up, pregnant women can go to a healthcare professional, to the test centre, to the radiology centre for procedures required during follow-up, by contacting them beforehand and by appointment only. For visits to the offices of midwives, obstetricians, medical gynaecologists, and general practitioners, it is recommended that women wear a mask only if they have respiratory symptoms. Wearing surgical masks in waiting rooms should be recommended, if the consultation is in a hospital environment. ## Follow-up of women in precarious situations or in situations of psychological or social vulnerability Face-to-face consultations are preferable. It is advisable that a pregnancy consultant accompanies them to identify a need for further follow-up or referral to the appropriate channels. Follow-up of women at risk of obstetrical complications should be adapted to the progression of the pregnancy Depending on whether the risk is refuted or confirmed, whether the prognosis is favourable or not, this follow-up can be carried out by a midwife depending on the level of risk. If hospitalization at home is indicated, it should be preferred depending on the resources available locally. Follow-up by the midwife is to be encouraged as far as possible at home (while ensuring hygiene rules are followed) or at the practice if it is easy for the pregnant woman to visit (if she has a car, to avoid taking public transport). Recommend medical leave for pregnant patients in the 3rd trimester: As part of the prevention measures aimed at limiting the spread of the coronavirus, these patients can benefit from the waiver allowing people at risk of developing a serious form of infection to benefit from preventive maternity leave. ## Psycho-social support for pregnant women During lockdown, it is advisable to maintain early prenatal care, preferably by remote consultation, in order to identify signs of stress, anxiety, vulnerability, sleep disorders, depressive episodes, addictions, and any form of insecurity early on, and to refer women who request it for psychological support, even remotely, or to a suitable solution in the event of risk of domestic violence. Birth and prenatal classes can be carried out by remote consultation by midwives, individually, prioritizing the participation of couples in the 3rd trimester of pregnancy. This will help reinforce the mother's or couple's self-confidence in view of the birth, the return home and care of the newborn, and accompany them in their parenting practices. Psychological support must be maintained if necessary. It is essential to prepare for childbirth and the recommended early discharge from the maternity ward at 48 h of life during the COVID-19 pandemic. Skin-to-skin contact and breastfeeding are permitted according to the current state of knowledge. Support must be provided for initiation of breastfeeding and mother-child bonding in the delivery room and during the post-natal period. ## Admission for childbirth, delivery and post-natal care It is important to recall the need for accurate questioning about possible signs of COVID-19 infection on admission of pregnant women (and their partner). ## Screening of pregnant women on admission According to a recent publication, the prevalence of women diagnosed with COVID-19 in a cohort of 215 women in labour admitted to two New York maternity hospitals was 13.8 % (29/215). In light of this study, it would be relevant to recommend, in a comparable epidemic context, systematic screening of women on admission. This would make it possible to refer mothers to a COVID-19 sector and to protect the healthcare teams (personal protective equipment) and newborns [bib_ref] Universal screening for SARS-CoV-2 in women admitted for delivery, Sutton [/bib_ref]. While the delays in obtaining the results of current tests will not have an impact on the management of childbirth, a positive result for the mother would however have a collective impact (social distancing and isolation of the mother and child, reduced circulation of the virus within the hospital and after discharge). This potential impact is comparable to that when screening any patient seeking care in a structure where there is a risk of contamination (stay, high risk procedure) and raises the question of ethics in this type of situation. The HAS recalls the WHO recommendation to increase testing. The particular case of pregnant women arriving at or hospitalised in the maternity hospital or the obstetrical emergency unit in labour will be clarified according to the HAS's recommendation on the use of tests, which can be adapted to the local epidemic context. ## Support from partners/family members Homogeneity of practices is desirable on this point in order to avoid women having to travel any distance. Professionals must inform women, for their safety and that of their child, that it is not recommended to change health facility at the last minute. The woman's partner is allowed in the delivery room under certain conditions [bib_ref] SARS-CoV-2 infection during pregnancy. Information and proposal of management care, Peyronnet [/bib_ref]. No visits are allowed after the birth [bib_ref] SARS-CoV-2 infection during pregnancy. Information and proposal of management care, Peyronnet [/bib_ref]. According to the recommendations of the RCOG, the accompanying person may assist at the birth if he/she is asymptomatic. The place of the accompanying person in post-natal care is left to the teams' discretion, depending on the equipment available and with an emphasis on the protection of mothers, newborns and staff. The HAS considers that the asymptomatic accompanying person can remain in the room provided that they comply with the strict rules set out by the establishment and that the establishment has the appropriate personal protective equipment and staff to ensure that these rules are applied without affecting the smooth running of the maternity ward. Adapting teamwork during the epidemic period Teamwork, communication and information sharing must be strengthened by inpatient and outpatient coordination between the ambulatory and hospital care. Ambulatory care is defined as medical care carried out by any health non-hospital personnel (midwife, general practitioner and gynaecologist-obstetrician who work in the city). The methods are determined jointly by the healthcare professionals involved in caring for women (midwives, obstetricians, medical gynaecologists, paediatricians, general practitioners). They are essential in particular for the referral of high-risk pregnancies, women in precarious situations or women in situations of social or psychological vulnerability. ## Support for ambulatory care care It appears that some of the day care structures (in France) are closed. These structures have an important role to play in the continuity of care and must participate in the follow-up of low-risk women by restricting their activities, while following barrier measures. Given the role of ambulatory care midwives in the follow-up of pregnant women, it is essential to reinforce the means of protection allocated to them (masks, overalls, gloves, hand sanitizer etc.). Institutions must draw up a list of ambulatory care midwives who can provide follow-up care for pregnant women to reinforce in and outpatient coordination between the ambulatory and hospital care. The role of perinatal networks is essential in the epidemic outbreak context. All of these measures aim to step up outpatient care and facilitate the management of patients with COVID-19 by obstetrical teams in health facilities. Organisation of follow-up of pregnant women should be modulated according to the geographical particularities of the epidemic outbreak and access to local resources. ## Cases of pregnant women suspected to have and/or confirmed to have covid-19 Pregnant woman with signs suggesting COVID-19: fever, cough, respiratory signs (dyspnoea), or signs of pneumonia If infection is suspected, the patient should consult to rule out any other illnesses (fever). Her state of severity should be assessed, and any obstetric complications identified where there are any. She should consult her general practitioner; in accordance with the hygiene measures in place and a COVID-19 diagnostic test must be offered. This consultation must be carried out while ensuring barrier measures are followed as far as possible (the patient should wait alone in the waiting room, and wear a mask). The patient can also phone the emergency services or go to the obstetric emergency unit in the hospital or clinic in which she is being monitored, ensuring she calls them first (special phone line) and informs the team on arrival of the risk of infection so that she can be provided with a mask and be isolated. If a screening ultrasound was scheduled within two weeks for a woman with suspected or confirmed COVID-19, it may be rescheduled at a later date, once the patient has recovered, within the ultrasound deadline. According to the opinion of 8th April 2020, any woman suspected or confirmed to have the virus must be managed by the general practitioner and the referring obstetrical team. Any woman with signs of severity or aggravating comorbidities should be managed in the hospital setting [bib_ref] Maternal and Perinatal Outcomes with COVID-19: a systematic review of 108 pregnancies, Zaigham [/bib_ref]. ## Obstetrical emergency management The CNGOF guidelines describe management in obstetric emergencies [bib_ref] SARS-CoV-2 infection during pregnancy. Information and proposal of management care, Peyronnet [/bib_ref]. In particular, they specify the criteria for hospital or intensive care admission and known comorbidities (women in third trimester of pregnancy, overweight women, women with pregnancy-related hypertension, pre-eclampsia, gestational or pre-existing diabetes, chronic respiratory failure, history of heart disease or transplant). Hospitalization should be discussed for pregnant women with co-morbidities even in the absence of initial clinical signs of severity, particularly during the third trimester. In the absence of reasons for hospitalization, it is recommended to test (RT-PCR on nasopharyngeal swab) all suspect pregnant women: With pending result: to automatically be considered positive. Return home is possible while waiting for the results with respect to isolation measures. Negative test: given the sensitivity of the test, it cannot be completely ruled out that women are not contagious (relative sensitivity of RT-PCR). It is recommended to keep the mask on to avoid transmitting any infectious agent responsible for the symptoms. Disappearance of symptoms should be confirmed by an outpatient monitoring procedure according to local organization. Positive test: it is recommended to keep the mask on outside and in all circumstances, outpatient monitoring procedure according to local organization. ## Hospitalization management protocol The CNGOF recommendations describe the management protocol in the event of hospitalization. ## Management of a patient returning home from an emergency room visit or hospitalization Contact every 48 h (trace results to be recovered and calls made) by the obstetrical emergency team. Minimize the risk of COVID-19 transmission with home isolation for 14 days for the woman and her partner (to whom selfmonitoring instructions and hygiene precautions to be followed should have been given and explained). Give priority to remote consultation whenever possible. Consultation with a doctor three weeks after discharge. Follow-up of pregnant women after recovery Due to the lack of knowledge as to the consequences of the disease, clinical and ultrasound monitoring of pregnant women and their unborn child by an obstetrician is recommended. This is necessary to assess foetal growth and the volume of amniotic fluid. Management is similar to that for high-risk pregnancies with medical follow-up by the referring doctor and continuity of follow-up by a midwife at home or a midwife in hospital. The need for additional ultrasound scans should be discussed on a case-by-case basis depending on the severity of the mother's symptoms (no known teratogenic risk and no impact on term or method of delivery). Specific prenatal diagnosis management of infected patients is not required except in rare cases of severe hypoxia requiring mechanical ventilation, which may result in foetal hypoxia and abnormal brain development (diagnostic ultrasound + MRI recommended). In case of severe pneumonia without severe hypoxia, additional ultrasound to control foetal growth should be discussed. ## Recommendationa Rapid Response #1: Pregnant women in the 3rd trimester of pregnancy are considered to be at significant risk of developing a severe form of COVID-19. Lockdown and barrier measures must be followed and reinforced. Rapid Response #2: Comply with lockdown measures for all pregnant women. Rapid Response #3: Structure the follow-up of pregnancies around the three obstetrical ultrasounds. Rapid Response #4: Follow-up on women with low obstetric risk in ambulatory care as far as possible. Rapid Response #5: A woman's psychological and emotional state should be closely monitored by healthcare professionals during all follow-up consultations, early prenatal assessments and prenatal classes. Rapid Response #6: Offer psychological support, preferably remotely, if the need is identified by the healthcare professional or if it is requested by the patient. Rapid Response #7: Offer follow-up by remote consultation or face-to-face depending on the obstetric risk and the development of the clinical situation, but also depending on the woman's social and psychological situation and the domestic violence risk. Rapid Response #8: Adapt monitoring of high-risk pregnancies, while ensuring closer monitoring of associated co-morbidities and the risk of severe forms of COVID-19. Rapid Response #9: Ensure closer follow-up of pregnancies suspected or diagnosed COVID-19, giving priority to remote consultation. Rapid Response #10: Maintain prenatal classes by remote consultation or by combining them with other consultations lasting a sufficient amount of time and prepare women for birth and early discharge from the maternity unit. Rapid Response #11: Modulate the organization of follow-up of pregnant women according to the geographical particularities of the epidemic and access to local resources. ## Declaration of competing interest The authors declare no competing interests	None	None	None
bcd2a7d58c9297c8b1b470900d1e4d91742255ea	pubmed	Consensus report on the radiological management of patients with gastrointestinal stromal tumours (GIST): recommendations of the German GIST Imaging Working Group	Consensus report on the radiological management of patients with gastrointestinal stromal tumours (GIST): recommendations of the German GIST Imaging Working Group The aim was to reach consensus in imaging for staging and follow-up as well as for therapy response assessment in patients with gastrointestinal stromal tumours (GIST). The German GIST Imaging Working Group was formed by 9 radiologists engaged in assessing patients with GIST treated with targeted therapy. The following topics were discussed: indication and optimal acquisition techniques of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT; tumour response assessment considering response criteria and measurement techniques on CT, MRI and PET/CT; result interpretation; staging interval and pitfalls. Contrastenhanced CT is the standard method for GIST imaging. MRI is the method of choice in case of liver-specific questions or contraindications to CT. PET/CT should be used for early response assessment or inconclusive results on morphologic imaging. All imaging techniques should be standardized allowing a reliable response assessment. Response has to be assessed with respect to lesion size, lesion density and appearance of new lesions. A critical issue is pseudoprogression due to myxoid degeneration or intratumoural haemorrhage. The management of patients with GIST receiving a targeted therapy requires a standardized algorithm for imaging and an appropriate response assessment with respect to changes in lesion size and density. # Introduction Gastrointestinal stromal tumours (GIST) represent the most common mesenchymal malignancy arising from the gastrointestinal tract. Most frequently, GISTs are located in the stomach (60%) and the small bowel (30%) but can occur anywhere from the oesophagus to the rectum and in the omentum, mesentery and retroperitoneum [bib_ref] Gastrointestinal stromal tumor workshop, Berman [/bib_ref] [bib_ref] Gastrointestinal stromal tumorsdefinition, clinical, histological, immunohistochemical, and molecular genetic features and differential..., Miettinen [/bib_ref]. GISTs metastasize most often to the liver, omentum and peritoneum by hematogenous spread and peritoneal seeding [bib_ref] Comparison of RECIST and Choi criteria for computed tomographic response evaluation in..., Dudeck [/bib_ref]. During the last century no effective drugs for advanced GISTs were available. For the first time, Joensuu et al. [bib_ref] Effect of the tyrosine kinase inhibitor STI571 in a patient with a..., Joensuu [/bib_ref] reported in 2001 that the tyrosine kinase inhibitor (TKI) imatinib mesylate revealed striking effects in the treatment of GISTs. Imatinib mesylate, a small molecule, has an antiproliferative and antiangiogenetic effect as it inhibits the mutated subset of the protooncogene cKIT and the plateletderived growth factor receptor alpha (PDGFRA) that is frequently found in GISTs. Over the last decade, this new approach raised a still ongoing discussion with regard to tumour response assessment: in most patients undergoing imatinib therapy, GIST lesions showed only a minor reduction in size despite an obvious response, but the lesions regularly became hypoattenuated in contrastenhanced CT . Moreover, patients with progressive disease not necessarily present with an increase in lesion size or with new lesions but with a new phenomenon called nodule within a mass [bib_ref] Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to..., Shankar [/bib_ref]. These characteristics are not addressed by the Response Evaluation Criteria in Solid Tumors (RECIST), which are based on measurements of the longest axial lesion diameter and commonly applied to assess therapy response [bib_ref] New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eisenhauer [/bib_ref] [bib_ref] New guidelines to evaluate the response to treatment in solid tumors, Therasse [/bib_ref]. Therefore, Choi et al. [bib_ref] CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate..., Choi [/bib_ref] [bib_ref] Correlation of computed tomography and positron emission tomography in patients with metastatic..., Choi [/bib_ref] introduced CT criteria additionally addressing changes in lesion density. Other studies evaluated the use of [ 18 F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) due to the fact that density changes of GIST lesions and therefore tumour vitality might be reflected by changes in the glucose metabolism . However, for the optimal management of patients with GIST receiving a targeted therapy, it is required that the applied algorithm in imaging for staging and follow-up as well as for therapy response assessment is widely standardized. But to the best of our knowledge, current reports about the management of patients with GIST are primarily addressed to treatment strategies [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] [bib_ref] Perspective on updated treatment guidelines for patients with gastrointestinal stromal tumors, Blay [/bib_ref] [bib_ref] Towards global consensus in the treatment of gastrointestinal stromal tumor, Reichardt [/bib_ref] and imaging algorithms are not mentioned. Therefore, the German GIST Imaging Working Group was formed and composed this consensus report to build an algorithm for the imaging management of patients with GISTs. # Materials and methods The German GIST Imaging Working Group was organized by 2 radiologists (S.D., G.A.) who invited German radiologists known for their engagement in the radiological assessment of patients with GISTs at specialized centres. All participants of the German GIST Imaging Working Group have extensive expertise in clinical trials of targeted drugs like imatinib or sunitinib. The Working Group was supported by an unrestricted grant from Novartis Pharma, Nuremberg, Germany. The summit was performed to address and discuss the following end points: (a) indication and optimal acquisition technique for CT, magnetic resonance imaging (MRI) and [ 18 F]FDG-PET/CT scan at baseline (before onset of a targeted therapy), during and after the end of treatment with respect to the scan region, application of intravenous or oral contrast agent (sort, amount, flow rate), need for dynamic studies, scanning and reconstruction parameters and MRI sequences, respectively; (b) tumour response assessment considering measurement techniques on CT, MRI and [ 18 F]FDG-PET/CT and result interpretation; (c) identifying pitfalls; (d) staging interval. In preparation for the consensus meeting, all participants studied the German and English literature that was selected stepwise. First, a search for the paired key words imaging and gastrointestinal stromal tumo(u)rs using the US National Library of Medicine PubMed was performed and yielded 127 articles. Second, these articles were screened for topics concerning diagnostic quality of CT, MRI and PET and/or methods to assess therapy response. Sixty-one journal articles remained for systematic review including 24 original contributions that evaluated the diagnostic quality of PET [bib_ref] Comparison of PET, CT, and dual-modality PET/CT imaging for monitoring of imatinib..., Antoch [/bib_ref] [bib_ref] The role of 18 F-FDG PET in staging and early prediction of..., Gayed [/bib_ref] and MRI [bib_ref] Gastrointestinal stromal tumors: CT and MRI findings, Sandrasegaran [/bib_ref] in comparison with CT as well as by histological work-ups for PET [bib_ref] Clinical significance of performing 18 F-FDG PET on patients with gastrointestinal stromal..., Kaneta [/bib_ref] , CT [bib_ref] Gastrointestinal stromal tumors: CT and MRI findings, Sandrasegaran [/bib_ref] [bib_ref] Gastrointestinal stromal tumour: spiral computed tomography features and pathologic correlation, Da Ronch [/bib_ref] [bib_ref] Gastrointestinal stromal tumor of the stomach: preliminary results of preoperative evaluation with..., Lee [/bib_ref] and MRI [bib_ref] Gastrointestinal stromal tumors: CT and MRI findings, Sandrasegaran [/bib_ref]. Methods to assess therapy response by different imaging modalities were explored by CT [bib_ref] Cystic changes in hepatic metastases from gastrointestinal stromal tumors (GISTs) treated with..., Chen [/bib_ref] , PET [bib_ref] Early prediction of response to sunitinib after imatinib failure by 18 F-fluorodeoxyglucose..., Prior [/bib_ref] [bib_ref] Clinical significance of performing 18 F-FDG PET on patients with gastrointestinal stromal..., Kaneta [/bib_ref] [bib_ref] Very early detection of response to imatinib mesylate therapy of gastrointestinal stromal..., Heinicke [/bib_ref] , PETþCT [bib_ref] Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to..., Shankar [/bib_ref] [bib_ref] The role of 18 F-FDG PET in staging and early prediction of..., Gayed [/bib_ref] and MRI [bib_ref] Follow-up of gastrointestinal stromal tumours (GIST) during treatment with imatinib mesylate by..., Stroszczynski [/bib_ref] [bib_ref] Magnetic resonance imaging of gastrointestinal stromal tumor in the abdomen and pelvis, Amano [/bib_ref] [bib_ref] Gastrointestinal stromal tumors treated with imatinib mesylate: apparent diffusion coefficient in the..., Tang [/bib_ref]. Benjamin et al. [bib_ref] We should desist using RECIST, at least in GIST, Benjamin [/bib_ref] performed the only validating study with regard to the modified CT criteria proposed by Choi et al. [bib_ref] Correlation of computed tomography and positron emission tomography in patients with metastatic..., Choi [/bib_ref] In view of this weak data situation, the consensus determined by this Working Group could not be evidence-based and, therefore, is primarily based on the experience of the panellists. The consensus meeting was led by an independent professional moderator to reach consensus on the end points and to avoid a unilateral consensus formation by individual panellists. The discussion on each end point was started with an introductory presentation by one of the panellists including a review of the literature. The other panellists contributed with information derived from the literature and their experience of imaging GIST patients including examinations within clinical trials. Subsequently, potential controversial aspects were discussed. If panellists disagreed on a specific aspect, resolution was attempted by suggesting a compromise all panellist could agree on. Only if all panellists agreed unanimously was this opinion regarded as a consensus. The results of the German GIST Imaging Working Group are presented here. To our knowledge, these specific radiological end points have not been addressed in earlier statements on GIST management. ## Imaging acquisition protocol and indication ## Computed tomography CT is the standard imaging method in patients with GISTs [bib_ref] Gastrointestinal stromal tumors: a pictorial review, Chourmouzi [/bib_ref] [bib_ref] Consensus meeting for the management of gastrointestinal stromal tumors, Blay [/bib_ref] [fig_ref] Figure 1: Algorithm for optimal use of different imaging modalities [/fig_ref]. CT has a high reliability in tumour detection and staging and has been established as the standard method for assessing therapy response. Furthermore, CT is widely available, has high patient comfort and is an economically competitive method. Due to known difficulties in assessing response in GIST patients, it is important to preferably provide the same examination protocol and therapy response assessment to all GIST patients. Therefore, patients with GIST should routinely be staged by CT with a standardized protocol as follows. Thorax. As the incidence of pulmonary metastases at the first presentation is rare (2%) [bib_ref] Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival, Dematteo [/bib_ref] , a CT scan of the chest is only recommended at the baseline staging. Patients do not have to be followed up by chest CT if they initially had no pulmonary metastases. Additional CT of the chest is recommended in case of progression of abdominal disease. Abdomen. For baseline staging (before onset of therapy), the CT protocol should be triphasic consisting of a non-enhanced phase, an arterial phase, and a portal venous phase of the liver [bib_ref] Consensus meeting for the management of gastrointestinal stromal tumors, Blay [/bib_ref] with the portal venous phase covering the complete abdomen and pelvis. During therapy, patients should be followed by biphasic CT containing a non-enhanced and a portal venous phase [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] [fig_ref] Figure 2: Overview about the scanning region, the recommended contrast-enhanced CT phases and the... [/fig_ref]. The follow-up CT of patients after the end of therapy should be the same as the protocol at baseline [fig_ref] Figure 1: Algorithm for optimal use of different imaging modalities [/fig_ref]. In general, CT should be performed after intravenous administration of 120 ml of a nonionic iodine contrast agent (300 mg/ml) or an equivalent iodine dose followed by 30 ml of a saline bolus. A flow rate of 34 ml/s is preferable. The delay ideally should be determined by bolus triggering; thereafter, the portal venous phase should start after 3040 s. Otherwise, the arterial and portal venous phases should be started after 3040 s and 6070 s after injection, respectively. Patients receiving their baseline staging CT should receive a negative/water-equivalent oral contrast agent allowing for the detection of gastrointestinal tract wall lesions [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] [bib_ref] Computed tomography imaging of gastrointestinal stromal tumors with pathology correlation, Horton [/bib_ref]. During therapy and after the end of treatment, patients should receive a positive oral contrast agent allowing for detection of recurrent tumour or peritoneal metastases. In these cases, the use of negative oral contrast agents seems to be dispensable [fig_ref] Figure 2: Overview about the scanning region, the recommended contrast-enhanced CT phases and the... [/fig_ref] , as metastases most often involve the liver and peritoneum, whereas intramural metastases occur rarely in the intestine [bib_ref] Gastrointestinal stromal tumors: a pictorial review, Chourmouzi [/bib_ref] [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref]. The scan parameters (tube voltage, tube current, slice thickness) should be similar for all examinations to afford comparable measurements of Hounsfield units (HU) reflecting density changes [bib_ref] Correlation of computed tomography and positron emission tomography in patients with metastatic..., Choi [/bib_ref]. A reconstructed slice thickness of 5 mm and a multiplanar reformation in a second plane (e.g. coronal) is preferable. The parameters of intravenous contrast agent injection and scan parameters should be ideally registered on images or in the report. A patient presenting with a baseline staging CT that deviates from these requirements should receive a new appropriate CT scan. MRI should be applied in cases of potential resection of liver metastases due to the higher sensitivity in detecting small liver lesions. Moreover, MRI is an alternative method to CT if contraindications to CT exist (e.g. allergy to iodine contrast agents) [fig_ref] Figure 1: Algorithm for optimal use of different imaging modalities [/fig_ref] [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref]. Thorax. Patients should receive a non-enhanced CT of the thorax at baseline as CT allows more sensitive lesion detection than MRI [fig_ref] Figure 1: Algorithm for optimal use of different imaging modalities [/fig_ref]. Abdomen. Patients with a liver-related question (e.g. potential hepatic resection) should receive an MRI of the liver [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref]. Patients with contraindications to CT should receive a scanning protocol that includes the complete abdomen and pelvis [fig_ref] Figure 1: Algorithm for optimal use of different imaging modalities [/fig_ref]. ## Mri of the liver in addition to a ct due to a liver-related question This protocol should consist of a non-enhanced T1weighted sequence with an in-phase and opposed-phase acquisition and T2-weighted sequence. One sequence should be acquired with fat saturation. Images should have a maximum slice thickness of 7 mm. If possible, diffusion-weighted imaging (DWI) should be performed. Every patient should undergo a multiphase study of the liver after intravenous administration of a single dose (0.1 mmol/kg) of a gadolinium contrast agent followed by 40 ml of a saline bolus. Thereby a flow rate of 2 ml/s should be used to inject 0.5 M contrast agent, otherwise the flow rate has to be adapted. This study should at least consist of a non-enhanced, an arterial and a portal venous phase and should be acquired as a T1-weighted sequence with fat saturation in an axial plane and with a slice thickness of a maximum of 5 mm [fig_ref] Table 1: List of sequences that should be used in MRI of the liver... [/fig_ref]. In case of an intended resection of a liver lesion, the application of a liver-specific contrast agent is preferable. ## Mri abdomen (liver and pelvis) in patients with contraindication to ct The required sequences for an MRI of the abdomen are almost similar to the MRI protocol of the liver. Except for the sequence of the multiphase study of the liver, sequences have to be adapted to cover the complete abdomen and pelvis. In addition, a T1-weighted sequence with fat saturation should be performed in a coronal plane with a slice thickness of at most 7 mm [fig_ref] Table 1: List of sequences that should be used in MRI of the liver... [/fig_ref]. Patients receiving their baseline staging MRI should be prepared with an intravenous spasmolytic agent such as butylscopolamine and an oral contrast agent. Depending on the site of metastases, patients may also receive spasmolysis and/or an oral contrast agent at follow-up or after the end of therapy. The application data of the intravenous contrast agent and scan parameters should be ideally registered on images or in the report. ## Positron emission tomography PET/CT with [ 18 F]FDG is a potential alternative to CT and is particularly indicated in terms of ambiguous CT or MRI results [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] [bib_ref] Early effects of imatinib mesylate on the expression of insulin-like growth factor..., Trent [/bib_ref]. Furthermore, [ 18 F]FDG-PET allows early response assessment [fig_ref] Figure 1: Algorithm for optimal use of different imaging modalities [/fig_ref]. At baseline, the PET/CT scan should cover the complete thorax, abdomen and pelvis. During follow-up, a scan of the abdomen is always necessary, while further scans of the thorax are only required in patients with pulmonary metastases or progressive disease. For PET, [ 18 F]FDG should be applied as the radionuclide of choice and the activity administered should be in accordance with the European Organization for Research and Treatment of Cancer (EORTC) guidelines [bib_ref] Measurement of clinical and subclinical tumour response using [ 18 F]-fluorodeoxyglucose and..., Young [/bib_ref]. Generally, a full-dose CT with an iodine contrast agent should be included according to the CT guidelines introduced above. PET/CT with a low-dose or non-enhanced CT does not compensate for a CT as described above [bib_ref] New guidelines to evaluate the response to treatment in solid tumors, Therasse [/bib_ref]. A low-dose [ 18 F]FDG-PET/CT should only be applied if a short-term follow-up for an early response assessment during therapy is clinically indicated. ## Therapy response assessment ## Measurement technique Therapy response is commonly assessed according to RECIST 1.1 [bib_ref] New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eisenhauer [/bib_ref] Therefore, the longest axial lesion diameter (RECIST diameter) of a maximum of 2 target lesions per organ and 5 per patient should be measured [fig_ref] Table 2: Response criteria and modified CT criteria according to RECIST and Choi [/fig_ref]. The assessment of patients with GIST also requires evaluation of lesion density [bib_ref] CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate..., Choi [/bib_ref] [bib_ref] Computed tomography perfusion in evaluating the therapeutic effect of transarterial chemoembolization for..., Chen [/bib_ref] [bib_ref] Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients..., Demetri [/bib_ref]. ## Computed tomography On CT images, lesion density is reflected by intratumoural attenuation in Hounsfield units (HU) and should be assessed in the portal venous phase. Preferably, the measurement is performed on the level of the RECIST diameter by a polygonal region of interest (ROI) that borders the entire lesion including the hypervascularized rim, if present . Alternatively, an ellipsoid or circular ROI may be used and should contain the maximum of the target lesion. In inhomogeneous lesions, an additional ROI should be similarly measured in the centre of the upper and/or lower half of the target lesion and the mean value should be calculated. Changes in HU during follow-up should be assessed analogously to RECIST: HU measurements of all lesions should be averaged at each follow-up and the resulting mean HU value should be compared with the nadir of the mean HU measurements during follow-up. New or increasing nodule(s) within a mass SD Decrease of less than 30% and increase of less than 20% in SLD Decrease of less than 10% and increase of less than 10% in SLD and decrease of less than 15% in MLD a PR Decrease of at least 30% in SLD Decrease of at least 10% in SLD and decrease of at least 15% in MLD a CR Complete remission Complete remission PD, progressive disease; SD, stable disease; PR, partial complete response; CR, complete response; SLD, sum of the longest diameter according to RECIST [bib_ref] New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eisenhauer [/bib_ref] ; MLD, mean lesion density according to modified CT criteria [bib_ref] CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate..., Choi [/bib_ref]. a Complementary recommendation of the German GIST Working Group: density changes should account for at least 10 HU. ## Figure 3 Liver metastasis with hypervascularized rim that should be included in the density measurement by a polygonal ROI. ## Magnetic resonance imaging On MRI, therapy response is assessed by the same methods introduced for CT. So far, assessment of therapy response by changes in signal intensity (SI) has only been explored in 2 studies [bib_ref] Follow-up of gastrointestinal stromal tumours (GIST) during treatment with imatinib mesylate by..., Stroszczynski [/bib_ref] [bib_ref] Magnetic resonance imaging of gastrointestinal stromal tumor in the abdomen and pelvis, Amano [/bib_ref]. Compared with measurements of HU at CT, SI changes are less reliably assessable even if standardized MRI protocols are used. ## Positron emission tomography Evaluation of a PET/CT is based on the assessment of the CT component as described above and the PET component. On [ 18 F]FDG-PET/CT, the glucose metabolism is reflected by the maximum standardized uptake value (SUV max ) and recorded by a single ROI covering the entire lesion. In general, it is highly recommended to reassess the previous measurements of lesion size and density during follow-up although this is different to common requirements of clinical trials. # Interpretation of results Therapy response assessment in patients with GIST consists of changes in lesion size, in lesion density and the appearance of new lesions [bib_ref] Molecular target modulation, imaging, and clinical evaluation of gastrointestinal stromal tumor patients..., Demetri [/bib_ref]. Lesion size should generally be measured according to the RECIST criteria [fig_ref] Table 2: Response criteria and modified CT criteria according to RECIST and Choi [/fig_ref] [bib_ref] New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eisenhauer [/bib_ref]. In addition, the assessment of lesion density is important, as therapy response is commonly reflected by a decrease in lesion attenuation due to myxoid degeneration [bib_ref] Gastrointestinal stromal tumor workshop, Berman [/bib_ref] [bib_ref] Effect of the tyrosine kinase inhibitor STI571 in a patient with a..., Joensuu [/bib_ref]. Therefore, changes in lesion density should be assessed quantitatively and qualitatively by ROI measurements as mentioned above and by a visual analysis regarding lesion homogeneity as described below. ## Computed tomography Choi et al. [bib_ref] Correlation of computed tomography and positron emission tomography in patients with metastatic..., Choi [/bib_ref] suggested a threshold of 15% in decrease of lesion attenuation to quantitatively assess response on CT images. However, up to now its validity has not been proven by a large prospective trial. With respect to the measurement variability of a manually drawn ROI, we recommend that the difference in lesion density should account for at least 10 HU and that the standard deviation of ROI measurements should be considered. ## Magnetic resonance imaging Compared with an assessment based on CT, at MRI it is more difficult to obtain reproducible measurements of the SI and up to now, no potential reference values were defined. ## Positron emission tomography In [ 18 F]FDG-PET/CT the baseline SUV max can be used as a reference to determine therapy response. A decrease of the SUV max indicates tumour response. PET response criteria introduced by the EORTC group [bib_ref] Measurement of clinical and subclinical tumour response using [ 18 F]-fluorodeoxyglucose and..., Young [/bib_ref] may be applied, however, the reading physician has to be aware that these criteria are discussed controversially. In case of inconsistent results between the evaluation of the CT and PET components, the response has to be determined on an individual basis. In general, the morphological response assessment of GISTs using CT or MRI is not only based on measurements of lesion size and density. It is important to critically evaluate these measurements with respect to the homogeneity of all lesions that may change due to variations of a hypervascularized rim, the appearance of a nodule within a mass or intratumoural haemorrhage. It is of paramount importance to distinguish pseudoprogression from real disease progression. Pseudoprogression can be caused by an increase in lesion size due to myxoid degenerationhaemorrhage. Pseudoprogression can also be caused by the appearance of a pseudo-new lesion that becomes hypoattenuated due to myxoid degeneration after onset of targeted therapy [bib_ref] Consensus meeting for the management of gastrointestinal stromal tumors, Blay [/bib_ref] [bib_ref] Early effects of imatinib mesylate on the expression of insulin-like growth factor..., Trent [/bib_ref]. In contrast, real disease progression can be reflected by true new lesions, increasing lesion size, increasing attenuation of the rim or the entire lesion as well as the appearance of a new nodule within a mass, which presents a hyperattenuated nodule within a hypoattenuated lesion [bib_ref] Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to..., Shankar [/bib_ref]. ## Or intratumoural ## Pitfalls Response evaluation of GISTs occasionally can be difficult due to specific characteristics of this tumour treated with TKI. Therefore, it is recommended to consider the following characteristics for lesion selection, measurement and overall assessment. In principle, target lesions should represent the largest lesions but should also be well defined allowing accurate measurement. Confluent lesions and lesions that will probably be merged with other lesions at the next follow-up scan should be avoided. GIST lesions are frequently located in the peritoneum or intestine and may change their position between follow-up scans. This causes a misalignment of the lesion and prior measurements are not comparable with current measurements. Intestinal lesions can additionally mimic a decrease in size when liquid contents are drained. In summary, target lesions should preferably be immobile such as liver lesions. As mentioned above, it is difficult to obtain reproducible measurements of the lesion density. Therefore, it is crucial that density measurements are not affected by adjacent vessels, hollow organs or oral contrast agent in the gastrointestinal tract. In addition, the ROI should avoid areas that are affected by a partial volume effect, otherwise a preferably larger lesion should be chosen. Furthermore, the visual evaluation should particularly attend to intratumoural haemorrhage as well as the nodule within a mass phenomenon. An increase in lesion size and density due to intratumoural haemorrhage does not reflect disease progression. Another incorrect response assessment may result from a missed nodule within a mass that is potentially not reflected by a target lesion or even a density measurement. ## Follow-up interval In general, the follow-up intervals are determined interdisciplinarily. Up to 4 weeks after onset of targeted therapy, the acquisition of an early follow-up CT is only indicated if a disease progression or a potential complication, e.g. haemorrhage is clinically suspected. Therefore, the CT follow-up protocol should be applied. In cases of a contraindication to CT, the indications can similarly be evaluated by the MRI follow-up protocol. PET/CT with [ 18 F]FDG is the method of choice to assess early response [bib_ref] The role of 18 F-FDG PET in staging and early prediction of..., Gayed [/bib_ref] although this requires the existence of a baseline [ 18 F]FDG-PET/CT as reference. The first regular follow-up imaging is commonly performed at the end of the first month up to the third month after onset of therapy. At this time, therapy response should be primarily based on changes in lesion density. At the same time, changes in lesion size as well as the appearance of new lesions should be critically evaluated with respect to a potential pseudoprogression. PET/CT should only be applied to evaluate inconclusive results obtained by morphological imaging [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] [bib_ref] Early effects of imatinib mesylate on the expression of insulin-like growth factor..., Trent [/bib_ref]. After 3 months of therapy, the response assessment should be based on changes in lesion density, size and the appearance of new lesions. As mentioned above, [ 18 F]FDG-PET/CT should only be applied to evaluate inconclusive results [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] [bib_ref] Early effects of imatinib mesylate on the expression of insulin-like growth factor..., Trent [/bib_ref]. # Discussion The introduction of targeted therapy in metastatic GIST raised new questions regarding imaging and therapy response assessment. Therefore, the German GIST Imaging Working Group elaborated recommendations for the radiological management of GIST patients. Consensus was reached on all questions related to application and imaging acquisition techniques with respect to the time of imaging (baseline, during and after treatment), scan region, application of contrast agents, need for multiphase studies, postprocessing parameters and sequences. An adequate staging interval has to be determined in an interdisciplinary discussion, but with respect to indication and time of follow-up, the Working Group composed recommendations for the imaging methods. The standard imaging technique in patients with GIST should be contrast-enhanced CT. CT is widely available, allows high patient comfort, is cost effective and has a high sensitivity in lesion detection [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] , particularly for mesenteric and peritoneal metastases [bib_ref] Gastrointestinal stromal tumors: CT and MRI findings, Sandrasegaran [/bib_ref]. MRI is the method of choice in patients with contraindications to CT or liver-specific questions [bib_ref] Towards global consensus in the treatment of gastrointestinal stromal tumor, Reichardt [/bib_ref]. Due to the fact that targeted therapies induce metabolic changes in glucose metabolism, the relevance of [ 18 F]FDG-PET/CT was also discussed. In GIST, the primary domain of [ 18 F]FDG-PET or [ 18 F]FDG-PET/CT is to assess an early response if necessary [bib_ref] The role of 18 F-FDG PET in staging and early prediction of..., Gayed [/bib_ref] and as an additional method in the case of inconclusive results on CT or MRI [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] [bib_ref] Early effects of imatinib mesylate on the expression of insulin-like growth factor..., Trent [/bib_ref]. Choi et al. [bib_ref] CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate..., Choi [/bib_ref] reported that 20% of lesions did not show a significant glucose uptake on pretreatment [ 18 F]FDG-PET. In summary, [ 18 F]FDG-PET/CT is a promising method especially with regard to assessment of therapy response but it suffers from a limited availability and relatively high cost [bib_ref] New guidelines to evaluate the response to treatment in solid tumors, Therasse [/bib_ref] [bib_ref] CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate..., Choi [/bib_ref]. Therefore, the Working Group could not recommend the routine use of PET/CT in GIST patients. GIST lesions responding to targeted therapy with imatinib commonly show myxoid degeneration [bib_ref] Gastrointestinal stromal tumor workshop, Berman [/bib_ref] [bib_ref] Effect of the tyrosine kinase inhibitor STI571 in a patient with a..., Joensuu [/bib_ref] that is reflected by distinctly hypodense, almost cystic-appearing lesions on imaging. Consequently, CT lesion density should be considered in assessing response. For reproducible results, it is recommended to choose the target lesions according to the common and widely known RECIST criteria and measure the lesion density on the same level as the RECIST diameter. In inhomogeneous lesions, additional ROIs centrically in the upper and lower half should be measured. To further minimize measurement variability, we recommend that patients should always receive the same imaging technique and protocol. On MRI, measurements of SI are possible but less reliable due to large variability in the imaging technique. The response assessment might be difficult in lesions with increased density and size due to bleeding into the target lesion. Similarly, myxoid degeneration could cause an increase in size or a hypoattenuated pseudo-new lesion that has not been visible before [bib_ref] Gastrointestinal stromal tumor workshop, Berman [/bib_ref] [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref] [bib_ref] Effect of the tyrosine kinase inhibitor STI571 in a patient with a..., Joensuu [/bib_ref]. Finally, it is of paramount importance that the radiologist critically reviews the results of all evaluation criteria. In a case of inconclusive results on CT or MRI, [ 18 F]FDG-PET/CT might allow a more conclusive assessment of therapy response [bib_ref] NCCN Task Force report: update on the management of patients with gastrointestinal..., Demetri [/bib_ref]. But as GIST lesions can be negative on [ 18 F]FDG-PET before onset of targeted therapy [bib_ref] CT evaluation of the response of gastrointestinal stromal tumors after imatinib mesylate..., Choi [/bib_ref] , ideally a baseline [ 18 F]FDG-PET/CT should be available [bib_ref] Early effects of imatinib mesylate on the expression of insulin-like growth factor..., Trent [/bib_ref]. # Conclusion The management of patients with GIST receiving targeted therapy requires a standardized imaging algorithm for staging and follow-up that allows appropriate response assessment with respect to changes in lesion size and density. Furthermore, response criteria considering HU or SI changes should be validated by futures studies. [fig] Figure 1: Algorithm for optimal use of different imaging modalities. CM, contrast media. [/fig] [fig] Figure 2: Overview about the scanning region, the recommended contrast-enhanced CT phases and the choice of negative or positive oral contrast agents (CA) at baseline, during and after treatment. Abdomen always consists of upper abdomen and pelvis. CM, contrast media. [/fig] [fig] Figure 4: (a) Before onset of imatinib therapy, this liver metastasis is hypervascularized and (b) at the next follow-up this lesion presents hypoattenuated reflecting myxoid degeneration. [/fig] [fig] Figure 6: (a) A non-enhanced CT phase shows 2 hypoattenuated liver lesions (white arrows). (b) These lesions were not detectable on the simultaneously acquired portal venous CT phase. (c, d) At the next follow-up CT scan, both lesions increased and are visible on the non-enhanced and portal venous CT phase. [/fig] [fig] Figure 5: (a) Large metastastic liver lesion with hypervascularized center. (b) Twelve days later the patient presented with acute abdominal pain and a decrease in the haemoglobin level of 2.4 mg/l. CT revealed intratumoural haemorrhage and due to this an obvious increase in lesion size. [/fig] [fig] Figure 7: (a) Multiple GIST metastases with myxoid degeneration. (b) In the follow-up CT scan, the size of the lesions was almost stable but new hyperattenuated nodules within a mass (white arrows) appeared within 3 lesions as a sign of progressive disease. [/fig] [table] Table 1: List of sequences that should be used in MRI of the liver and abdomen [/table] [table] Table 2: Response criteria and modified CT criteria according to RECIST and Choi [/table]	None	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362866/pdf/ci120013.pdf	Abstract The aim was to reach consensus in imaging for staging and follow-up as well as for therapy response assessment in patients with gastrointestinal stromal tumours (GIST). The German GIST Imaging Working Group was formed by 9 radiologists engaged in assessing patients with GIST treated with targeted therapy. The following topics were discussed: indication and optimal acquisition techniques of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT; tumour response assessment considering response criteria and measurement techniques on CT, MRI and PET/CT; result interpretation; staging interval and pitfalls. Contrast-enhanced CT is the standard method for GIST imaging. MRI is the method of choice in case of liver-specific questions or contraindications to CT. PET/CT should be used for early response assessment or inconclusive results on morphologic imaging. All imaging techniques should be standardized allowing a reliable response assessment. Response has to be assessed with respect to lesion size, lesion density and appearance of new lesions. A critical issue is pseudoprogression due to myxoid degeneration or intratumoural haemorrhage. The management of patients with GIST receiving a targeted therapy requires a standardized algorithm for imaging and an appropriate response assessment with respect to changes in lesion size and density.
eab0d69319c953e55125f3ea3cbd46509a4bf317	pubmed	Use of Tracheostomy During the COVID-19 Pandemic	Use of Tracheostomy During the COVID-19 Pandemic BACKGROUND: The role of tracheostomy during the coronavirus disease 2019 pandemic remains unknown. The goal of this consensus statement is to examine the current evidence for performing tracheostomy in patients with respiratory failure from COVID-19 and offer guidance to physicians on the preparation, timing, and technique while minimizing the risk of infection to health care workers (HCWs).METHODS: A panel including intensivists and interventional pulmonologists from three professional societies representing 13 institutions with experience in managing patients with COVID-19 across a spectrum of health-care environments developed key clinical questions addressing specific topics on tracheostomy in COVID-19. A systematic review of the literature and an established modified Delphi consensus methodology were applied to provide a reliable evidence-based consensus statement and expert panel report.RESULTS:Eight key questions, corresponding to 14 decision points, were rated by the panel. The results were aggregated, resulting in eight main recommendations and five additional remarks intended to guide health-care providers in the decision-making process pertinent to tracheostomy in patients with COVID-19-related respiratory failure.CONCLUSION: This panel suggests performing tracheostomy in patients expected to require prolonged mechanical ventilation. A specific timing of tracheostomy cannot be recommended. There is no evidence for routine repeat reverse transcription polymerase chain reaction testing in patients with confirmed COVID-19 evaluated for tracheostomy. To reduce the risk of infection in HCWs, we recommend performing the procedure using techniques that minimize aerosolization while wearing enhanced personal protective equipment. The recommendations presented in this statement may change as more experience is gained during this pandemic. CHEST 2020; 158(4):1499-1514 KEY WORDS: aerosol generating procedure; COVID-19; open surgical tracheostomy; percutaneous dilatational tracheostomy; SARS-CoV-2; tracheostomy ABBREVIATIONS: AGP = aerosol generating procedure; CDC = Centers for Disease Control and Prevention; CHEST = American College of Chest Physicians; COVID-19 = coronavirus disease 2019; ETT = endotracheal tube; HCW = health-care worker; HEPA = high-efficiency particulate air; NP = negative pressure; OST = open surgical tracheostomy; PDT = percutaneous dilatational tracheostomy; PPE = personal protective equipment;RT-PCR = reverse transcription polymerase chain reaction; SARS = severe acute respiratory syndrome; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2019; VAP = ventilator-associated pneumonia ## Summary of recommendations 1. We suggest that tracheostomy be considered in coronavirus disease 2019 (COVID-19) patients when prolonged mechanical ventilation is anticipated (Strong Consensus). 2. There is insufficient evidence for recommending a specific timing for tracheostomy in COVID-19 related respiratory failure (Consensus). 3. We suggest that in patients with COVID-19 related respiratory failure, either open surgical tracheostomy (OST) or percutaneous dilatational tracheostomy (PDT) can be performed in patients expected to require prolonged mechanical ventilation (Strong Consensus). Remarks: Utilization of techniques which minimize aerosolization is recommended when performing tracheostomy (Strong Consensus). [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref]. We recommend that enhanced personal protective equipment (PPE) be used to mitigate the risk of health care worker (HCW) related infection during tracheostomy (Strong Consensus). Remarks: Tracheostomy is an aerosol generating procedure (AGP) and poses an infection risk to HCW involved in the procedure (Strong Consensus). [bib_ref] Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to..., Grasselli [/bib_ref]. We suggest that in patients with COVID-19 related respiratory failure, tracheostomy is performed in a negative-pressure room, preferably in the ICU. As an alternative, a negative-pressure room in the OR could be used, with special attention to minimizing transportationrelated risk of exposure (Strong Consensus). Remarks: If negative pressure rooms are unavailable, the procedure could be performed in a normal pressure room equipped with HEPA filters in the presence of a strict door policy (Strong Consensus). [bib_ref] Surgical considerations for tracheostomy during the COVID-19 pandemic: lessons learned from the..., Tay [/bib_ref]. We do not recommend routine RT-PCR testing (nasopharyngeal swab or lower respiratory sample) prior to performing tracheostomy in patients with confirmed COVID-19 related respiratory failure (Strong Consensus). Remarks: There is insufficient evidence to recommend RT-PCR testing in patients with non-COVID-19 respiratory failure prior to tracheostomy. If such testing is performed, we suggest that a lower respiratory sample (endotracheal aspirate) rather than a nasopharyngeal swab be obtained (Consensus).. We recommend that in patients with COVID-19 related respiratory failure, tracheostomy is performed by a team consisting of the least number of providers with the highest level of experience (Strong Consensus). Remarks: We suggest that prior to the initiation of tracheostomy, a multidisciplinary group of providers including the primary critical care team, palliative care, infectious disease, the procedural and airway team utilize respective expertise to determine the goals of care, patient selection, procedural considerations, as well as workflow to optimize safety of both patient and HCW (Strong Consensus). [bib_ref] Performing tracheostomy during the Covid-19 pandemic: guidance and recommendations from the Critical..., Michetti [/bib_ref]. We suggest that patients be maintained with a closed circuit while on mechanical ventilation with a tracheostomy tube and with in-line suction (Strong Consensus). # Background In the current viral pandemic, critically ill patients with COVID-19 account for approximately 5% of all cases and are responsible for one-quarter of all hospitalizations. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] It appears that most critically ill patients require mechanical ventilation. [bib_ref] Clinical characteristics of coronavirus disease 2019 in China, Guan [/bib_ref] [bib_ref] SARS-CoV-2 viral load in clinical samples of critically ill patients, Huang [/bib_ref] [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] [bib_ref] Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to..., Grasselli [/bib_ref] Because of the acute respiratory failure often requiring deep sedation and neuromuscular blockers, these patients may need prolonged mechanical ventilation and may benefit from a tracheostomy. Tracheostomy data from prior respiratory viral outbreaks are sparse, and the available literature from the current outbreak is very limited. [bib_ref] Surgical considerations for tracheostomy during the COVID-19 pandemic: lessons learned from the..., Tay [/bib_ref] The decision to proceed with tracheostomy in patients with COVID-19 must be patient-centric while protecting the safety of health care workers (HCWs). Tracheostomy is considered an aerosol generating procedure (AGP), and based on the 2003 severe acute respiratory syndrome (SARS) outbreak, it appears to pose the risk of infection to HCWs. Some experts recommend delaying tracheostomy for at least 2 to 3 weeks in patients with COVID-19-associated respiratory failure. [bib_ref] Performing tracheostomy during the Covid-19 pandemic: guidance and recommendations from the Critical..., Michetti [/bib_ref] Physicians must determine the role of tracheostomy in patients with COVID-19, which may depend on the predicted clinical course. In some heavily affected areas, the COVID-19 pandemic is impacting health-care systems in an unprecedented manner. Tracheostomy may allow faster liberation from mechanical ventilation, may allow shorter ICU stay, [bib_ref] Clinical progression of patients with COVID-19 in Shanghai, Chen [/bib_ref] [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] and may impact availability of ICU resources. There are unanswered questions regarding staff preparation and protection, timing, location, technique, and postintervention care for this procedure. This consensus statement was created to address the knowledge gap. The expert panel represented the American College of Chest Physicians (CHEST), the American Association for Bronchology and Interventional Pulmonology, and the Association of Interventional Pulmonology Program Directors. Eight key questions, corresponding to 14 decision points, were rated by the panel [fig_ref] TABLE 1 ]: Key Questions Pertinent to Tracheostomy During the COVID-19 Pandemic In patients with... [/fig_ref]. The results were aggregated, resulting in eight main recommendations and five additional remarks intended to guide healthcare providers in the decision-making process pertinent to tracheostomy in patients with COVID-19. The statement focuses on selected important issues relating to performing a tracheostomy in critically ill patients with COVID-19 requiring mechanical ventilation. # Methods ## Literature search A comprehensive literature search of MEDLINE (PubMed interface) was executed. The search strategy included both controlled vocabulary, such as the National Library of Medicine's Medical Subject Headings and key words using "tracheostomy" OR "percutaneous tracheostomy" OR "percutaneous dilatational tracheostomy" OR "PEG" OR "percutaneous epigastric tube" AND "coronavirus" OR "coronavirus 2019" OR "COVID-19" OR "2019-nCoV" OR "SARS-CoV-2" OR "SARS" OR "MERS" OR "COVID" OR "SARS-CoV" OR "nCoV" between 2000 and the present time (ie,. Additional Medical Subject Heading searches were performed by using the words "tracheostomy" OR "percutaneous tracheostomy" OR "percutaneous dilation tracheostomy" AND "ultrasound," and "Reverse Transcription Polymerase Chain Reaction," "PCR testing," and "viral shedding" with no language or time restrictions. Each article was assessed for relevance to the primary objective, and useful references and similar articles were retrieved. No language restrictions were applied. The title, abstract, and full text of all articles captured with these search criteria were assessed, and those reporting the tracheostomy and techniques in patients with and without SARS COVID-19 were included. The reference list of all identified studies was also analyzed to detect additional articles. The typical guideline methodology was not used for this expert panel report. This paper is not a systematic review of the literature using PICO (Patient, Problem or Population, Intervention, Comparison control or comparator) questions, PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagrams, and tables of evidence. # Consensus methodology Written from multi-institutional and multisociety perspectives, this statement is intended to provide context for the use of tracheostomy We recommend that enhanced personal protective equipment (PPE) be used to mitigate the risk of health care worker (HCW) related infection during tracheostomy. Tracheostomy is an aerosol generating procedure (AGP) and poses an infection risk to HCW involved in the procedure. If negative pressure rooms are unavailable, the procedure could be performed in a normal pressure room equipped with HEPA filters in the presence of a strict door policy. We do not recommend routine RT-PCR testing (nasopharyngeal swab or lower respiratory sample) prior to performing tracheostomy in patients with confirmed COVID-19 related respiratory failure. There is insufficient evidence to recommend reverse transcriptase polymerase reaction (RT-PCR) testing in patients with non-COVID-19 respiratory failure prior to tracheostomy. If such testing is performed, we suggest that a lower respiratory sample (endotracheal aspirate) rather than a nasopharyngeal swab be obtained. We recommend that in patients with COVID-19 related respiratory failure, tracheostomy is performed by a team consisting of the least number of providers with the highest level of experience. We suggest that prior to the initiation of tracheostomy, a multidisciplinary group of providers including the primary critical care team, palliative care, infectious disease, the procedural and airway team utilize respective expertise to determine the goals of care, patient selection, procedural considerations, as well as workflow to optimize safety of both patient and HCW. We suggest that patients be maintained with a closed circuit while on mechanical ventilation with a tracheostomy tube and with in-line suction. We suggest that in patients with COVID-19 related respiratory failure, tracheostomy is performed in a negative-pressure room, preferably in the ICU. As an alternative, a negative-pressure room in the OR could be used, with special attention to minimizing transportation-related risk of exposure. Strongly Against Weakly Against Neutral Weakly in Favor Strongly in Favor April 22, 2020 (Zoom Video Communications). The results and recommendations were presented, discussed, and refined. The panel independently and anonymously rated the appropriateness of the recommendations on a five-point Likert scale [fig_ref] Figure 1 -: Voting results for the recommendations and remarks [/fig_ref]. We required 75% of the panel to respond to a vote for considering a specific recommendation. The strength of the recommendations is based on the degree of consensus resulting from the modified Delphi method. At least 70% agreement on the direction of a recommendation was considered consensus. A threshold of $ 80% for agreement was required for each item to reach strong consensus [fig_ref] Figure 1 -: Voting results for the recommendations and remarks [/fig_ref]. We make a suggestion when referring to an action for physicians to consider and a recommendation when referring to a preferred choice of action. # Results Outcomes of Tracheostomy 1. We suggest that tracheostomy be considered in coronavirus disease 2019 (COVID-19) patients when prolonged mechanical ventilation is anticipated. Data are lacking on the subject of clinical utility of tracheostomy vs prolonged intubation and mechanical ventilation in patients with COVID-19 respiratory failure. In the medical and surgical literature reviewed by our team, prolonged intubation and late tracheostomy were grouped together and were defined as 10 to 15 days after initiation of mechanical ventilation. One study from New York University Langone Health showed that 33% of patients who underwent percutaneous dilatational tracheostomy (PDT) at a mean of 10 days were liberated from mechanical ventilation.The followup of 18 days is too short to comment on how tracheostomy impacts long-term outcomes in this patient population, especially in the absence of a control group. We surveyed the literature reporting the benefits of tracheostomy regarding ICU length of stay, hospital stay, mortality, and complications such as ventilatorassociated pneumonia (VAP). A prospective randomized study comparing 120 patients with early (within 48 h) to late tracheotomy (14-16 days) in critically ill medical patients demonstrated that the early group had lower mortality, less pneumonia, and fewer accidental extubations compared with late tracheostomy. [bib_ref] A prospective, randomized, study comparing early percutaneous dilational tracheotomy to prolonged translaryngeal..., Rumbak [/bib_ref] A prospective randomized controlled trial compared early (day 3) vs delayed (day 15) tracheostomy in surgical ICU adult patients anticipated to require prolonged mechanical ventilation via endotracheal intubation. The study concluded that the early PDT resulted in more ventilator-free, sedationfree, and ICU-free days; higher successful weaning and ICU discharge rate; and lower incidence of VAP, but did not change the cumulative 60-day incidence of death in the patients' anticipated requiring prolonged mechanical ventilation. [bib_ref] Early versus late percutaneous dilational tracheostomy in critically ill patients anticipated requiring..., Zheng [/bib_ref] A large Cochrane Database systematic review from 2015 comparing early (2-10 days after intubation) to late (> 10 days after intubation) tracheostomy in critically ill adults included eight randomized controlled trials with almost 2,000 participants. [bib_ref] Early versus late tracheostomy for critically ill patients, Andriolo [/bib_ref] This analysis did not show a lower VAP incidence, but there was a lower mortality rate in the early compared with the late tracheostomy group (number needed to treat for an additional beneficial outcome, approximately 11). [bib_ref] Early versus late tracheostomy for critically ill patients, Andriolo [/bib_ref] A large retrospective study of almost 125,000 tracheostomies did show an association between early tracheostomy and decreased rate of sepsis and VAP. [bib_ref] Outcomes of early versus late tracheostomy, Villwock [/bib_ref] Another prospective randomized study from surgical critical care units with slightly different criteria for early (< 4 days) and late (> 10 days) did not find any statistically significant difference in 30-day or 2-year mortality. [bib_ref] Effect of early vs late tracheostomy placement on survival in patients receiving..., Young [/bib_ref] The available literature suggests potential benefits of tracheostomy compared with prolonged mechanical ventilation, but the data on mortality and VAP, however, remain unclear. Tracheostomy appears to be clinically useful in patients with COVID-19 when prolonged ventilator support is anticipated. The data from the COVID-19 pandemic are limited, but the procedure was performed safely for patients and operators.Most data reviewed pre-COVID-19 are from medical and surgical clinical trials in critically ill patients with ARDS. The information from publications suggests that tracheostomy could potentially offer better outcomes including ventilatorfree days, shorter stay in the ICU, shorter stay in the hospital, and perhaps reduced incidence of hospitalacquired pneumonia when compared with prolonged mechanical ventilation. Therefore, we suggest that tracheostomy be considered in patients with COVID-19 when mechanical ventilation is anticipated to be > 10 to 15 days. Timing of Tracheostomy 2. There is insufficient evidence for recommending a specific timing for tracheostomy in COVID-19 related respiratory failure. Conventionally, in the medical ICUs, tracheostomy has been performed in patients with ongoing mechanical ventilatory needs, 2 to 3 weeks after endotracheal intubation. The decision regarding timing of chestjournal.org tracheostomy, while dependent on the understanding of disease pathogenesis, is composed of a variety of factors including patient and family preferences, expected outcomes, and the likelihood of weaning from mechanical ventilation. [bib_ref] Hospital variation in early tracheostomy in the United States: a population-based study, Mehta [/bib_ref] Early tracheostomy has justifiable benefits, including lower sedation requirements and increased patient comfort. [bib_ref] Early percutaneous tracheotomy versus prolonged intubation of mechanically ventilated patients after cardiac..., Trouillet [/bib_ref] Many studies have demonstrated shorter duration of mechanical ventilation and ICU stay with early tracheostomy, 15,22,23 but others have not. [bib_ref] Early percutaneous tracheotomy versus prolonged intubation of mechanically ventilated patients after cardiac..., Trouillet [/bib_ref] [bib_ref] Early tracheotomy versus prolonged endotracheal intubation in unselected severely ill ICU patients, Blot [/bib_ref] [bib_ref] The timing of tracheotomy in critically ill patients undergoing mechanical ventilation: a..., Wang [/bib_ref] As previously mentioned, published literature does not clearly support a mortality benefit [bib_ref] Effect of early vs late tracheostomy placement on survival in patients receiving..., Young [/bib_ref] [bib_ref] Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult..., Terragni [/bib_ref] [bib_ref] Early versus late tracheostomy for critically ill patients, Silva [/bib_ref] [bib_ref] Effect of early tracheostomy on resource utilization and clinical outcomes in critically..., Szakmany [/bib_ref] or reduction of VAP with early tracheostomy. [bib_ref] Systematic review and meta-analysis of studies of the timing of tracheostomy in..., Griffiths [/bib_ref] [bib_ref] Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult..., Terragni [/bib_ref] Determining a patient's prognosis in the ICU remains challenging. In a large multicenter trial, 55% of patients randomized to a late tracheostomy group never received the intervention. [bib_ref] Effect of early vs late tracheostomy placement on survival in patients receiving..., Young [/bib_ref] Therefore, committing patients to early tracheostomy could lead to procedures in patients who may not need it altogether during the course of their illness. The procedural, stomal, and cuff-related complications associated with tracheostomy should be considered. During the current pandemic, transmission of viral illness to HCWs performing AGPs relative to timing is also a consideration. [bib_ref] Aerosol generating procedures and risk of transmission of acute respiratory infections to..., Tran [/bib_ref] Based on available published literature, the optimal timing of performing a tracheostomy in critically ill patients still remains debatable. Specifically, there are no studies addressing the optimal timing of tracheostomy in patients infected with severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2). There is little we can infer from case series published during the 2003 SARS outbreak because the timing of the procedure was not documented. [bib_ref] Surgical considerations for tracheostomy during the COVID-19 pandemic: lessons learned from the..., Tay [/bib_ref] The initial experience from New York University Langone Health suggests the feasibility and safety of a modified bedside PDT performed at a mean of 10 days from intubation in patients with confirmed COVID-19. After a mean follow-up posttracheostomy of 11 days, 33% of patients were liberated from mechanical ventilation.Early tracheostomy in carefully selected patients with COVID-19 may optimize ICU resources in a system that is experiencing an escalating number of critically ill patients. Faster liberation from mechanical ventilation and discharge from the ICU along with decreased use of neuromuscular blocking agents and sedatives may be helpful in circumstances where there are critical resource constraints. In addition, because viral clearance is slower in critically ill patients, the risk of transmission of infection to HCWs should not be the main basis for deciding between early or late tracheostomy. 3,10,12 In a study of hospitalized patients, median duration of viral shedding, as detected in upper respiratory specimens, was 20 days in survivors, with the virus being detectable until death in nonsurvivors. [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] In another study on critically ill patients, viral RNA was detectable in lower respiratory tract specimens in 69% of patients beyond 28 days from symptom onset. [bib_ref] SARS-CoV-2 viral load in clinical samples of critically ill patients, Huang [/bib_ref] These data argue against waiting 3 weeks for performing the tracheostomy. However, published reports from China, Italy, and the United States demonstrate that COVID-19 has a high ICU mortality. [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] [bib_ref] Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to..., Grasselli [/bib_ref] [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Clinical course and outcomes of 344 intensive care patients with COVID-19, Wang [/bib_ref] [bib_ref] Covid-19 in critically ill patients in the Seattle region -case series, Bhatraju [/bib_ref] [bib_ref] Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington..., Arentz [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] ICU mortality in studies with longer follow-up rates is 42% and 78%. [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Clinical course and outcomes of 344 intensive care patients with COVID-19, Wang [/bib_ref] In addition, 12% to 58% of patients remain in the ICU at the end of their respective follow-up periods. [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] [bib_ref] Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to..., Grasselli [/bib_ref] [bib_ref] Covid-19 in critically ill patients in the Seattle region -case series, Bhatraju [/bib_ref] [bib_ref] Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington..., Arentz [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] Institutions now face the decision of pursuing a tracheostomy in many patients with COVID-19, most of whom may require prolonged mechanical ventilation. [bib_ref] Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to..., Grasselli [/bib_ref] In a study on 1,591 critically ill patients with COVID-19 from Italy, 58% of patients were still in the ICU at the end of their follow-up (minimum of 7 days). [bib_ref] Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to..., Grasselli [/bib_ref] The median ICU length of stay in those who survived and those who died in the ICU was 8 and 7 days, respectively. These data suggest that waiting until at least the second week to assess a patient's ICU course may be prudent because many patients would have by then declared their disease trajectory. The existing evidence regarding early vs late tracheostomy in critically ill patients in medical ICUs does not favor one approach. There is no generalizable best timing to perform tracheostomy in patients with COVID-19-related respiratory failure requiring mechanical ventilation. There is insufficient evidence to suggest performing a tracheostomy in the second week of mechanical ventilation or later, and this decision should be individualized based on the physician's best estimate regarding prognosis and factoring in institutional critical care resource constraints. The lack of COVID-19 tracheostomy-related evidence, the conflicting published data on early vs late tracheostomy in general, and the unique COVID-specific scenarios of HCW exposure and resource utilization in stretched systems make it impossible to provide specific guidance on timing of tracheostomy. Remarks: Utilization of techniques which minimize aerosolization is recommended when performing tracheostomy. Tracheostomy is considered an AGP, and in COVID-19related respiratory failure, it can potentially increase the risk of transmission to HCWs. The optimal technique in these patients remains unknown because both procedures have pros and cons, as summarized in [fig_ref] TABLE 2 ]: Pros and Cons of PDT vs OST ETT ¼ endotracheal tube [/fig_ref]. A metaanalysis and a systematic review of the pre-COVID literature suggest that PDT results in lower rates of wound infection and bleeding when compared with open surgical tracheostomy (OST) in the operating room. [bib_ref] Percutaneous dilatational tracheostomy versus surgical tracheostomy in critically ill patients: a systematic..., Delaney [/bib_ref] During the SARS outbreak, mostly OST was performed on infected patients, with several reports documenting no infection to the HCWs when enhanced personal protective equipment (PPE) was being used. [bib_ref] Surgical considerations for tracheostomy during the COVID-19 pandemic: lessons learned from the..., Tay [/bib_ref] At that time, it was thought that PDT involved more extensive airway manipulation that resulted in an increased aerosolization risk. [bib_ref] Elective and emergency surgery in patients with severe acute respiratory syndrome (SARS), Tien [/bib_ref] [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] Since then, the techniques for PDT have continued to evolve. Operators now include ultrasonography as a reliable method of delineation of anatomic structures, further improving technique. [bib_ref] Real-time ultrasoundguided percutaneous dilatational tracheostomy: a feasibility study, Rajajee [/bib_ref] [bib_ref] Comparison of bronchoscopy-guided and real-time ultrasound-guided percutaneous dilatational tracheostomy: safety, complications, and..., Saritas [/bib_ref] [bib_ref] Comparison between ultrasound-and bronchoscopy-guided percutaneous dilational tracheostomy in critically ill patients: a..., Gobatto [/bib_ref] [bib_ref] Ultrasound-guided percutaneous dilational tracheostomy: a systematic review of randomized controlled trials and..., Gobatto [/bib_ref] Because of its performance at the bedside and safety profile, bronchoscopy-guided PDT has become the preferred practice in many institutions. [bib_ref] Percutaneous dilatational tracheostomy versus surgical tracheostomy in critically ill patients: a systematic..., Delaney [/bib_ref] [bib_ref] Death after percutaneous dilatational tracheostomy: a systematic review and analysis of risk..., Simon [/bib_ref] PDT has been demonstrated to be at least as safe as the conventional surgical approach in most critically ill patients. There is also emerging evidence from this pandemic that a novel modified technique of PDT in which the endotracheal tube (ETT) cuff remains inflated and in the distal trachea and the bronchoscope inserted next to the ETT 7 can be safely performed with no major immediate complications for patients and no documented infection to HCWs. This modified technique may be more feasible with earlier tracheostomies before the development of laryngeal edema that may preclude scope insertion alongside the ETT. To date, it is unclear, however, which technique is safer for patients with COVID-19 while reducing transmission to HCWs. In our literature search, we identified case series from the 2003 SARS outbreak and statements from professional societies or institutions regarding tracheostomy in the COVID-19 pandemic.Most of these articles comment on the aerosolization potential of each procedure to HCWs and the various techniques described to minimize such risk [fig_ref] TABLE 3 ]: General Risk Reduction Best Practices [/fig_ref]. In these position or perspective papers, PDT is considered a procedure that involves more extensive airway manipulation because it uses bronchoscopy and dilation of the tracheal intercartilaginous space. These factors may indeed result in an increased aerosolization risk and exposure to the operators and ancillary personnel. [bib_ref] Surgical considerations for tracheostomy during the COVID-19 pandemic: lessons learned from the..., Tay [/bib_ref] On the other hand, PDT is a procedure that offers the ease of performing it in the ICU in a negative pressure (NP) room, minimizing the risk associated with transporting a patient with COVID-19 to the operating room. PDT generally results in less bleeding and therefore less need for cautery (often needed with OST), which itself carries a risk of aerosolizing particles. [bib_ref] Safe tracheostomy for patients with severe acute respiratory syndrome, Wei [/bib_ref] PDT typically may require fewer HCWs involved in the procedure when compared with OST. Finally, the role of ultrasonography has been highlighted as a tool during PDT in patients with COVID-19, thereby reducing the need for bronchoscopic guidance with its potential risk of aerosolization. In fact, three pre-COVID-19 studies demonstrated shorter procedure duration and lower hemorrhage using ultrasound compared with bronchoscopic guidance during PDT. [bib_ref] Real-time ultrasoundguided percutaneous dilatational tracheostomy: a feasibility study, Rajajee [/bib_ref] [bib_ref] Comparison of bronchoscopy-guided and real-time ultrasound-guided percutaneous dilatational tracheostomy: safety, complications, and..., Saritas [/bib_ref] [bib_ref] Comparison between ultrasound-and bronchoscopy-guided percutaneous dilational tracheostomy in critically ill patients: a..., Gobatto [/bib_ref] [bib_ref] Ultrasound-guided percutaneous dilational tracheostomy: a systematic review of randomized controlled trials and..., Gobatto [/bib_ref] With OST, the use of bronchoscopy is avoided; therefore, aerosolization risks may be diminished. There is the added possible risk of aerosolization with cautery and use of suction. Logistical considerations, such as space and personnel, should be carefully considered when this procedure is performed at the bedside because some operating rooms do not have NP capabilities. In these circumstances, meticulous planning with institutional-specific infection control teams and simulated rehearsing should be considered by the operating team. Performing OST at the bedside may be preferred to avoid aerosolization because of inadvertent disconnection of the ventilator circuit during patient transport. Regardless of technique, the portions of the tracheostomy procedure with the highest risk of aerosolization to personnel are during ETT repositioning with cuff deflation, the incision portion of the tracheotomy into the anterior tracheal wall, dilation of the trachea, and the tracheostomy cannula insertion. The operators should strive to implement techniques that are considered best practices to minimize aerosolization. These include ensuring complete neuromuscular blockade, packing the oropharynx, performing apnea at times when aerosolization risk is highest or when manipulating the ETT, reducing or avoiding the use of suction and diathermy, and using gauze or a sponge at the stoma site. All techniques should ideally be performed at the patient's bedside to avoid unnecessary transfers to the operating room where the risk of ventilator circuit interruption and exposure to other areas of the hospital may occur. Our recommendation highlights the fact that the optimal technique, OST or PDT, is unknown because there are pros and cons to both procedures. Therefore, the technique used should be based on individual institutional expertise and defined protocols. Not every institution has the ability to perform PDT or bedside OST. Importantly, this recommendation outlines that OST is not absolutely necessary, as once thought during the SARS outbreak. We recognize that institutions may change their practice as more evidence is emerging during or after this pandemic. The type of tracheostomy (PDT vs OST) should be at the discretion and expertise of the performing operator and the ICU team. ## Risk of infection to hcws and the role of enhanced ppe 4. We recommend that enhanced personal protective equipment (PPE) should be used to mitigate the risk of HCW infection during tracheostomy. Remarks: Tracheostomy is an aerosol generating procedure (AGP) and poses an infection risk to HCW involved in the procedure. HCWs performing AGPs are at occupational risk for infectious diseases transmitted from patients, sometimes despite existing safety protocols. 12 COVID-19 is transmitted via respiratory droplets, and interventions which exacerbate the production of droplets and aerosols could exacerbate the risk of infection.The Chinese Center for Disease Control and Prevention statistics indicate that HCWs represented 3.8% of the reported cases. Of these, 14.8% had severe disease and the overall mortality rate was 0.6%. [bib_ref] Coronavirus Disease 2019 (COVID-19): emerging and future challenges for dental and oral..., Meng [/bib_ref] [bib_ref] Reasons for healthcare workers becoming infected with novel coronavirus disease 2019 (COVID-19)..., Wang [/bib_ref] In Italy, approximately 20% of responding HCWs were infected. [bib_ref] COVID-19 and Italy: What next?, Remuzzi [/bib_ref] As of April 9, 2020, per the Centers for Disease Control and Prevention (CDC) in the United States, 9,282 HCWs have been infected with SARS-COV-2, accounting for 11% of all the reported cases, with 27 reported deaths. More than one-half of these HCWs reported contact with patients with COVID-19 only in health-care settings. The total number of cases of HCWs infected with COVID-19 in the United States may be an underestimation because only 16% of respondents were asked to comment on their health-care exposures.The scientific evidence for the creation of aerosols associated with tracheostomy, the load of viable viruses within the aerosols, and the precise mechanism of transmission to the host have not been clearly studied. However, a systematic review of 10 studies from the 2003 SARS outbreak suggests that tracheostomy has an OR of 4.2 for risk of transmission to HCWs. [bib_ref] Which preventive measures might protect health care workers from SARS?, Chen [/bib_ref] There is evidence that personnel education and the use of PPE are associated with a decreased risk of transmission of SARS. [bib_ref] BC Interdisciplinary Respiratory Protection Study Group. Protecting health care workers chestjournal.org from..., Moore [/bib_ref] Most SARS cases involved nosocomial transmission in hospitals via AGPs. [bib_ref] Practical considerations for performing regional anesthesia: lessons learned from the COVID-19 pandemic, Lie [/bib_ref] This risk is maximal during intubation, tracheostomy, or open airway procedures, where the exposure will occur in close proximity, often involving positive pressure ventilation. Understanding how to mitigate these risks is critical. [bib_ref] COVID-19 pandemic: what every otolaryngologist-head and neck surgeon needs to know for..., Balakrishnan [/bib_ref] Studies specifically evaluating the risk of infection to the HCWs performing these procedures in COVID-19 are not available. However, one of the earliest reports from Wuhan, China, found that among the first 138 consecutive patients hospitalized, 40 were HCWs. [bib_ref] Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in..., Wang [/bib_ref] During the SARS outbreak of 2003 in Canada, 51% of the 438 cases were HCWs, and three died from SARS-related causes. [bib_ref] BC Interdisciplinary Respiratory Protection Study Group. Protecting health care workers chestjournal.org from..., Moore [/bib_ref] Although the figures are concerning, other data suggest that by respecting the personal protective measures, HCWs can stay safe. Although standard PPE is 1. Equipment and medications should be preplanned with checklist and procedure kits prior to entering the room. 2. Avoid using carts in the room to reduce the need to undergo decontamination. Consider a disposable bronchoscope. 3. Universal protocol and time out may be performed outside the room with procedure team followed by appropriate donning of enhanced PPE per institutional protocol. 4. Use of ultrasound to assess anatomy and point of entry (use standard decontamination protocol of durable equipment). ## 5. Deep sedation and neuromuscular blockers should be used for the procedure to minimize cough and agitation. 6. Before start, perform a trial of apnea to mimic apnea. a. Withhold ventilation (apnea). b. Discontinue positive end-expiratory pressure. c. Increase the FIO 2 to prevent desaturation, for a duration of 30 s to 1 min. If apnea is not tolerated, reduce the ventilatory pressures and respiratory frequency to minimize the risk of aerosolization. Otherwise, consider deferring the procedure until ventilatory requirements are optimized. 7. Key intervals where apnea must be performed during a traditional bronchoscopic-guided percutaneous dilational tracheostomy are as follows: When the bronchoscope adaptor is added to the circuit. Prior to inserting the bronchoscope into the ETT. During the pullback of the ETT with cuff deflation. Time of insertion of the introducer needle, angiocatheter, dilation, and insertion of the tracheostomy tube, bronchoscopic confirmation of placement, until connected to closed circuit connection with ventilator. Removal of the ETT from oropharynx. 8. The oropharynx and the hypopharynx may be packed. A suction tip may be placed in the mouth to lessen the risk of aerosolization of oral secretions during the ETT pullback. 9. During the procedure, place a moist gauze or sponge around the guidewire, during dilation, and neck stoma as needed. 10. Ultrasound can be incorporated into PDT to avoid the need for bronchoscopic guidance. Sonography equipment will need to be decontaminated at the end of the procedure. Additionally, a modified PDT technique with placement of bronchoscope alongside the ETT while advancing the ETT below the intended stomal point of entry might reduce aerosolization. ## 11 . During an open tracheostomy, in addition to the aforementioned steps using apnea during ETT manipulation and prior to incision into the anterior wall of the trachea, avoid or minimize the use of diathermy and suction because it carries a risk of aerosolizing particles. 12. Place a petrolatum gauze dressing at the site of the fresh stoma until it heals to prevent aerosolization or air leak. See [fig_ref] TABLE 1 ]: Key Questions Pertinent to Tracheostomy During the COVID-19 Pandemic In patients with... [/fig_ref] and 2 legends for expansion of abbreviations. chestjournal.org essential (N95 mask, goggles or face shield, surgical gown, and gloves), the case series of tracheostomies performed in five health-care institutions in Singapore, Hong Kong, and Canada during the SARS outbreak also document that in addition to standard PPE, enhanced PPE measures were applied ranging from the addition of face shields to standard PPE or powered air-purifying respirators. All members of the surgical teams remained healthy after performing a total of 23 tracheostomy procedures. [bib_ref] Surgical considerations for tracheostomy during the COVID-19 pandemic: lessons learned from the..., Tay [/bib_ref] From this COVID-19 pandemic, published data are limited. A case report of early COVID-19 experience from Singapore 52 revealed that none of the 41 HCWs who took care of a patient with severe pneumonia before diagnosis of COVID-19 became infected themselves or developed symptoms. These HCWs had been present during intubation and extubation of the patient and they were present for at least 10 min at a distance of < 2 m from the patient, with 85% wearing a surgical mask and the remainder wearing N95 masks. Similarly, at New York University, a team composed of eight HCWs reported 98 PDTs. The personnel strictly respected the use of enhanced PPE and no members tested positive or developed COVID-19 symptoms.As of this writing, there are no hard data regarding aerosolization risk between OST and PDTs. In summary, the data on the risk of HCW infection during tracheostomy are mixed. The available data suggest that the rate of infection, when enhanced PPE measures are used, is considerably lower than when they are not used or are used improperly. [bib_ref] COVID-19 and the risk to health care workers: a case report, Ng [/bib_ref] Although the specific risk associated with tracheostomy during COVID-19 is not known, tracheostomy is one of the high-risk AGPs, and prior SARS experience suggests that adequate protection is essential to prevent HCWs from contacting the infection. In addition to PPE, other ways of mitigating the risks for HCWs involved in the tracheostomy procedure include location and technique. Location of Tracheostomy Procedure 5. We suggest that in patients with COVID-19 related respiratory failure, tracheostomy is performed in a negative-pressure room, preferably in the ICU. As an alternative, a negative-pressure room in the OR could be used, with special attention to minimizing transportation-related risk of exposure. Remarks: If negative pressure rooms are unavailable, the procedure could be performed in a normal pressure room equipped with HEPA filters in the presence of a strict door policy. Performing OSTs in the operating room is a common practice worldwide. However, during previous SARS outbreaks, OST at the bedside in the ICU has evolved as an alternative approach. [bib_ref] Surgical considerations for tracheostomy during the COVID-19 pandemic: lessons learned from the..., Tay [/bib_ref] [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] It has been suggested that performing tracheostomies in the ICU rooms minimizes the risk of exposure of HCWs and decreases aerosol generating maneuvers (eg, disconnection of mechanical ventilator circuit) caused by transportation of patients to the operating room. Furthermore, the presence of NP rooms, which are recommended for this type of procedure, [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] [bib_ref] COVID-19 pandemic: what every otolaryngologist-head and neck surgeon needs to know for..., Balakrishnan [/bib_ref] [bib_ref] Safety recommendations for evaluation and surgery of the head and neck during..., Givi [/bib_ref] [bib_ref] Open tracheostomy in a suspect severe acute respiratory syndrome (SARS) patient: brief..., Ahmed [/bib_ref] has historically been limited in the operating room. [bib_ref] Novel approach to reduce transmission of COVID-19 during tracheostomy, Foster [/bib_ref] However, challenges to performing open tracheostomies in ICU rooms have been described in relationship to limited space, possible suboptimal patient positioning, and limited movement of the surgical equipment. [bib_ref] Surgical considerations for tracheostomy during the COVID-19 pandemic: lessons learned from the..., Tay [/bib_ref] [bib_ref] Safe tracheostomy for patients with severe acute respiratory syndrome, Wei [/bib_ref] [bib_ref] Novel approach to reduce transmission of COVID-19 during tracheostomy, Foster [/bib_ref] Nevertheless, the available published data on bedside tracheostomies in SARS-CoV and the initial reports from COVID-19 were successful. Our literature search found no study that compares tracheostomy performed in the operating room vs ICU room in COVID-19-related respiratory failure. Six nonrandomized studies were found about tracheostomy in the SARS-CoV population, [bib_ref] Elective and emergency surgery in patients with severe acute respiratory syndrome (SARS), Tien [/bib_ref] [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] [bib_ref] Novel approach to reduce transmission of COVID-19 during tracheostomy, Foster [/bib_ref] [bib_ref] Tracheostomy in a patient with severe acute respiratory syndrome, Kwan [/bib_ref] [bib_ref] COVID-19 pandemic: effects and evidence-based recommendations for otolaryngology and head and neck..., Kowalski [/bib_ref] with three of them being case series that included three or more patients. [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] [bib_ref] Safe tracheostomy for patients with severe acute respiratory syndrome, Wei [/bib_ref] [bib_ref] COVID-19 pandemic: effects and evidence-based recommendations for otolaryngology and head and neck..., Kowalski [/bib_ref] The other three were single case reports. There was only one case report that included infection by SARS-CoV-2 2019. [bib_ref] Tracheostomy in a patient with severe acute respiratory syndrome, Kwan [/bib_ref] In these studies, 24 tracheostomies were performed successfully. All of them were done using OST technique. The use of a NP room was a common characteristic in all procedures. Only two procedures were performed in the operating room (case reports), [bib_ref] Elective and emergency surgery in patients with severe acute respiratory syndrome (SARS), Tien [/bib_ref] [bib_ref] Tracheostomy in a patient with severe acute respiratory syndrome, Kwan [/bib_ref] and the rest were performed at bedside in ICU rooms. In the largest case series, 15 tracheostomies were performed at bedside in the ICU rooms to avoid transportation of patients and to minimize exposure. [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] None of the studies reported complications because of the procedure. ICU rooms with NP that have an anteroom adjacent to it are ideal to allow appropriate donning and doffing of PPE for the surgical team. If the operating room is used, the room should have its own ventilation system and be separated from the main operating room.The use of portable ventilators with enough distance from the transport team and minimizing disconnection of ventilator circuit during the process are extremely important to decrease exposure of HCWs. [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] Small highefficiency particulate air (HEPA) filters attached to ventilator circuit could be used to minimize aerosol dissemination. The use of specific routes and dedicated elevators to transport patients could minimize exposure. [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] The use of a special team for transportation (different from the surgical team) could allow time for the surgical team to do appropriate donning and doffing before and after the procedure, [bib_ref] Elective and emergency surgery in patients with severe acute respiratory syndrome (SARS), Tien [/bib_ref] but it also increases the number of people exposed to the patient. Recommendations by the CDC establish that an airborne infection isolation room, formerly called NP isolation room, should be used for aerosol generating procedures.Although not specifically mentioned, based on the CDC recommendations and prior experience, positive pressure rooms should be avoided for these procedures, if possible. This measure minimizes the concentration of aerosol inside the room, which leads to less exposure of the operators and less aerosol dissemination outside the room when the door is opened. In the absence of NP rooms, Chee et al. [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] described the use of single rooms, with locked and sealed doors (with tape) as an alternative (strict door policy). The use of small HEPA filters attached to the airway tubing/ventilator circuit 60 and large HEPA filters for the room have been described in case reports to minimize aerosol dissemination. Reports from the COVID-19 pandemic suggest that PDT has been successfully performed at the bedside in the ICU in New York City, without any documented COVID-19 transmission to HCWs. [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] Exercising a standard process of donning and doffing PPE including ongoing education is extremely important and enhances the protection of the staff. [bib_ref] Infection control measures for operative procedures in severe acute respiratory syndrome-related patients, Chee [/bib_ref] Although the use of PPE has been reported to limit communication (hearing) among members of the team, 42,56 no complications were reported as a consequence of wearing PPE. In addition, the use of NP canopies is currently under investigation. The review of existing studies from prior viral outbreaks and the frontline experience from the COVID-19 pandemic are based on these recommendations. Tracheostomy should ideally be performed at the bedside in the ICU, with patients being located in NP rooms or normal pressure rooms with strict door policy with the use of HEPA filters. Role of Preprocedural COVID-19 Testing 6. We do not recommend routine RT-PCR testing (nasopharyngeal swab or lower respiratory sample) prior to performing tracheostomy in patients with confirmed COVID-19 related respiratory failure. Remarks: There is insufficient evidence to recommend RT-PCR testing in patients with non-COVID-19 respiratory failure prior to tracheostomy. If such testing is performed, we suggest that a lower respiratory sample (endotracheal aspirate) rather than a nasopharyngeal swab be obtained. Diagnostic testing to identify infected individuals is considered essential to the control of the global pandemic of COVID-19. Important gaps remain in screening asymptomatic people during the incubation phase, and in the accurate determination of the live viral shedding during convalescence. [bib_ref] Diagnostic testing for severe acute respiratory syndrome-related coronavirus-2: a narrative review, Cheng [/bib_ref] It is critical to minimize the risk of transmission of infection to HCWs during the procedural and postprocedural care. [bib_ref] Improving staff safety during tracheostomy in COVID-19 patients, Vargas [/bib_ref] Guidance on repeat testing prior to AGPs and how it impacts duration of isolation precautions, utilization of available resources, and discharge management is lacking. Evidence is emerging of active viral replication in the upper respiratory tract tissues, given successful live virus isolation from throat swabs. [bib_ref] Virological assessment of hospitalized patients with COVID-2019, Wolfel [/bib_ref] We based the remarks to this recommendation on the limited published evidence suggesting a greater number of positive RT-PCR tests and a higher viral respiratory load in lower respiratory tract samples compared with nasopharyngeal swabs. [bib_ref] SARS-CoV-2 viral load in clinical samples of critically ill patients, Huang [/bib_ref] [bib_ref] Detection of SARS-CoV-2 in different types of clinical specimens, Wang [/bib_ref] [bib_ref] Quantitative detection and viral load analysis of SARS-CoV-2 in infected patients, Yu [/bib_ref] Additionally, data from a well-conducted study suggest a higher viral load and a slower decline in RNA concentration in lower respiratory tract samples compared with the nasopharyngeal swabs. [bib_ref] Virological assessment of hospitalized patients with COVID-2019, Wolfel [/bib_ref] We recognize that the test results depend on a wide variety of factors including sample collection technique, transportation, processing, and method used for RT-PCR testing. Therefore, when obtained, a lower respiratory sample should be processed using validated tests available at individual institutions. Role of a Multidisciplinary Team 7. We recommend that in patients with COVID-19 related respiratory failure, tracheostomy is performed by a team consisting of the least number of providers with the highest level of experience. Remarks: We suggest that prior to the initiation of tracheostomy, a multidisciplinary group of providers including the primary critical care team, palliative care, infectious disease, the procedural and airway team utilize respective expertise to determine the goals of care, patient selection, procedural considerations, as well as workflow to optimize safety of both patient and HCW. Prior to COVID-19, the practice of PDT was increasingly performed by multidisciplinary teams at large tertiary care hospitals. Multidisciplinary PDT teams often include nonsurgical and surgical physicians (otolaryngologists, trauma surgeons, general surgeons, thoracic surgeons, interventional pulmonologists, and intensivists), anesthesiologists, nurses, respiratory therapists, and speech and language pathologists. These teams have reported improved outcomes, including the incidence of airway bleeding, physiological disturbances, and efficiency of care delivery. [bib_ref] Reduction of complication rate in percutaneous dilation tracheostomies, Bhatti [/bib_ref] [bib_ref] Safety, efficiency, and costeffectiveness of a multidisciplinary percutaneous tracheostomy program, Mirski [/bib_ref] Implementation of a multidisciplinary PDT service was shown to result in a marked decrease in major complications (25.4% preimplementation and 4.9% postimplementation) and a reduction in wait time for the performance of tracheostomy (2.6 days preimplementation and 1.3 days postimplementation). [bib_ref] Safety, efficiency, and costeffectiveness of a multidisciplinary percutaneous tracheostomy program, Mirski [/bib_ref] Several other reports of tracheostomy-centered multidisciplinary teams have been published and support these findings. [bib_ref] Evaluation of the role of a specialist tracheostomy service. From critical care..., Norwood [/bib_ref] [bib_ref] Dysphagic patients with tracheotomies: a multidisciplinary approach to treatment and decannulation management, Frank [/bib_ref] [bib_ref] Driving standards in tracheostomy care: a preliminary communication of the St Mary's..., Arora [/bib_ref] [bib_ref] Improving tracheostomy care: a prospective study of the multidisciplinary approach, Cetto [/bib_ref] Review of the literature revealed several articles supporting the use of a multidisciplinary team; however, there are limited or no data specifically evaluating this paradigm in the setting of pandemic illness. We found two case series [bib_ref] Safe tracheostomy for patients with severe acute respiratory syndrome, Wei [/bib_ref] [bib_ref] Open tracheostomy in a suspect severe acute respiratory syndrome (SARS) patient: brief..., Ahmed [/bib_ref] and four editorials/technical communications/systematic reviews of the literature. [bib_ref] Elective and emergency surgery in patients with severe acute respiratory syndrome (SARS), Tien [/bib_ref] [bib_ref] Tracheotomy in ventilated patients with COVID-19, Chao [/bib_ref] [bib_ref] CORONA-steps for tracheotomy in COVID-19 patients: a staff-safe method for airway management, Pichi [/bib_ref] [bib_ref] Practical recommendations for critical care and anesthesiology teams caring for novel coronavirus..., Wax [/bib_ref] Both case series discussed tracheostomy during the SARS-CoV epidemic of 2003. The systematic reviews included one from the SARS-CoV epidemic and three pertaining to the current COVID-19 pandemic. All the papers discussed the need to minimize the number of procedural team members because of concerns for pathogen exposure and conservation of PPE, with the number of personnel ranging between three and five. Four of the six papers recommended a three-person team consisting of one to two surgeons, one person to manage the ventilator/ETT, and if there was only one surgeon performing the procedure one additional staff member (bronchoscopist, nurse, or respiratory therapist). In addition, there are pre-COVID-19 data that suggest performing tracheostomy and gastrostomy procedures using a gastroscope and/or bronchoscope in the same sitting by a single specialty has a good safety profile with possible advantages of shorter ICU and hospital length of stay. [bib_ref] Safety and feasibility of interventional pulmonologists performing bedside percutaneous endoscopic gastrostomy tube..., Yarmus [/bib_ref] [bib_ref] Bronchoscope-guided percutaneous endoscopic gastrostomy tube placement by interventional pulmonologists: a feasibility and..., Folch [/bib_ref] [bib_ref] Outcomes of tracheostomy with concomitant and delayed percutaneous endoscopic gastrostomy in the..., Nobleza [/bib_ref] [bib_ref] Interventional pulmonology in the intensive care unit: percutaneous tracheostomy and gastrostomy, Belanger [/bib_ref] This could be considered in institutions with such expertise, but there might be concerns for the additional time required to perform percutaneous endoscopic gastrostomy placement, leading to extended exposure time. In summary, published data suggest an improvement in patient outcomes when using a multidisciplinary approach in percutaneous endoscopic gastrostomy. Therefore, we recommend that a multidisciplinary team be formed at each institution, to optimize expertise in the support and performance of tracheostomies to minimize risk and limit the size of the procedure team. Palliative care and infectious disease teams could offer meaningful insights into patients' overall goals of care, chance of meaningful recovery, and duration of viral shedding, factors that could affect the decision or the timing of tracheostomy. This multidisciplinary team paradigm is vital in the setting of a pandemic illness crisis when critical care needs exceed standard capacity resulting in surge level in which non-ICU providers definitively benefit from an expert multidisciplinary team for collaborative decision-making in all aspects of tracheostomy care. Posttracheostomy Care of Patients With COVID-19 [bib_ref] Performing tracheostomy during the Covid-19 pandemic: guidance and recommendations from the Critical..., Michetti [/bib_ref]. We suggest that patients be maintained with a closed circuit while on mechanical ventilation with a tracheostomy tube and with in-line suction. The inner cannula and tracheostomy tube changes and airway clearance are all considered to be AGPs. The optimal techniques for posttracheostomy care and timing of inner cannula and tracheostomy tube changes is not known in COVID-19, SARS, or Middle East Respiratory Syndrome. The best guidance comes from societal statementsthat balance an emphasis on chestjournal.org safety both for patients and HCWs in the setting of viral pandemics [bib_ref] Safety recommendations for evaluation and surgery of the head and neck during..., Givi [/bib_ref] [bib_ref] COVID-19 pandemic: effects and evidence-based recommendations for otolaryngology and head and neck..., Kowalski [/bib_ref] [bib_ref] CORONA-steps for tracheotomy in COVID-19 patients: a staff-safe method for airway management, Pichi [/bib_ref] [fig_ref] TABLE 4 ]: Summary of Posttracheostomy Care of Patients With COVID-19Limit the number of providers... [/fig_ref]. The recommendations include use of enhanced PPE when performing tracheostomy care in patients with COVID-19 with the least number of HCWs present. If available, single-use disposable equipment should be used. Whenever possible, the patient should maintain a closed circuit at all times regardless of mechanical ventilation requirements. If the patient no longer requires mechanical ventilation but is not ready for capping trials, a closed circuit can be fashioned using a heat moisture exchanger with viral filter and in-line suction to minimize aerosol generation [fig_ref] Figure 2 -: A [/fig_ref]. Of note, heat moisture exchanger filters on patients with tracheal masks increase the resistance of the flow and may get clogged because of secretions. Inner cannulas should be changed on an as-needed basis rather than a scheduled routine. Tracheostomy tube changes can potentially be delayed until the patient tests negative for COVID-19, unless there is a clinical reason to proceed earlier. When using inhaled therapies, if the patient is on mechanical ventilation, an in-line nebulizer is preferred and if decannulated, a metered-dose inhaler with a spacer is recommended. Institutions have developed local guidance for when patients with COVID-19 can be cleared to move to a non-NP room (can be two negative nasopharyngeal swabs vs a negative nasopharyngeal swab and a negative tracheal aspirate). The timing of when to clear patients is unknown because most patients are asymptomatic when they first contract the virus. For decannulation, a rapid protocol is recommended to minimize aerosol generation. If the patient can tolerate their initial tracheostomy tube with the cuff deflated and either a speaking valve or a capping trial, then minimizing tracheostomy tube changes is advised. If a larger tracheostomy tube has been placed, HCWs could try to limit the number of tracheostomy tube changes and expedite a decannulation protocol as able. These recommendations are designed to minimize risk for HCWs performing necessary AGPs on patients who have undergone placement of a tracheostomy tube. Some questions that are not addressed in the literature include how to provide appropriate nutrition and swallow evaluations for patients with tracheostomy and when airway clearance can begin for these patients. The disposition of posttracheostomy patients with COVID-19 has not been addressed in the published literature. Typically, these patients are discharged to a long-term acute care facility; however, some long-term acute care facilities may not accept a patient with a tracheostomy tube prior to the first tracheostomy tube change and may require conversion to negative COVID-19 testing. ## Summary This consensus statement on tracheostomy is intended to offer guidance in the decision-making, preparation, timing, techniques, and postprocedural care of patients with COVID-19-related respiratory failure. We think we addressed the most common questions being faced by physicians during this pandemic pertinent to the practice of tracheostomy. One of the strengths of this expert panel report is that it represents the opinions and perspectives of intensive care and interventional pulmonary experts from 10 states with the highest burden of COVID-19 in the United States. The recommendations presented may change as more experience and data are collected during the COVID-19 pandemic. Because of the urgency of this situation, information needs to be made available to provide physicians general recommendations based on limited published data and panel's expertise. This statement should be considered a living document that could be updated in the future in a timely manner as new evidence becomes available. [fig] Figure 1 -: Voting results for the recommendations and remarks. AGP ¼ aerosol generating procedure; COVID-19 ¼ coronavirus disease 2019; HCW ¼ health-care worker; HEPA ¼ high-efficiency particulate air; OR ¼ operating room; OST ¼ open surgical tracheostomy; PDT ¼ percutaneous dilatational tracheostomy; PPE ¼ personal protective equipment; RT-PCR ¼ reverse transcription polymerase chain reaction. [/fig] [fig] Figure 2 -: A [/fig] [table] TABLE 1 ]: Key Questions Pertinent to Tracheostomy During the COVID-19 Pandemic In patients with COVID-19-related respiratory failure, should tracheostomy be offered to patients expected to require prolonged mechanical ventilation? COVID-19 ¼ coronavirus disease 2019; HCW ¼ health-care worker; PCR ¼ polymerase chain reaction; PPE ¼ personal protective equipment. [/table] [table] TABLE 2 ]: Pros and Cons of PDT vs OST ETT ¼ endotracheal tube; OR ¼ operating room; OST ¼ open surgical tracheostomy; PDT ¼ percutaneous dilatational tracheostomy. [/table] [table] TABLE 3 ]: General Risk Reduction Best Practices [/table] [table] TABLE 4 ]: Summary of Posttracheostomy Care of Patients With COVID-19Limit the number of providers participating in tracheotomy procedural and postprocedural management Avoid circuit disconnections and suction via closed circuit Place a HME with viral filter or a ventilator filter once the tracheotomy tube is disconnected from mechanical ventilation Delay routine postoperative tracheotomy tube changes until COVID-19 testing is negativeCanadian Society of Otolaryngology-Head and Neck SurgeryAvoid open suction and instead use closed, in-line suction whenever possible Avoid repeated suctioning and disconnection of the ventilator circuit Use an HME with HEPA-level filter (preferred) to provide humidity, reduce secretions with minimal increase in perceived respiratory resistance in the ventilator circuit or on the ventilator exhaust portion; monitor filter for obstruction risk Minimize nebulization, instillation of fluids Avoid all unnecessary examinations or procedures including decannulation until the patient is considered COVID-19 negative For mature at-home tracheotomy patients, defer all routine tracheotomy changes during pandemicSpeech Language and Audiology CanadaIdentify the minimum number of people required to safely conduct a session Consider bundling care with other health-care professionals Carefully consider equipment use and discuss with infection control services to ensure it can be properly decontaminated Avoid moving equipment between infectious and noninfectious areas Wherever possible, single patient use, disposable equipment is preferred AGP ¼ aerosol generating procedure; HEPA ¼ high-efficiency particulate air; HME ¼ heat moisture exchanger. SeeTable 1legend for expansion of other abbreviations. [/table]	None	http://journal.chestnet.org/article/S0012369220316391/pdf	None
7c36343a95d7d95acbced5d29a65e49488282194	pubmed	Position Paper for the State-of-the-Art Application of Respiratory Support in Patients with COVID-19	Position Paper for the State-of-the-Art Application of Respiratory Support in Patients with COVID-19 Against the background of the pandemic caused by infection with the SARS # Introduction Against the background of the pandemic caused by infection with the SARS-CoV-2 virus, the German Respiratory Society (DGP, Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin), in cooperation with other associations, has appointed a team of experts to answer questions on how to deal with COVID-19 patients at a stage when, as far as is foreseeable at present, hospitals will not be overburdened (last updated: 04/15/2020). Due to the effectiveness of epidemiological measures such as social distancing as a result of a partial curfew, the pandemic in Germany can currently be expected to slow down and lessen in severity. For this reason, great importance was attached to the accuracy of the statements even outside of a pandemic situation, and the key position statements were coordinated by the authors in an elaborate consensus process. This paper is intended as a supplement, continuation, and impetus for the development of cross-disciplinary consensus based on existing guidelines [bib_ref] Recommendations for critically ill patients with COVID-19, Kluge [/bib_ref] [bib_ref] Management of adult community-acquired pneumonia and prevention -update, Ewig [/bib_ref] [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref]. Previous publications on COVID-19 show a remarkable heterogeneity of accompanying symptoms of SARS-CoV-2 infection. This is due to different definitions of certain disease states (e.g., shock), different but unspecified degrees of severity, different disease stages, and different populations. This renders comparisons difficult. In addition, information is currently being published quite quickly, and the patient groups described sometimes only include a few individuals. This paper was prepared in a process compliant with the requirements of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) and is subdivided into 5 thematic statements. Key points are highlighted in the form of key position statements and findings. This article is based on the current state of knowledge about COVID-19, which will improve in the short term due to the increasing number of patients in Germany. The manuscript is, therefore, already slated to be updated at the time of publication. # Method The recommendation is based on the consensus of a group of experts against the background of a selective literature search. These experts were appointed by the Board of the DGP based on their expertise concerning the matter and their experience in structured consensusbuilding according to AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.) criteria. The different chapters were defined in advance and developed by teams of authors. These teams (2-3 authors in each) were given the task of preparing a draft version and developing key position statements so that the first level of consensus-building would be in a small group. Up to 3 key position statements could be made per thematic area. Authors not assigned to work on the chapters were asked to avoid commenting before consensus was reached. The literature, on which the key position statements are based, was evaluated according to the guidelines of the Center for Evidence-Based Medicine based on the currently available data. As per the requirements of AWMFcompliant guideline development, the key position statements were worded according to a grade of recommendation (GOR), whereby grade A means "should/should not," grade B "ought to/ought not to," and grade 0 "may M. Pfeifer, S. Ewig, and T. Voshaar compiled this position statement. ## General The COVID-19 outbreak, caused by infection with the human viral pathogen coronavirus SARS-CoV2 and first described in China in late December 2019, has become a global pandemic [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] [bib_ref] A Novel Coronavirus from Patients with Pneumonia in China, Zhu [/bib_ref] [bib_ref] Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia..., Chen [/bib_ref]. According to current studies, the disease is mild in approximately 80% of those testing positive, more severe in 20% with signs of hypoxic respiratory failure, and it requires intensive medical treatment in approx. 5% of cases [bib_ref] Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak..., Wu [/bib_ref]. The reported mortality rate is between 1 and 10% [bib_ref] Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak..., Wu [/bib_ref] (https://coronavirus.jhu.edu/ map.html). However, these figures relate to the number of people who tested positive and underestimates the situation due to the significantly higher number of unreported cases of infected persons that can be assumed. SARS-CoV-2 is primarily transmitted through droplets (droplet transmission); to what extent droplet nuclei (airborne transmission) or transmission by touching contaminated objects (fomite-based transmission) may play an additional role has not been conclusively established. The virus binds to the angiotensin-converting enzyme-2 (ACE2) receptor in the lungs, a membrane-bound aminopeptidase of alveolar epithelial cells [bib_ref] COV-ID-19 and the cardiovascular system, Zheng [/bib_ref]. This makes the lungs the primary target organ of the virus. The virus primarily replicates in the bronchial epithelium of the upper airways, in the nasopharyngeal region, with 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 IIb . Significance of immune defense and systemic inflammatory response for the symptoms of COVID-19 patients. Clinical progression of COVID-19 (mild, green; severe, grey; critical, red) over time [bib_ref] Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, Channappanavar [/bib_ref] [bib_ref] COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal, Siddiqi [/bib_ref]. further multiplication in the lower airways and the gastrointestinal mucosa [bib_ref] Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection, Lin [/bib_ref]. At this stage, some infections are controlled by the immune response and patients can remain asymptomatic. COVID-19 has 3 phases, which are described as follows: early infection, pulmonary involvement, and severe hyperinflammation [bib_ref] Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology, Channappanavar [/bib_ref] [bib_ref] COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal, Siddiqi [/bib_ref]. During the early phase of infection, the virus infiltrates the pulmonary parenchyma and starts replicating; this triggers an inflammatory response involving local vasodilation, increased endothelial permeability, and leukocyte recruitment [bib_ref] Clinical progression and viral load in a community outbreak of coronavirus-associated SARS..., Peiris [/bib_ref]. This focal pneumonia leads to hypoxemia and cardiovascular stress responses. Current data indicate that preexisting cardiovascular conditions and arterial hypertension are major risk factors for a lethal outcome of COV-ID-19 [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref]. The disease is characterized by lymphopenia, which is a relevant pathognomonic sign of the infection. It is caused by apoptosis [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] [bib_ref] A Novel Coronavirus from Patients with Pneumonia in China, Zhu [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. It is also possible that preexisting antibodies against other coronaviruses could be activated in the sense of "antibody dependent enhancement". Prolonged lymphopenia predicts poor prognosis [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. The marked systemic inflammation is characterized by a cytokine storm, with an increase in interleukin (IL)-6, IL-2, IL-7, tumor necrosis factor (TNF)-α, interferon-γ, inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, granulocyte-colony stimulating factor (G-CSF), C-reactive protein (CRP), procalcitonin, and ferritin [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref] [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. Of prognostic relevance are the elevated or increasing concentrations of IL-6 and ferritin [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. In retrospective clinical studies, deceased COVID-19 patients had significantly elevated IL-6, ferritin, and CRP levels [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. Additional prognostic markers are D-dimers and troponin [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. Severe, primarily local inflammation can lead to severe damage to the lung parenchyma, resulting in progressive respiratory distress. Further in the course of the disease, systemic inflammatory response can lead to multiorgan failure. In anatomical pathology studies, vasculitis and thrombosis of the small vessels can also be seen, e.g., in SARS [bib_ref] Multiple organ infection and the pathogenesis of SARS, Gu [/bib_ref]. To what extent these phenomena may play a role in an infection with SARS-CoV2 has not yet been established. ## Covid-19 and respiratory failure The severity of respiratory failure is determined by the interaction of 3 factors: (1) the severity of infection, the immune response and function, and comorbidities, (2) the patient's ventilatory response to hypoxia (hypoxic drive), and (3) the time between the onset of the initial symptoms and the start of clinical treatment. In computed tomography (CT) images of the lungs, inflammation of the lung tissue at the onset of the disease is characterized by focal areas of ground-glass opacities seen bilaterally in regions contiguous with the pleura, mostly in the middle and lower fields [bib_ref] Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT, Bai [/bib_ref]. As the disease progresses, some patients show increased density in the sense of consolidated lung areas, which, measured by radiological methods, results in an increase in lung weight [bib_ref] Reclassifying Acute Respiratory Distress Syndrome, Maiolo [/bib_ref]. It cannot be excluded that these changes are caused by additional, nosocomial pneumonia. In terms of pathophysiology, respiratory failure is primarily characterized by mild to severe hypoxic respiratory distress. In the course of the disease, however, some patients have considerable, recurrent CO 2 increases. Patients intubated and ventilated in this phase of the disease have an increased alveolar-arterial oxygen gradient (also taking into account a high inspired oxygen fraction [FiO 2 ] and assuming a respiratory quotient of 0.85) and a remarkably large difference between arterial and end-tidal CO 2 . In line with the changes observed in imaging and based on data in Gattinoni et al., 2 chronological CT manifestations can be distinguished, the so-called type L and type H COVID-19 pneumonia (see below). The definition of acute respiratory distress syndrome (ARDS) in accordance with the Berlin definition can be met in both manifestations; however, it has been shown that COVID-19 pneumonia, especially in the early stage (type L), but also in the late stage (type H), differs significantly from the familiar changes accompanying ARDS, such as those observed in septic shock or bacterial pneumonia. The following describes a model developed based on CT scans that has not been clinically or histopathologically validated at this time. ## Covid-19 pneumonia, type l This early phase, which can be compensated by the patient with oxygen support, is described as COVID-19 pneumonia, type L, by Gattinoni et al., where L stands for: − low (low elastance, i.e., high compliance) − low ventilation/perfusion mismatch − low lung weight with low inflammatory fluid retention, the radiological correlate of ground-glass densities, and no or little consolidation. This type, therefore, also has a low potential for recruitment. While, according to the Berlin definition, ARDS is present, from a functional and radiological point of view, this phase differs from ARDS in terms of diffuse alveolar damage (DAD). In DAD, the alveolar functional unit would be impaired, along with a loss of alveolar stability and the development of alveolar and interstitial edema. There are so far no systematic studies of deceased COV-ID-19 patients during this phase in which pathologicalanatomical findings would have correlated with imaging findings. From a pathophysiology point of view, however, the so-called type L COVID-19 pneumonia must be distinguished from ARDS. We believe this to have significant implications for the indication for respiratory support in COVID-19-related acute respiratory failure (ARF). In the early phase of pulmonary infection, hypoxemia is the main symptom. The main difference to ARDS as we know it, in which a significant decrease in compliance due to pulmonary damage is seen, is that pulmonary elastance is preserved in COVID-19 pneumonia. Data presented by Dreher et al.also show a rather good average compliance in ventilated patients, underlining the difference from normal ARDS. In terms of function, this phenomenon of significant hypoxemia with maintained pulmonary compliance is most likely explained by a marked ventilation-perfusion distribution disorder. In the early phase, the viral infection leads to moderate local, subpleural inflammation with interstitial fluid accumulation (morphologically corresponding to the ground-glass pattern seen on CT). The greater part of the lungs is not affected, which explains the preserved normal pulmonary elastance [bib_ref] Early Clinical and CT Manifestations of Coronavirus Disease 2019 (COV-ID-19) Pneumonia, Han [/bib_ref]. In affected areas, the vessels are maximally dilated [bib_ref] Early Clinical and CT Manifestations of Coronavirus Disease 2019 (COV-ID-19) Pneumonia, Han [/bib_ref] [bib_ref] Relation between Chest CT Findings and Clinical Conditions of Coronavirus Disease (COVID-19)..., Zhao [/bib_ref] [bib_ref] Coronavirus Disease 2019 (CO-VID-19): Role of Chest CT in Diagnosis and Management, Li [/bib_ref] with a postulated loss of hypoxic vasoconstriction (the Euler-Liljestrand mechanism) and there is thus an increase in shunt volume. It is not clear whether this is the result of endothelial damage or active vascular smooth muscle relaxation regulated by inflammatory mediators. The physiological response to hypoxemia is an increase in ventilation. Due to the preserved lung compliance, however, patients do not perceive this as dyspnea. This explains that no/only minor dyspnea symptoms are felt, despite pronounced hypocapnia with a PaCO 2 < 22 mm Hg and simultaneous significant hypoxemia. In addition to recording the gas exchange and blood gas parameters, the leading clinical parameter is the measured respiratory rate and its changes over time, which can be interpreted as a surrogate parameter of respiratory effort. While it would be desirable and helpful to determine the respiratory effort as well as intrathoracic pressure changes by means of esophageal pressure measure-ment [bib_ref] COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Gattinoni [/bib_ref] , this approach cannot be applied in the clinical setting, especially since the technology and experience required to measure esophageal pressure are not generally available in intensive care units (ICUs). The increased respiratory rate and increased ventilation possibly lead to further lung damage due to the associated mechanical stress (shear forces and high intrapleural pressure amplitude). This phenomenon was first described experimentally by Barach et al. [bib_ref] Positive Pressure Respiration and Its Application to the Treatment of Acute Pulmonary..., Barach [/bib_ref] [bib_ref] Studies on positive pressure respiration; general aspects and types of pressure breathing;..., Barach [/bib_ref] and Mascheroni et al. [bib_ref] Acute respiratory failure following pharmacologically induced hyperventilation: an experimental animal study, Mascheroni [/bib_ref] and was labeled patient self-inflicted lung injury (P-SILI) [bib_ref] Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure, Brochard [/bib_ref]. The supply of oxygen during this phase can, to a certain extent, provide ventilatory relief. Due to an assumed shunt, however, the efficiency of oxygen delivery is potentially increasingly limited. From a pathophysiology point of view, mechanical support by means of noninvasive ventilation (NIV) or continuous positive airway pressure (CPAP) via a mask system or helmet could be helpful during this phase to prevent possible P-SILI (see position statement 3). However, this should be viewed with caution if the support, allowing for the lowest possible mechanical load on the lungs, does not also reduce the respiratory rate to < 30/min. In this situation, with vulnerable tissue in the lung parenchyma, a lack of synchronization between patient and ventilator or excessive pressure amplitudes will contribute to progressive damage. Whether such stress can be reduced by low-dose morphine administration needs to be clinically verified. However, the question remains, and in the event of a failure of oxygen therapy or NIV (or CPAP), on a case-by-case basis, it should be assessed whether controlled intubation and invasive ventilation should be performed to reduce the mechanical stress caused by the increased breathing effort. Finally, due to additional lung damage to be expected from invasive ventilation, extracorporeal membrane oxygenation (ECMO) should also be considered; it is certainly more lung-protective, but brings with it its own additional risks (see position statement 5). ## Covid-19 pneumonia, type h According to current studies, approximately 15-20% of hospitalized patients develop severe lung damage. Accordingly, extensive densifications, similar to those seen in other types of severe pneumonia and patients with extrapulmonary ARDS, are seen on the CT. Such imaging patterns can also be caused by nosocomial infections. The working group of Gattinoni et al.describes the progressive, critical state as COVID-19 pneumonia, type H: − high (high elastance, i.e., low compliance) as a result of increasing edema 6 DOI: 10.1159/000509104 − high right-left shunt − high lung weight and a high share of recruitable lung volume. This condition reflects the pathophysiology of severe pneumogenic ARDS with signs of DAD [bib_ref] Pathological findings of CO-VID-19 associated with acute respiratory distress syndrome, Xu [/bib_ref]. Very similar changes were seen in patients who died of SARS [bib_ref] The clinical pathology of severe acute respiratory syndrome (SARS): a report from..., Ding [/bib_ref] and MERS [bib_ref] Clinicopathologic, Immunohistochemical, and Ultrastructural Findings of a Fatal Case of Middle East..., Ng [/bib_ref]. The model of Gattinoni et al.has been shown to provide a good basis to better understand the pathophysiology of COVID-19 pneumonia. Nevertheless, many questions remain unanswered. From a clinical point of view, it is imperative to have comprehensive diagnostic procedures for both spontaneously breathing patients and particularly for postintubation patients. In addition, assessing the patient's cardiovascular condition is of crucial importance. The first data from China showed a high proportion of cardiac patients (20-30% of hospitalized patients) at an early stage of the pandemic. These numbers were confirmed in the European patient collectives [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] [bib_ref] Critical Care Utilization for the CO-VID-19 Outbreak in Lombardy, Italy: Early Experience..., Grasselli [/bib_ref]. The elevated troponin levels regularly described in studies and associated with poor prognosis must be considered an indicator of cardiac damage. Analysis of the deceased patients in the Wuhan cohort found cardiac damage in 34% and cardiac failure in 40%, either as the sole cause or in combination with respiratory failure [bib_ref] Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a..., Shi [/bib_ref] [bib_ref] Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19), Guo [/bib_ref] [bib_ref] Community-Acquired Pneumonia-China Network. Association between Cardiac Injury and Mortality in Hospitalized Patients..., Gao [/bib_ref]. In this context, the associated mortality risk of acute cardiac damage was higher than age, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and preexisting cardiac disease. Several factors must be discussed as causes and, given the administration of a variety of drugs, possible drug-related toxic effects cannot be excluded; this has frequently been described. Increased cardiac stress, particularly that starting early on with the development of hypoxemia, must be assumed. ## Significance of cardiovascular stress Hypoxemia with a decrease in oxygen levels requires an increase in cardiac output to maintain adequate oxygen transport since oxygenation supply is calculated by multiplying cardiac output and oxygen saturation. At the same time, the heart can be additionally stressed as a result of hyperventilation due to an increase in right ventricular (RV) afterload. The greater respiratory effort causes an increase in the negative intrathoracic pressure, resulting in an increase in transmural left ventricular (LV) pressure. From a pathophysiology point of view, the development of hypoxemia can induce RV overload, but there is currently no evidence that this is the case in the early phase of the disease. The extent to which a severe progression goes along with increasing RV overload, as seen in severe ARDS, still requires further investigation. As in community-acquired pneumonia (CAP), the systemic inflammatory response can foster cardiac complications such as arrhythmia, heart failure, and coronary events. However, the rate of cardiac manifestations is higher than with CAP (approx. 25%). Another cause of cardiac damage may be myocarditis. So far, however, only a few significant case studies are available. To what extent the regularly identified elevated D-dimers reflect increased coagulation activity has also not yet been established. Indeed, the disease seems to be associated with an increased risk of thrombotic events and coagulation system disorders. For example, pulmonary embolism was detected in 25% of a series of 81 seriously ill COVID-19 patients [bib_ref] Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia, Cui [/bib_ref]. It is unclear, however, whether these are thromboembolic events or in situ thromboses. Key Statement 1.1. Two types of COVID-19 pneumonia can be distinguished, with different pathologies (type L and type H) corresponding to early-and late-phase pneumonia. This differentiation can be taken into consideration in the respiratory support of ARF. Key Statement 1.2. Cardiac comorbidity, whether preexisting or COVID-19-associated, has a significant impact on both the progression and prognosis of the disease, and should therefore, always be taken into consideration during each treatment phase. Finding 1.1: The early phase is not typical of pneumogenic ARDS. Late phases can correspond to pneumogenic ARDS; nosocomial infections and cardiac and thromboembolic complications must be considered in a differential diagnosis. ## Position statement 2: chronological sequence and prognosis of arf in the course of the disease W.J. Randerath and T. Bauer compiled this position statement. # Introduction The pulmonary disease COVID-19, caused by the SARS CoV-2 virus, is a pneumonia characterized by lack of immunity in the pandemic situation. Comparable diseases are infections with recombinations of the influenza virus and a lacking or low immunity in the population (e.g., influenza A/H1N1) [bib_ref] Management of a New Influenza A/H1N1 Virus Pandemic within the Hospital. Statement..., Schaberg [/bib_ref]. According to the epidemiological definition, it is a type 3 pandemic with a high Respiration DOI: 10.1159/000509104 number of infected people but a comparatively low mortality. Worldwide, 6.1% of patients with confirmed infection die (https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200410-sitrep-81-covid-19.pdf?sfvrsn = ca96eb84_2, accessed on 4/11/2020). However, the mortality rate is most probably significantly underestimated at present, as the estimated number of unrecorded cases is high. This assumption is also supported by the large regional differences in overall mortality, ranging from 0.9% in Korea to 7.2% in Italy [bib_ref] Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in..., Onder [/bib_ref]. In the absence of causal treatment, COVID-19 damages the organism via 2 mechanisms, firstly, the direct cytotoxic effect of infiltration, intracellular replication, expulsion, and death of the host cell; and secondly, via the body's failure to develop sufficient immunity to control the infection. In a type 3 pandemic, it is assumed that the direct cytotoxic effect affects mortality only in exceptional cases since mortality in the early phase of the infection would have to be higher, and age and comorbidities would play a subordinate role. Zhou et al. [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] retrospectively studied 191 patients who had been hospitalized with confirmed COVID-19 disease; 54 of them died (28%). The most frequent comorbidities were arterial hypertension (30%), diabetes mellitus (19%), and coronary heart disease (8%). Multivariate analyses showed significantly increased mortality with increasing age (odds ratio [OR] 1.10, 95% CI 1.03-1.17, per year of life; p = 0 0043), a higher Sequential Organ Failure Assessment (SOFA) score (5.65, 2.61-12.23; p < 0.0001) and D-dimers of > 1 μg/mL (18.42, 2.64-128.55; p = 0.0033). The virus was detectable up to the time of death (up to 37 days) [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. In the chronological sequence of the disease, dyspnea occurred at a median of 13 days (range 9-16.5 days) and was not different in survivors and nonsurvivors. The 3-stage classification system of the disease, as proposed by Siddiqi and Mehra [bib_ref] COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal, Siddiqi [/bib_ref] , therefore seems to be clinically meaningful . ## Phase i: early infection SARS-CoV-2 is introduced via ACE2, which is present in varying densities in the mucous membranes of the throat, lungs, and small intestine. Clinical symptoms include impaired taste, sore throat, cough and, more rarely, diarrhea. Swabs are taken from the nasopharynx for further testing by PCR to detect the virus. However, recent data show that nasal swabs can be negative in 27% and throat swabs in 68% of cases, even though a patient has COVID-19 [bib_ref] Detection of SARS-CoV-2 in Different Types of Clinical Specimens, Wang [/bib_ref]. The Robert Koch Institute (RKI) therefore recommends that, if COVID-19 continues to be suspected and samples from the upper respiratory tract pro-vide negative results, samples from the primary replication site of the virus, i.e., the deep respiratory tract, should also be analyzed. From a clinical point of view, the beginning of the disease is best determined by the onset of fever or flu-like symptoms [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref]. All 3 clinical developments (mild, severe, and critical) can develop from phase I, depending on immunity and comorbidity. ## Phase ii: pulmonary involvement Evidence of the virus in the throat is high on the first days of the disease, while pulmonary involvement only begins with viral multiplication in the lungs, marking the onset of viral pneumonia [bib_ref] Viral load of SARS-CoV-2 in clinical samples, Pan [/bib_ref] [bib_ref] SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients, Zou [/bib_ref]. The clinical symptoms now also include shortness of breath and cough and increased density in the lungs seen on chest X-ray or chest CT in the form of ground-glass opacities. The differentiated severity classification in this publication of phase II is phase IIa without hypoxemia (PaO 2 /FiO 2 ≥300 mm Hg, corresponding to an arterial or capillary PaO 2 of ≥63 mm Hg on room air) and phase IIb with hypoxemia (PaO 2 /FiO 2 < 300 mm Hg, corresponding to an arterial or capillary PaO 2 of < 63 mm Hg on room air) seems to be plausible with regard to the initial decision concerning the respiratory support and place of care for COVID-19 patients [bib_ref] COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal, Siddiqi [/bib_ref]. The initial assessment of hypoxemia under supplemental oxygen using conversion tables is unreliable and has not been validated in nonventilated patients. Concerning the practical implementation of respiratory support in ARF, see recommendation 3 of this manuscript for phase IIa and recommendations 4 and 5 for phase IIb and subsequent stages. COVID-19 patients in phase II are mainly treated in hospitals, and medication can currently not influence the progression of the disease with sufficient certainty. Hence, the adequate treatment of comorbidities and the monitoring of organ function are of crucial importance. provides an example of clinical progression. The following parameters should be measured at regular intervals in phase II to be able to detect the indicators of critical processes as early as possible (therapy monitoring). ## Therapy monitoring The SOFA score is a significant predictor of mortality in multivariable analysis (older age, higher SOFA score, and D-dimer > 1 μg/mL on admission) [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref]. In univariate comparison, the SOFA score ( FiO 2 ), the nervous system (the Glasgow Coma Scale, GCS), the cardiovascular system (catecholamine dosage), liver function (bilirubin), coagulation (thrombocytes), and kidney function (creatinine). COVID-19 outside the ICU is usually not associated with septic conditions, which means that monitoring of respiratory rate, clouding of consciousness, blood pressure, and SaO 2 should suffice (qSOFA) [bib_ref] Role of qSOFA in predicting mortality of pneumonia: a systematic review and..., Jiang [/bib_ref]. A differential blood count is recommended at admission and throughout treatment because of the presumed predictive power of lymphocyte concentration. In the analysis by Zhou et al. [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] , a lymphocyte count of < 800/ µL was more prevalent in nonsurvivors (76 vs. 26%, p < 0.0001). Persistently low lymphocyte concentrations are described more frequently in nonsurvivors in the publication by Wang et al. [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref]. Myocardial damage ("cardiac injury") defined as elevated troponin levels (high-sensitivity troponin I [hs-TnI] > 28 ng/L, corresponding to the upper limit of the 99% percentile of the analysis system used) was observed less frequently in survivors than in nonsurvivors (15 vs. 28%) [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref]. In a multivariate analysis of 416 patients, myocardial damage, and the development of ARDS were independent risk factors for nonsurvival (Kaplan-Meier, log-rank test) [bib_ref] Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in..., Shi [/bib_ref] [bib_ref] Potential Effects of Coronaviruses on the Cardiovascular System: A Review, Madjid [/bib_ref]. ## D-dimers Coagulation disorders are an important factor in assessing the severity of the disease in patients with severe infections in the context of sepsis [bib_ref] Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions..., Seymour [/bib_ref]. In 3 retrospective studies, elevated D-dimers, especially if they remained elevated during the course of the disease, were associated with a higher probability of death [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref] [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Abnormal coagulation parameters are associated with poor prognosis in patients with novel..., Tang [/bib_ref]. Yin et al. [bib_ref] Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2, Yin [/bib_ref] compared the partial thromboplastin time (PTT), platelet count, and D-dimers in COVID-19 patients with those in patients with severe pneumonia from other causes. They found no difference in D-dimer levels (CO-VID-19: 1.94 µg/mL [range 0.90-9.44] vs. non-COV-ID-19 2.25 µg/mL [range 1.40-5.81]). However, the absolute D-dimer values in both groups were, in all cases, above the upper limit of 0.5 µg/mL. Although the platelet count was slightly elevated in COVID-19 patients, it was still consistently within the reference range. Whether the observed coagulation disorders in COVID-19 patients are specific to SARS-CoV-2 infection or should be interpreted in the context of (incipient) sepsis cannot be answered at present. The following additional laboratory parameters may also indicate severe disease progression: elevated liver enzymes, lactate dehydrogenase (LDH), and creatinine. El-evated inflammatory parameters such as CRP, IL-6, and ferritin are also indicators of an unfavorable prognosis [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref]. ## Phase iii: hyperinflammation An insufficient humoral immune response, and thus insufficient inactivation and elimination of SARS-CoV-2 leads to the hyperinflammatory phase III, with an increased incidence of organ failure and, specifically, the possibility of additional lung damage in the form of ARDS. The development of ARDS is largely independent of the damaging pathogen and can occur in pneumonia as well as in extrapulmonary single-or multiorgan damage. From a pathophysiology point of view, hyperinflammation in COVID-19 due to the lack of an immune response is crucial [bib_ref] ARDS -An Update -Part 1: Epidemiology, Pathophysiology and Diagnosis, Dembinski [/bib_ref]. Based on the current Berlin definition of ARDS, the onset of the disorder can be within 1 week of the occurrence of risk factors or new or increasing respiratory symptoms and is therefore relevant for the characterization of COVID-19 pneumonia [bib_ref] ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition, Ranieri [/bib_ref]. Under nosological aspects, however, the ARDS definition is not fully transferable to COVID-19 (see position statement 1). It also includes 3 degrees of severity which have not been differentiated in all publications: In the context of COVID-19 pneumonia, the Berlin definition was not consistently applied in the publications described below, which means that a comparison of the clinical outcomes is subject to reservation. Nevertheless, we would like to present these results for orientation purposes. The temporal analysis of the data of COVID-19 patients in intensive care shows that the median onset of dyspnea in this group of patients was 6.5 days after the onset of the first symptoms. However, moderate to severe ARDS then developed rapidly, within a median of 2.5 days after the onset of dyspnea [bib_ref] Clinical course and risk factors for mortality of adult inpatients with COVID-19..., Zhou [/bib_ref] [bib_ref] Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington..., Arentz [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. Wang et al. [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref] described the characteristics and development of 138 hospitalized COVID-19 patients. A total of 26% had to be transferred to ICUs due to complications, 61% of which were due to ARDS. The median PaO 2 /FiO 2 was 136 mm Hg (range 103-234 mm Hg), which means that most patients had moderate to severe ARDS. Other reasons were arrhythmia (44%) and shock (31%). The average time from admission to moderate to severe ARDS in this col-Respiration DOI: 10.1159/000509104 lective was 8 days. Patients requiring intensive care received the following respiratory support for ARF: nasal high-flow therapy (NHF; 11%), NIV (42%), and invasive ventilation (47%) [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref]. The study by Wu et al. [bib_ref] Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients..., Wu [/bib_ref] , which does not contain a definition of ARDS or its severity, must be viewed critically in this context. The composition of respiratory support therapies in the ARDS cohort (n = 84) in this study (NHF 20%, NIV 73%, and invasive ventilation ± ECMO 7%) suggests that these were predominantly mild cases. A different group was studied by Yang et al. [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref] , consisting of 52 critically ill adults in a cohort of 710 patients with SARS-CoV-2 pneumonia. After 28 days, 32 patients had died, on average 7 days after being transferred to ICU. In critically ill patients, pronounced hypoxemic respiratory failure and ARDS were the predominant features, while hypercapnic failure occurred only in rare cases. Mechanical ventilation (MV) was required in 42-100% [bib_ref] Clinical features of patients infected with 2019 novel coronavirus in Wuhan, Huang [/bib_ref] [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. The risk factors for developing ARDS described to date include age, concomitant diseases, a high fever > 39 ° C, a history of smoking, and laboratory parameters (marked lymphopenia and elevated procalcitonin levels) [bib_ref] Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington..., Arentz [/bib_ref] [bib_ref] CDC COVID-19 Response Team. Severe Outcomes Among Patients with Coronavirus Disease 2019..., Bialek [/bib_ref]. According to initial reports, the intensive care period is described as extended and weaning as delayed. Reported recovery times are up to 6 weeks. Typical complications in connection with COVID-19-associated ARDS include acute renal failure (29%), elevated liver parameters (29%), and cardiac damage (23-33%) such as cardiomyopathy, pericarditis, cardiac arrhythmia, and sudden cardiac death. However, these usually only occur when the pulmonary symptoms have already subsided [bib_ref] Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington..., Arentz [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. Multiorgan failure, septic shock (13%), and secondary pneumonia are described less frequently (12%). Key Statement 2.1. The assessment of the extent of ARF in COVID-19 pneumonia should be based on arterial or capillary blood gas analysis on room air. It must include the calculation of oxygen supply (measured from the parameters of oxygen saturation, hemoglobin, corrected values of Hüfner's factor and cardiac output). Key Statement 2.2. The clinical assessment of the progression of COVID-19 pneumonia patients should include clinical monitoring (e.g., qSOFA) as well as laboratory parameter-based monitoring (at least D-dimers, CRP, PCT, platelets, LDH, troponin, ferritin, and NT-proBNP) to detect multiple organ failure, in conjunction with another parameter of respiratory failure (e.g., SaO 2 ). Finding 2.1. COVID-19 progresses in 3 sequential disease phases (early infection, pulmonary disease, and hyperinflammation). ## Principles of aerosol physics and transmission of infectious particles Sars-CoV-2 has a diameter of between 60 and 140 nm [bib_ref] A Novel Coronavirus from Patients with Pneumonia in China, Zhu [/bib_ref]. The main transmission route of the virus is aerogenic spread. Viruses can be detected on surfaces by PCR but cannot be cultured there. The viruses are transported through aerosols produced in the respiratory tract of infected individuals [bib_ref] The size distribution of droplets in the exhaled breath of healthy human..., Papineni [/bib_ref]. Another important aspect is that the infectivity of viruses already decreases in the aerosol. When the quantity of viral RNA and the quantity of vital, and thus potentially infectious, virus in influenza A were examined simultaneously in an experiment, the number of vital and thus infectious viruses was reduced by a factor of 10 2 after only 90 min -despite there being same quantity of viral RNA [bib_ref] Influenza virus survival in aerosols and estimates of viable virus loss resulting..., Brown [/bib_ref]. ## Physical properties of aerosols The following aspects are important for the spread of aerosols from human lungs: aerosol formation, release, and behavior in a room as well as aerosol deposition after reinhalation by another person. ## Formation and release The release of aerosols requires energy, whereby the energy of normal resting breathing is already sufficient [bib_ref] The size distribution of droplets in the exhaled breath of healthy human..., Papineni [/bib_ref] [bib_ref] EMIT Consortium. Infectious virus in exhaled breath of symptomatic seasonal influenza cases..., Yan [/bib_ref] [bib_ref] Respiratory virus shedding in exhaled breath and efficacy of face masks, Leung [/bib_ref] [bib_ref] Influenza virus in human exhaled breath: an observational study, Fabian [/bib_ref]. Coughing or sneezing increases the exit speed by a factor of approximately 4 vs. resting breathing [bib_ref] Airflow dynamics of human jets: sneezing and breathing -potential sources of infectious..., Tang [/bib_ref]. The maximum range of the aerosol cloud in front of a person's face does not differ significantly and is 0.6 m for normal breathing, 0.6 m for sneezing, and 0.8 m for coughing [bib_ref] Airflow dynamics of human jets: sneezing and breathing -potential sources of infectious..., Tang [/bib_ref]. However, looking at particle quantity or mass is not sufficient to evaluate the infectiousness. The virus concentration in the particles also matters. It can differ by a factor of 32 in patients with acute viral infection [bib_ref] Exposure to influenza virus aerosols during routine patient care, Bischoff [/bib_ref]. ## Behavior of aerosols in a room Aerosols are solid or liquid particles suspended in gases (in this case, air) with a diameter of approximately 0.001-100 µm. The aerodynamic diameter (d ae ) is an important parameter for the essential dispersion mechanisms of sedimentation and impaction. It is calculated as the ratio of particle size (d o ) and particle density (p) (d ae = d o /p). The mass median aerodynamic diameter DOI: 10.1159/000509104 (MMAD) is generally used to classify aerosols. However, the ability of an aerosol particle to transport viruses depends on the particle mass. It is important to note that the mass depends upon the third power of the diameter. A particle with a diameter of 10 µm has the same mass as 1,000 particles of 1 µm. Exhaled aerosols change their particle size depending on the relative humidity of the environment. The particles shrink at low humidity but can increase in size at high humidity and thus change their physical properties [bib_ref] Study of SARS transmission via liquid droplets in air, Wang [/bib_ref]. In an unconfined space, the force of gravity causes particles to sediment. According to Stoke's law, the frictional force of the air prevents sedimentation below a particle size of 0.5-1 µm. Aerosols of this size thus remain at almost a constant level in a room and can be inhaled. As larger-mass aerosols sink faster, the risk of encountering these will be greatest near the aerosol source (i.e., the patient) [fig_ref] Table 1: The sedimentation/diffusion ratio as a function of particle diameter[75] Particle diameter, µm... [/fig_ref]. In general, the question arises as to whether smaller aerosol particles that do not immediately sink are also present in the air of patient rooms in concentrations able to cause infections. Since these data are not available for coronaviruses, the following statements are mainly based on experiments and measurements with influenza viruses. Blachere et al. [bib_ref] Measurement of airborne influenza virus in a hospital emergency department, Blachere [/bib_ref] were able to measure room air samples and found that 46% of the virus particles were seen in aerosol particles > 4 µm. However, 49% of viruses were found in particles with a size of 1-4 µm and 4% in particles < 1 µm. Fabian et al. [bib_ref] Influenza virus in human exhaled breath: an observational study, Fabian [/bib_ref] even found 99% of viral DNA in particles < 5 µm. Both studies therefore found that 99% of viruses were in the respiratory aerosol fraction and were able to remain airborne for several hours. In samples taken from room air in health care facilities as well as day-care centers and aircraft cabins during the influenza season, 5.8 × 10 3 to 3.7 × 10 4 copies of the virus were found per cubic meter of room air [bib_ref] Concentrations and size distributions of airborne influenza A viruses measured indoors at..., Yang [/bib_ref] , which is 2-to 20-times the number of viral particles needed to establish an infection [bib_ref] Human influenza resulting from aerosol inhalation, Alford [/bib_ref]. This would mean that, assuming a ventilation of 10 L/min, this threshold would already be reached after 5 min in a worst-case scenario, and after 50 min in a best-case scenario. Also to be included in the consideration is the vitality (survival time) of the virus in aerosols. New experimental data on coronavirus have shown that Sars-CoV-2 in aerosols has a half-life of 1.1 h [bib_ref] Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1, Van Doremalen [/bib_ref]. Whether a critical steady-state virus concentration in a patient room is possible also depends on the patient's viral load (low-or super-spreader), the respiratory minute volume, and the size and ventilation of the room. In general, aerosol transmission of viruses seems to be quite possible. Calculation models assume, for example, that approximately 50% of all influenza cases are transmitted in this way [bib_ref] Aerosol transmission is an important mode of influenza A virus spread, Cowling [/bib_ref]. The square of the particle diameter, the particle density, and the viscosity of the gas (in this case, room air) also influence sedimentation velocity. In addition, particles < 1 µm are subject to Brownian motion and diffuse. The particles thus remain in the air for different lengths of time before they deposit. Although an increased risk of infection has not yet been proven, systematic room ventilation should be ensured, and the wearing of masks in accordance with current RKI recommendations is advised. Some authors suggest that the arbitrary classification in aerosols and nonaerosols based on size facilitates practical handling [bib_ref] Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and..., Simonds [/bib_ref] , but this does not adequately reflect aerosol physics as such. ## Aerosol deposition following inhalation Aerosol particles up to a size of approx. 3-4 µm follow their carrier gas. In addition, mass inertia causes particles to try and move straight ahead when the direction of airflow changes. When a surface is hit, this is called impaction. The glottis region in the upper respiratory tract is where the inspiratory flow undergoes the greatest change of direction. Smaller particles, therefore, have a higher probability of being inhaled into the lower respiratory tract and reaching the alveolar epithelial cells, although particles with an MMAD of approximately 10 µm still have a 50% probability of being deposited at least within the bronchi [bib_ref] Aerosol Distribution Pattern of 16 Commonly Used Inhalation Instruments, Köhler [/bib_ref]. ## Aerosols in respiratory support therapy Additional external pressure or flow is applied to the respiratory system by NHF, CPAP, NIV, or invasive ventilation. A study on invasive ventilation was able to show that the number of exhaled particles increases along with a higher expiratory (E)PAP (in this case > 5 cm H 2 O) [bib_ref] Particle size concentration distribution and influences on exhaled breath particles in mechanically..., Wan [/bib_ref]. Since respirable aerosols are produced at alveolar level, it appears that increased alveolar recruitment can thus result in increased aerosol formation. [bib_ref] Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and..., Simonds [/bib_ref] were able to demonstrate that, in patients with cold symptoms who were ventilated with vented NIV, the number of particles > 3 µm increased significantly at 1 m from the patient's head. At close range (20 cm from the patient's head), on the other hand, only the number of particles > 10 µm increased, although this refers to patients with symptoms of a common cold or increased secretion. No increased spread of particles of any size was found in healthy subjects. In contrast, when a nonvented mask with a filter was used, the number of particles emitted decreased at 20 cm and at 1 m in all subjects, although not significantly. A simulation model using smoke particles as a proxy for droplets showed that the airflow from the vented system covered a maximum distance of 0.6 [bib_ref] Trends in drug-resistant Mycobacterium tuberculosis, Munsiff [/bib_ref] and 0.85 m, respectively [bib_ref] Exhaled air dispersion distances during noninvasive ventilation via different Respironics face masks, Hui [/bib_ref]. For mask leakages, the reach of leakage flow was < 10 cm [bib_ref] Noninvasive positivepressure ventilation: an experimental model to assess air and particle dispersion, Hui [/bib_ref]. We found no data on aerosol formation in NIV using dual-hose systems during our literature search. Since these systems work with nonvented masks, and infectious aerosols can be removed from expired air by installing a virus filter, the risk of generating potentially infectious aerosols is assumed to be as low as when using single-hose systems with nonvented masks. In a retrospective analysis of 9 SARS patients, Fowler et al. [bib_ref] Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation, Fowler [/bib_ref] calculated the relative risk (RR) of infection transmission to be 2.33 (95% CI 0.25-21.76; p = 0.5) for healthcare workers attending to patients on NIV. However, the risk in these cases was not significantly increased, and the study did not provide any information about the mask systems used. A retrospective analysis of virus transmissions to hospital staff during the SARS epidemic in 2003 showed an increased risk of infection to the staff involved in the application of NIV [bib_ref] Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation..., Raboud [/bib_ref]. However, that study also showed that simply recording a patient's ECG was associated with an even greater risk of infection, regardless of ventilation status. ## Invasive ventilation Invasive ventilation first requires intubation. During the SARS epidemic in Canada, Fowler et al. [bib_ref] Transmission of severe acute respiratory syndrome during intubation and mechanical ventilation, Fowler [/bib_ref] described a RR of infection of 13.3 for the intubation procedure. studied the viral RNA content of aerosols during various procedures in the context of the H1N1 epidemic in England. They found a significantly higher exposure to viral RNA from particles sized < 7.3 µm while patients were being intubated. The reach of aerosol contamination in a simulation model was up to 2 m around the patient's head [bib_ref] Barrier Enclosure during Endotracheal Intubation, Canelli [/bib_ref]. Wearing appropriate protective equipment is therefore absolutely essential. In addition, this last paper proposed placing a box over the patient's head to prevent aerosol contamination, although this has the downside that hand mobility during manipulation is restricted. The OR of aerosol production during intubation is 2.3. Endotracheal aspiration of a ventilated patient in the same study yielded an OR of 4.11 with respect to the production of virus-laden aerosols. No data on viral transmission in invasively ventilated patients outside of procedures have been published to date. If, for example, a defective or insufficiently blocked cuff can lead to aerosol formation is not known. Furthermore, not all ventilators have a virus filter in their expiratory limb. No data on this are available in published literature. ## Nasal high-flow therapy Transnasal flows of up to 80 L/min are generated during NHF. The air clears dead space and generates a positive airway pressure. Bräunlich et al.were able to demonstrate that the clearance and pressure effect can also be detected in the small airways. The increased transnasal inflow of air leads to an equally increased outflow of air from the nose and mouth. Exhaled air dispersion, marked with smoke particles for visualization, increased from 6.5 to 17.2 cm with an increase in nasal flow from 10 to 60 L/min [bib_ref] Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different..., Hui [/bib_ref]. In a study by Kotoda et al. [bib_ref] Assessment of the potential for pathogen dispersal during high-flow nasal therapy, Kotoda [/bib_ref] , no infectious particles were dispersed via NHF from the yeast particle-laden airways of a medical training manikin. Leung et al. [bib_ref] Comparison of highflow nasal cannula versus oxygen face mask for environmental bacterial..., Leung [/bib_ref] investigated bacterial excretion at 0.4 and 1.5 m from the patient's head in patients with bacterial pneumonia. They compared the use of NHF versus a simple oxygen mask in a room with 6-12 air exchanges per hour. They found no quantitative difference in terms of pathogen dispersal between the 2 types of treatment, although it can be assumed that an oxygen mask significantly reduces the expiratory flow. A recent study from China recommends the wearing of surgical masks for patients being treated with NHF, but does not provide any data on the achieved degree of infection protection or the possible limitations to the effectiveness of NHF. ## Nebulizer systems Simonds et al. [bib_ref] Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and..., Simonds [/bib_ref] described a sharp increase in aerosol volume near patients after inhalation with a jet nebulizer. However, their otherwise well-conducted study contains a systematic flaw in this respect, as aerosols from the nebulizer that did not even reach the patient were included in the measurement. Two retrospective analyses of the procedural risk of nebulizer applications were conducted during the 2003 SARS epidemic in Canada [bib_ref] Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation..., Raboud [/bib_ref]. Neither study could confirm an increased risk of infection for the medical staff performing the nebulizer 12 DOI: 10.1159/000509104 treatment. However, it should be emphasized that simple isotonic saline inhalation reduces the release of bioaerosols from the lungs by an average of 72% for up to 6 h [bib_ref] Inhaling to mitigate exhaled bioaerosols, Edwards [/bib_ref]. The reason for this seems to be the modified surface tension of the liquid film coating the respiratory epithelia. ## Oxygen therapy In the study conducted by Simonds et al. [bib_ref] Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and..., Simonds [/bib_ref] , oxygen administration via a Venturi mask did not result in increased aerosol formation near the patient. If the exhaled air of an artificially breathing manikin is marked with smoke particles for visualization, the exhaled air can be visualized up to 0.2, 0.22, 0.3, and 0.4 m from the manikin's face when oxygen is administered at 4, 6, 8, and 10 L/min through a Venturi mask [bib_ref] Exhaled air dispersion distances during noninvasive ventilation via different Respironics face masks, Hui [/bib_ref]. In the same experiment, the application of 1 or 5 L of O 2 via oxygen therapy glasses produced an expiratory "cloud" of 0.66 m or 1 m. Manipulation in connection with oxygen therapy was shown to be a risk factor for viral transmission to medical staff in one study, but in another it was not [bib_ref] Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation..., Raboud [/bib_ref]. ## Summary Aerosol physics shows that transmission of infectious, virus-containing particles via aerosols is a theoretical possibility. In particular, medical staff are concerned about an increase in activity at the patient's bedside, especially in connection with NIV, and thus possible exposure to potentially infectious aerosols. The evidence regarding the use of oxygen therapy, NHF, CPAP, and NIV is limited in terms of comparability due to the different approaches taken to demonstrate aerosols, but also due to different room conditions (with/ without a regular air exchange). For the assessment of the treatment situation, it appears essential to use the aerosol production of spontaneously breathing and also of coughing patients for comparison purposes. Here, a minor increase in aerosol range is observed as a result of the technical manipulations. However, it is less than with invasive ventilation, which is sometimes recommended as "protective intubation" to protect medical staff against infectious aerosols. Based on a comparison with data on intubation and endotracheal aspiration, the authors found that the latter goes along with a significantly higher risk of aerosol exposure. Key Statement 3.1. Open systems or vented systems (so-called vented masks) can increase the release of respirable particles. Mask leakage plays a rather subordinate role in aerosol formation. Closed systems (so-called nonvented masks) with an upstream virus deactivation filter in the expiratory system are safe and do not lead to in-creased aerosol formation. By analogy, dual-hose systems with virus deactivation filters in the expiratory tube are also safe and do not lead to increased aerosol formation. Key Statement 3.2. Closed suction systems should be used for suctioning via tube or tracheal cannula. During invasive ventilation, it is important to ensure that exhaled air is filtered accordingly. In the absence of appropriate filters in the ventilator, virus deactivation filters should be used in the expiratory limb. Key Statement 3.3. Based on current knowledge, inhalation therapy, NHF, CPAP, or NIV can be carried out by staff wearing PPE (goggles, an FFP2 or FFP3 mask, and a gown) without an increased risk of infection. Finding 3.1. Endotracheal intubation carries a high risk of infection. Procedures in which the invasive ventilation system needs to be opened are associated with an increased risk of infection. Finding 3.2. NHF extends the exhaled aerosol reach by several centimeters. To date, a relevant increased release of infectious aerosols compared to spontaneously breathing patients could not be demonstrated in an in vitro or an in vivo setting. Finding 3.3. Although nebulizers with nozzles increase the amount of aerosol in room air, they do not increase the risk of infection for medical staff. The inhalation of isotonic saline solution significantly reduces aerosol release from the lungs. Finding 3.4. Oxygen administration via mask or nasal tube does not lead to increased aerosol formation. Different oxygen systems (nasal tubes, oxygen masks, and Venturi masks) can deflect the air during exhalation in various ways. Only nasal tubes with high oxygen flows have a longer range than those used under spontaneous breathing. # Introduction In the context of the COVID-19 pandemic, approximately 5-6% of patients had severe hypoxemia requiring intensive care treatment, many requiring invasive ventilation or NIV [bib_ref] Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak..., Wu [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. Hypoxemic respiratory failure is caused either by severe pneumonia or a subsequently developing ARDS-like condition. Severe pneumonia is defined by the presence of fever or a suspected respiratory infection, and a respiratory rate of > 30/min, severe short-Respiration DOI: 10.1159/000509104 ness of breath, or SpO 2 < 90% on room air. The diagnosis of ARDS is based on the guidelines or recommendations available to date, with appropriate classification into mild, moderate, and severe ARDS based on PaO 2 /FiO 2 ratios [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref] [bib_ref] ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition, Ranieri [/bib_ref] [bib_ref] Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure, Rochwerg [/bib_ref] [bib_ref] Hospital Incidence and Outcomes of the Acute Respiratory Distress Syndrome Using the..., Riviello [/bib_ref]. The following section explains the options and limitations of NIV in ARF. Any therapy escalation requires the definition of a therapy goal based on the patient's will, which should be discussed at the initial doctor-patient contact and then verified daily [bib_ref] Management of adult community-acquired pneumonia and prevention -update, Ewig [/bib_ref]. ## Pathophysiology Severe respiratory failure in ARDS is believed to be caused by an intrapulmonary ventilation/perfusion mismatch or shunt. Recent data on ARDS in COV-ID-19 shows that the underlying pathophysiological changes can be manifold. For example, Gattinoni et al. [bib_ref] COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Gattinoni [/bib_ref] , in their studies on invasively ventilated patients who met the Berlin definition of ARDS, found that, in contrast to typical ARDS, so-called "atypical ARDS" may be seen. This was characterized by a loss of lung perfusion regulation and hypoxic pulmonary vasoconstriction with maintained mechanical function of the lungs. Furthermore, it was found in some patients, that improved oxygenation under PEEP was not always the result of improved lung tissue recruitability [bib_ref] COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Gattinoni [/bib_ref] [bib_ref] Lung Recruitability in COVID-19-associated Acute Respiratory Distress Syndrome: A Single-Center Observational Study, Pan [/bib_ref]. This resulted in different settings of the ventilation pressures, especially PEEP, and the effectiveness of the prone position [bib_ref] COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Gattinoni [/bib_ref] [bib_ref] Lung Recruitability in COVID-19-associated Acute Respiratory Distress Syndrome: A Single-Center Observational Study, Pan [/bib_ref]. However, since the statements made by the authors refer solely to invasively ventilated patients who had already been on NIV and invasive ventilation for different lengths of time, their transferability to NIV therapy for ARF in COVID-19 is currently limited. ## Indication algorithm The initial therapy of hypoxemia and respiratory failure focuses on oxygen administration via nasal tube, Venturi mask, and NHF. Once the gas exchange deteriorates progressively and oxygen demand increases, an indication for CPAP or ventilation should be reviewed. In addition to the indication, both the appropriate timing and type of ventilation, be it invasive or noninvasive, needs to be determined. In the case of a "do not intubate" (DNI) order, it should be established whether at least NIV, as described in the current [German] S3 guideline of NIV for ARF, is desired [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref]. If an indication for ventilation applies, the focus in traditional ARDS is on increasing the transpulmonary pressure and improving or normalizing the residual capacity to improve the gas exchange disorder. A high and constantly applied PEEP can prevent alveolar collapse and be used to achieve recruitment of collapsed alveolar regions. Due to mask leakage or intolerance, which makes longterm maintenance of PEEP possible only to a limited extent, and, in consequence, causes rapidly recurring derecruitment and consecutive gas exchange deterioration, the usefulness of NIV is limited as the severity of ARDS increases [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref] [bib_ref] Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure, Rochwerg [/bib_ref]. Using NIV in moderate and severe ARDS leads to therapy failure in > 50% of cases. This is associated with mortality rates of almost 50% in severe ARDS [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref] [bib_ref] Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure, Rochwerg [/bib_ref]. Besides the severity of the current clinical condition (a Simplified Acute Physiology Score [SAPS] > 37), the extent of the oxygenation disorder is a predictor of NIV failure; a PaO 2 /FiO 2 ratio < 150 mm Hg is described as the critical limit for increased mortality [bib_ref] LUNG SAFE Investigators; ESICM Trials Group. Noninvasive Ventilation of Patients with Acute..., Bellani [/bib_ref]. High tidal volumes (> 9.2 or 9.5 mL/kg) under NIV are associated with increased mortality [bib_ref] LUNG SAFE Investigators; ESICM Trials Group. Noninvasive Ventilation of Patients with Acute..., Bellani [/bib_ref] [bib_ref] REVA network. Predictors of Intubation in Patients with Acute Hypoxemic Respiratory Failure..., Frat [/bib_ref] [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref] [bib_ref] Failure of Noninvasive Ventilation for De Novo Acute Hypoxemic Respiratory Failure: Role..., Carteaux [/bib_ref]. This leads to the conclusion that NIV only has a positive impact on the outcome if it can be used to provide lung-protective ventilation with a correspondingly high PEEP in normal ARDS [bib_ref] REVA network. Predictors of Intubation in Patients with Acute Hypoxemic Respiratory Failure..., Frat [/bib_ref]. Spontaneously breathing patients with hypoxemic ARF exhibit high respiratory drive with high breathing volumes, and thus a potentially damaging transpulmonary pressure variation [bib_ref] COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Gattinoni [/bib_ref] [bib_ref] Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure, Brochard [/bib_ref]. Since the patient's respiratory drive is maintained under NIV, additional and (in particular) excessively high inspiratory pressure support in the context of NIV can require an increased and thus potentially risky high respiratory volume, worsening the damage to the lungs. In such situations, NIV no longer protects the lungs, as the tidal volumes considered to be lung protective cannot be applied. This connection is also underlined by Gattinoni et al. [bib_ref] COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Gattinoni [/bib_ref] in their study of atypical ARDS in COVID-19. With reference to the study of Brochard et al. [bib_ref] Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure, Brochard [/bib_ref] , they recommend intubation to avoid excessive intrathoracic negative pressures and P-SILI in patients with clinical signs of excessive inspiratory effort under CPAP or NIV. A therapy attempt with noninvasive procedures in the form of NIV or, primarily, CPAP with escalation to NIV, can be made in cases of hypoxemic respiratory insufficiency and insufficient response to pure oxygen administration or in mild ARDS, especially in cases of predominantly hypercapnic respiratory insufficiency (e.g., cardiac comorbidity, COPD, obesity hypoventilation, and neuromuscular disease) [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref] [bib_ref] Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure, Rochwerg [/bib_ref]. The current recommendations in Italy, for example, primarily call for high CPAP pressures, escalating the NIV only later. On the other hand, only 11% of the ICU patients in Lombardy were treated with NIV. Patients were intubated at a median PaO 2 /FiO 2 of 160 mm Hg, with subsequent high PEEP requirements. 14 DOI: 10.1159/000509104 A similar recommendation of CPAP/NIV is provided in the NHS recommendations in the UK, but with the important advice that the intubation threshold should be low, and that, in the case of clinical deterioration (an increasing O 2 requirement, steadily or rapidly falling SaO 2 , and/or an increase in respiratory rate and respiratory effort; see position statement 5), immediate intubation and MV should be considered. In their current review of the treatment of community-acquired severe respiratory viral infections, Arabi et al. [bib_ref] Critical care management of adults with community-acquired severe respiratory viral infection, Arabi [/bib_ref] conclude in analogy to the previous evidence that NIV can be used in selected patients during early stages and in milder types of acute hypoxemic respiratory failure. At the same time, they point out, however, that in patients with no early improvement, NIV merely delays intubation rather than preventing it. A similar conclusion can be drawn from the currently available publications on ventilation in COVID-19. The development from the onset of the first respiratory symptoms to ARDS and subsequent intubation, especially in COVID-19 patients, can proceed rapidly within a few days, making it necessary to make timely ventilation decisions [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref] [bib_ref] Rapid Progression to Acute Respiratory Distress Syndrome: Review of Current Understanding of..., Goh [/bib_ref]. The presence of bilateral pneumonia and a progressive worsening of the chest CT are unfavorable prognostic indicators of such a development [bib_ref] Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a..., Shi [/bib_ref] [bib_ref] Clinical Features of 85 Fatal Cases of COVID-19 from Wuhan. A Retrospective..., Du [/bib_ref]. In principle, close monitoring is required to determine the criteria for NIV failure, with the option to rapidly transition to invasive ventilation [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref] [bib_ref] High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure, Frat [/bib_ref] [bib_ref] Asian Critical Care Clinical Trials Group. Intensive care management of coronavirus disease..., Phua [/bib_ref]. Hence, treatment should ideally take place in an intensive care setting. Monitoring includes verifying oxygen saturation, blood gas levels, and tidal volumes, but also assessing the patient's clinical condition. Deteriorating oxygen supply with a PaO 2 /FiO 2 < 150 or 175 mm Hg after 1 h of NIV, a respiratory rate of > 30/min, a high APACHE score, and a HACOR score > 5 are associated with a significantly worse prognosis [bib_ref] Factors associated with noninvasive ventilation failure in postoperative acute respiratory insufficiency: an..., Wallet [/bib_ref] [bib_ref] Predictors of failure of noninvasive positive pressure ventilation in patients with acute..., Antonelli [/bib_ref] [bib_ref] Beyond the guidelines for noninvasive ventilation in acute respiratory failure: implications for..., Bourke [/bib_ref] [bib_ref] Assessment of heart rate, acidosis, consciousness, oxygenation, and respiratory rate to predict..., Duan [/bib_ref]. This results in the suggested therapy algorithm shown in [fig_ref] Figure 2: Respiratory support options in CO-VID-19-related acute respiratory failure [/fig_ref]. However, the decision for or against implementing each of these steps should be based on the specific clinical situation, the PaCO 2 , the dynamics of respiratory insufficiency, and the clinician's experience. ## Practical tips from a hygiene perspective Depending on the applied ventilation pressures or increasing flow values, both the use of NIV and intermittent NHF result in increased aerosol formation The protection of staff must, therefore, be a top priority. NIV failure should be identified early on so that intubation can be properly prepared and carried out. This prevents emergency intubation, which has been shown to be associated with poorer patient outcomes and, as a result of extended response times and inadequate protective measures, may put the emergency team at risk due to increased virus concentrations [bib_ref] Recommendations for critically ill patients with COVID-19, Kluge [/bib_ref]. For the above reasons, leakage needs to be reduced to a minimum when using NIV. Oronasal masks, full-face masks, or respiratory helmets should, therefore, be used for COVID-19 cases. In addition, nonvented masks must be used. The ventilators used for COVID-19 patients should preferably be dual-hose systems. When using single-hose systems, a virus filter should be inserted between the interface and the intended leakage (whisper swivel) or the exhalation valve. When using a patient's own device and pressure setting adapted to the emergency situation, patients with previous CPAP or NIV require an appropriate mask and tube change, including the insertion of a virus filter [bib_ref] Case for continuing community NIV and CPAP during the CO-VID-19 epidemic, Baker [/bib_ref]. ## Summary In conclusion, currently available evidence [bib_ref] Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection, Lin [/bib_ref] [bib_ref] Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with..., Alhazzani [/bib_ref] essentially confirms the recommendations and guidelines [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref] [bib_ref] Official ERS/ATS clinical practice guidelines: noninvasive ventilation for acute respiratory failure, Rochwerg [/bib_ref] [bib_ref] Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with..., Alhazzani [/bib_ref] for the treatment of ARF. According to these guidelines, moderately severe and severe ARDS associated with COVID-19 do not constitute a suitable indication for CPAP or NIV. Key Statement 4.1. Oxygen therapy including NHF and NIV/CPAP using an oronasal mask or a respiratory helmet are therapy escalation options when regular oxygen therapy is insufficient and for as long as the criteria for endotracheal intubation are not met. Please refer to the current S3 guideline regarding the use of CPAP/NIV [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref]. Key Statement 4.2. The pathophysiology of hypoxemic respiratory failure in COVID-19 is complex, and, according to current understanding, differs from other conditions accompanied by hypoxemia. Against this background, acute aggravation of hypoxemia, as well as a rapid increase in dyspnea and rapid clinical deterioration under CPAP/NIV, may occur. For this reason, continuous monitoring with readiness to carry out intubation must be ensured at all times. Key Statement 4.3. The protection of staff with PPE should have top priority. Fear of contagion should not be a primary reason for intubation. For this reason, leakages should be reduced to a minimum. Closed systems (socalled nonvented masks) with an upstream virus deactivation filter in the expiratory system are safe and do not lead to increased aerosol formation. By analogy, dual-hose systems with virus deactivation filters in the expiratory tube are also safe and do not lead to increased aerosol formation. Nonvented oronasal masks, full-face masks, or respiratory helmets should be used as interfaces. A virus deactivation filter should be inserted between the interface and the expiration device (intended leakage or expiration valve for single-hose systems). # Introduction Taking into account the findings described in the above position statements, this section intends to provide evidence-based treatment recommendations with due consideration of personalized medicine aspects. In contrast to disaster medicine, the personalized medicine approach means that individual patients can receive treatment as if there was unrestricted access to resources. This does not mean, however, that experimental therapies can or should be used indiscriminately just because all medical aspects of COVID-are not yet known. It also does not mean that therapies that are neither indicated nor pathophysiologically reasonable should be implemented. The use of intensive medical care must be based on the principles of good clinical practice. Since no causal treatment is available to date, adjuvant therapy of COVID-19 patients needs to focus on maintaining or restoring homeostasis. ## Indication for admission to the icu Patients requiring more intensive care should be quickly identified in the hospital's emergency room. Acute sepsis-or comorbidity-associated organ dysfunction is to be assessed in this context. This assessment, similar to the evaluation of community-acquired pneumonia, is intended to identify the so-called minor criteria of the American Thoracic Society and of the Infectious Diseases Society of America (ATS/IDSA) and include potentially unstable comorbidities [bib_ref] Management of adult community-acquired pneumonia and prevention -update, Ewig [/bib_ref]. Patients requiring MV and/or vasopressor therapy (major criteria) should always be treated in the ICU. In patients with clinically manifest hypoperfu-DOI: 10.1159/000509104 sion, lactate should be measured initially. Regular reevaluation, adjusted to the initial severity of organ dysfunction, should be performed until clinical stability is achieved. ## Major criteria 1 Need for intubation and MV 2 Necessity to administer vasopressors (septic shock) Various scores have been developed in recent years and evaluated in studies to predict patients who are at an increased risk of requiring intensive medical care or MV, and/ or catecholamine therapy, without the immediate need to initiate organ replacement therapy (i.e., without major criteria). All scores have in common that, clinical, laboratory chemical, and X-ray parameters of acute organ dysfunction are identified, which, when combined in different manners, produces approximately similar predictions. In meta-analyses, these scores were found to be consistently superior to the CRB-65 index in terms of risk prediction. The latter is therefore not applied to COVID-19. Minor Criteria A high risk of requiring intensive medical care exists if > 2 of 9 minor criteria are met. 1 Severe acute respiratory failure (PaO 2 ≤55 mm Hg or ≤7 kPa on room air) 2 A respiratory rate of ≥30/min 3 Multilobar infiltrates on chest X-ray 4 New disorder of consciousness 5 Systemic hypotension requiring aggressive volume therapy 6 Acute kidney failure (urea nitrogen ≥20 mg/dL) 7 Leukopenia (leukocytes < 4,000 cells/mm 3 ) 8 Thrombocytopenia (thrombocytes < 100,000 cells/mm 3 ) 9 Hypothermia (a body temperature < 36 ° C) ## Development of covid-19 patients in the intensive care setting A significant proportion of patients with respiratory failure present with relevant hypoxemia, which often cannot be fully corrected, even with a high FiO 2 , including NHF. Lung compliance is relatively high in the majority of cases (> 50 mL/cm H 2 O) [bib_ref] COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Gattinoni [/bib_ref]. As a result of hypoxemia, these patients have a significantly increased respiratory drive and respiratory volumes of > 15 L/min. Determining the Horovitz index usually provides significantly lower values of around 120-150. The bilateral changes in Xray imaging or chest CT alone are often not sufficient to explain the severe oxygenation disorder of these patients. When using a pulmonary arterial catheter, measurements show that some patients initially have normal pulmonary artery pressure and normal-to-reduced pulmonary vascular resistance in combination with a normal/ moderately increased cardiac output (range 6-9 L/min). The oxygenation disorder might, therefore, be explained by a relevant right/left shunt with impaired autoregulation of the pulmonary vasculature (impaired or absent "hypoxic pulmonary vasoconstriction") and severe distribution disorder (see recommendation 1). These patients should first be treated for hypoxemia, e.g., with NHF, nasal oxygen, or NIV, which can stabilize them. ## The place of niv With reference to the current S3 guideline of NIV for ARF [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref] , the following should be noted. NIV can improve oxygenation in most patients with severe community-acquired pneumonia, but the failure rate is relatively high [bib_ref] Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in..., Wang [/bib_ref] [bib_ref] Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in..., Yang [/bib_ref]. In addition to the severity of the clinical presentation, the extent of the oxygenation disorder can be a predictor of the success or failure of NIV. In general, a treatment attempt with NIV is justified in severe cases of COVID-19, especially in patients with COPD, with due consideration of the contraindications and termination criteria. In principle, close monitoring is required to identify the criteria of NIV failure, with the ability to rapidly transition to invasive ventilation [bib_ref] Non-invasive mechanical ventilation in acute respiratory failure, Westhoff [/bib_ref]. Therefore, treatment should ideally take place in an ICU. Major arguments for choosing the ICU as the place to perform NIV as an alternative to invasive ventilation are: the ability to continuously monitor the patient and to initiate potentially indicated vital treatments without delay. Concerning the qualifications of medical and nursing staff, NIV places the same high demands on staff as invasive ventilation does. The structural prerequisites must, therefore, be met. Exceptions are patients suffering from ventilatory failure, e.g., in the context of an acute exacerbation of COPD. In specific cases, ventilation can also be performed in an intermediate ICU specializing in ventilation. In patients with preexisting NIV, the transition between clinically stable chronic ventilatory failure and incipient decompensation is often blurred. Here, NIV can, in some cases, also be carried out in the general ward, provided that the technical and structural conditions are met. ## Evaluation of clinical development and management in icu The evaluation of patients should be oriented around physiological parameters (recapillarization time, lactate, diuresis, and normalization of respiratory rate) rather Respiration DOI: 10.1159/000509104 than numerical target parameters to estimate a sufficient oxygen supply. If the patient has a central venous access or pulmonary catheter, it is helpful to determine the central or mixed venous oxygen saturation. A deterioration in oxygen saturation with a PaO 2 /FiO 2 < 150 or 175 mm Hg after 1 h of NIV, a respiratory rate > 30/min, a high APACHE score, and a HACOR score > 5 are indications for endotracheal intubation in patients with a curative treatment goal [bib_ref] Factors associated with noninvasive ventilation failure in postoperative acute respiratory insufficiency: an..., Wallet [/bib_ref] [bib_ref] Predictors of failure of noninvasive positive pressure ventilation in patients with acute..., Antonelli [/bib_ref] [bib_ref] Beyond the guidelines for noninvasive ventilation in acute respiratory failure: implications for..., Bourke [/bib_ref] [bib_ref] Assessment of heart rate, acidosis, consciousness, oxygenation, and respiratory rate to predict..., Duan [/bib_ref]. In patients who are already intubated and ventilated, a prone position and a high PEEP are associated with varying success rates. These patients should be ventilated as recommended per S3 guideline recommendations. Due to the favorable risk/benefit ratio, an attempt should be made to improve the condition of patients with such measures. High PEEP levels in these patients also carry the risk of acute cor pulmonale if pulmonary embolism can be ruled out. Recruitment maneuvers are often not promising when compliance is good. The need for sedation can be high in this phase of the disease. Volume management should be restrictive while taking into account that patients have a disproportionately high fluid loss due to a high respiratory minute volume and fever. In the course of the disease, which can sometimes last for weeks, compliance often decreases, and the pulmonary situation becomes increasingly similar to COV-ID-19 pneumonia type H [bib_ref] COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome, Gattinoni [/bib_ref]. In COVID-19 patients with respiratory failure in whom invasive ventilation using the above-described measures is not sufficient to ensure adequate oxygen uptake and CO 2 elimination, ECMO should be considered. This is on condition that it is medically indicated and the patient has consented to its use. With regard to further management, please see the current S3 guideline on invasive ventilation and the use of extracorporeal procedures in ARF. It is difficult to compare data on the outcome of the various types of respiratory support as no precise settings and parameters have been reported. [fig_ref] Table 2: Overview of respiratory support in severe acute respiratory insufficiency as available to... [/fig_ref] provides an overview of the evaluations from China and the UK. Whether these figures also reflect the situation in Germany cannot be assessed at this stage, as the specific are not yet available. An overview of respiratory support in acute respiratory insufficiency shows the heterogeneity of the condition in severe courses of the disease [fig_ref] Table 2: Overview of respiratory support in severe acute respiratory insufficiency as available to... [/fig_ref]. Key Position Statement 5.1. In COVID-19 patients, NIV in hypoxemic ARF should be performed in an ICU or equivalent setting by adequately experienced staff. Key Statement 5.2. Please consult the applicable S3 guidelinefor the implementation of invasive ventilation. Key Statement 5.3. In COVID-19 patients with respiratory failure in whom invasive ventilation using the above-described measures is not sufficient to ensure adequate oxygen uptake and CO 2 elimination, ECMO should be considered. This is based on the condition that it is medically indicated and the patient's consent has been received. Finding 5.1. COVID-19 patients with ARF present a heterogeneous picture, even during treatment in ICU, and cannot be indiscriminately classified into one of the categories according to the Berlin definition of ARDS. [fig] Figure 2: Respiratory support options in CO-VID-19-related acute respiratory failure. fear of infection with COVID-19 on the part of the medical staff must not be a primary reason for intubation. [/fig] [fig] Position Statement 5: Continuity of Care in the Treatment of ARF S. Kluge and P. Lepper compiled this statement. [/fig] [table] Table 1: The sedimentation/diffusion ratio as a function of particle diameter[75] Particle diameter, µm Sedimentation, µm/s Diffusion, µm/s [/table] [table] Table 2: Overview of respiratory support in severe acute respiratory insufficiency as available to date Values in parentheses show the number and percentage of deceased patients. ECMO, extracorporeal membrane oxygenation; HFNC, nasal high-flow cannula; MV, mechanical ventilation; NIV, noninvasive ventilation; n.r., not reported. a The total of HFNC and NIV patients together. DOI: 10.1159/000509104 [/table]	None	https://karger.com/res/article-pdf/99/6/521/3523572/000509104.pdf	Against the background of the pandemic caused by infection with the SARS-CoV-2 virus, the German Respiratory Society has appointed experts to develop therapy strategies for COVID-19 patients with acute respiratory failure (ARF). Here we present key position statements including observations about the pathophysiology of (ARF). In terms of the pathophysiology of pulmonary infection with SARS-CoV-2, COVID-19 can be divided into 3 phases. Pulmonary damage in advanced COVID-19 often differs from the known changes in acute respiratory distress syndrome (ARDS). Two types (type L and type H) are differentiated, corresponding to early- and late-stage lung damage. This differentiation should be taken into consideration in the respiratory support of ARF. The assessment of the extent of ARF should be based on arterial or capillary blood gas analysis under room air conditions, and it needs to include the calculation of oxygen supply (measured from the variables of oxygen saturation, hemoglobin level, the corrected values of Hüfner’s factor, and cardiac output). Aerosols can cause transmission of infectious, virus-laden particles. Open systems or vented systems can increase the release of respirable particles. Procedures in which the invasive ventilation system must be opened and endotracheal intubation carried out are associated with an increased risk of infection. Personal protective equipment (PPE) should have top priority because fear of contagion should not be a primary reason for intubation. Based on the current knowledge, inhalation therapy, nasal high-flow therapy (NHF), continuous positive airway pressure (CPAP), or noninvasive ventilation (NIV) can be performed without an increased risk of infection to staff if PPE is provided. A significant proportion of patients with ARF present with relevant hypoxemia, which often cannot be fully corrected, even with a high inspired oxygen fraction (FiO2) under NHF. In this situation, the oxygen therapy can be escalated to CPAP or NIV when the criteria for endotracheal intubation are not met. In ARF, NIV should be carried out in an intensive care unit or a comparable setting by experienced staff. Under CPAP/NIV, a patient can deteriorate rapidly. For this reason, continuous monitoring and readiness for intubation are to be ensured at all times. If the ARF progresses under CPAP/NIV, intubation should be implemented without delay in patients who do not have a “do not intubate” order.
992ab5cb300e2e20466cc729ffcb182f29cded7f	pubmed	French consensus on management of head and neck cancer surgery during COVID-19 pandemic	French consensus on management of head and neck cancer surgery during COVID-19 pandemic In the context of the current pandemic, there is a need for specific advice concerning treatment of patients with Head and Neck cancers. The rule is to limit as much as possible the number of patients in order to reduce the risks of contamination by the SARS-Cov-2 virus for both patients and the caregivers, who are particularly exposed in ENT. The aim is to minimize the risk of loss of opportunity for patients and to anticipate the increased number of cancer patients to be treated at the end of the pandemic, taking into account the degree of urgency, the difficulty of the surgery, the risk of contaminating the caregivers (tracheotomy) and the local situation (whether or not the hospital and intensive care departments are overstretched). # Introduction In the context of the current pandemic, there is a need for specific advice concerning treatment of patients with Head and Neck cancers. This advice applies to both consultations and surgical procedures and is of course likely to change on a day-by-day basis according to how the epidemic develops, available technical resources and state of knowledge about the COVID-19 infection [bib_ref] Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China, Liang [/bib_ref] [bib_ref] Managing Cancer Care during the COVID-19 Pandemic: Agility and Collaboration Toward a..., Ueda [/bib_ref]. ## Consensus ## Surgery The rule is to limit as much as possible the number of patients in order to reduce the risks of contamination by the SARS-Cov-2 virus for both patients and the caregivers, who are particularly exposed in ENT. Indications for flexible nasal endoscopies and laryngoscopies, airway endoscopies, tracheotomies and endonasal surgical operations must be reduced to the absolute minimum. This should of course take into account the degree of emergency, the difficulty of the surgery, the risk of contaminating of the caregivers (tracheotomy) and the local situation (whether or not the hospital and intensive care services are overstretched). The aim is to minimize the risk of loss of opportunity for patients and to anticipate the increased number of cancer patients to be treated at the end of the pandemic. We can define 3 groups of patients, based on the treatment timescale: In such cases, the patient should be reassessed after 6 to 8 weeks in order to reconsider a rapid treatment according to the tumor growth velocity and evolution of the COVID-19 pandemic. ## Consultations Post-cancer treatment face-to-face follow-up consultations should be postponed as much as possible. Tele-consultations using phone or preferably video calls are recommended in order to ## Organizational aspects It is advisable to contact patients before they go to the hospital for consultation or surgery to check for signs of COVID-19 infection. If such signs exist, the patient should be referred to a COVID-19 diagnostic facility. ## Consultations The number of flexible naso-endoscopies and laryngoscopies should be limited as much as possible. During any face-to-face consultation, the patient should be regarded as potentially COVIDpositive, and the ENT specialist should wear an FFP2/N95 mask, a cap, a gown, protective goggles, and gloves. All disposable material must be eliminated through the infectious waste circuit. ## Hospitalization and surgery If possible, diagnostic work-up for COVID-19 should systematically be performed less than 24 hours before surgery (RT-PCR testing +/-chest CT-scan). In COVID-positive patients, surgery should possibly be postponed and the patient referred to a structure or a team specialized in the management of COVID-19. ## Postponement of surgery Page 7 of 8 J o u r n a l P r e -p r o o f The decision to postpone a surgical procedure for head and neck cancer should be made on a case-by-case basis, by the surgical team and in agreement with the patient. Apart from the above-mentioned Group C, the final decision to postpone should ideally be taken during a Tumor Board Setting with a written report that should be sent to all the doctors involved in the patient's care. The patient should be called by his ENT consultant who will explain the reason for the postponement, inform him or her of the probable delay before surgery and plan follow-up teleconsultations to consider moving the surgery forward in case of new symptoms or rapid tumor growth. It is advisable to draw up a list of patients waiting for treatment, in order of priority. It would also be advisable to set up a phone line or an email address that will allow the patient to contact the surgical team whenever needed. # Disclosure of interest The authors declare that they have no competing interest. [fig] : Group A: Life-threatening emergencies (shortness of breath, hemorrhage) Immediate treatment is required. A screening encompassing RT-PCR detection of SARS-Cov-2 from nasopharyngeal swabs and chest CT-scan should ideally be done less than 24 hours before surgery. If this screening is impossible, the patient must be regarded as COVID positive and the appropriate precaution measures must be observed, in line with the protocol established in each center. Group B: Cancers for whom postponing the treatment beyond one month could have a negative prognostic impact for the patient. Examples of such tumors are squamous cell cancers of the upper aerodigestive tract, aggressive cancers of the salivary glands, aggressive skin cancers. If tracheostomy is not required, patient's management should not be delayed. All necessary investigations and treatments (scans, dental treatment before RT, PAC, etc.) should be performed during a single hospital stay in order to minimize patient's comings and goings between home and hospital. If treatment is impossible due to the local evolution of the COVID-19 pandemic, the patient should ideally be referred to another center specialized in head and neck cancer surgery If tracheostomy is necessary, taking into account the high contamination risk of caregivers, the surgery should be postponed or a non-surgical alternative treatments should be chosen as far as possible. [/fig] [fig] : Group C: Cancers for which the treatment can be postponed for at least 6 to 8 weeks without any significant prognostic impact Examples of such tumors are well-differentiated thyroid cancers, non-progressive skin cancers such as basocellular cancers, some slow-growing cancers of the salivary glands, atypical nodules of the salivary glands which were not formally classified as malignant during the preoperative assessment, leukoplakia and superficial lesions of the vocal cords. [/fig]	None	None	None
efde0db26ca2107ce85728faac40bd703abbf733	pubmed	Coronavirus Disease 2019 (COVID-19) Vaccination for Children: Position Statement of Indian Academy of Pediatrics Advisory Committee on Vaccination and Immunization Practices	Coronavirus Disease 2019 (COVID-19) Vaccination for Children: Position Statement of Indian Academy of Pediatrics Advisory Committee on Vaccination and Immunization Practices Justification: Data generated after the first wave has revealed that some children with coronavirus 19 can become seriously ill. Multi-inflammatory syndrome in children (MIS-C) and long COVID cause significant morbidity in children. Prolonged school closures and quarantine have played havoc with the psychosocial health of children. Many countries in the world have issued emergency use authorisation (EUA) of selected COVID-19 vaccines for use in children. In India, a Subject Expert Committee (SEC) has recommended the use of Covaxin (Bharat Biotech) for children from the ages of 2-18 years. The recommendation has been given to the Drugs Controller General of India (DCGI) for final approval. Objective: To provide an evidence-based document to guide the pediatricians on the recommendation to administer COVID vaccines to children, as and when they are available for use. Process: Formulation of key questions was done by the committee, followed by review of literature on epidemiology and burden of COVID-19 in children, review of the studies on COVID vaccines in children, and the IAP stand on COVID-19 vaccination in children. The available data was discussed in the ACVIP focused WhatsApp group followed by an online meeting on 24 October, 2021, wherein the document was discussed in detail and finalized. Recommendations: The IAP supports the Government of India's decision to extend the COVID-19 vaccination program to children between 2-18 years of age. Children with high-risk conditions may be immunized on a priority basis. The IAP and its members should be a partner with the Government of India, in the implementation of this program and the surveillance that is necessary following the roll-out. ## E e e e n n n n n d d d d d a a a a a t t t t t i i i i i o o o o o n n n n n s s s s s C hildren of all ages are susceptible to coronavirus disease 2019 . Almost 70% of SARS-CoV-2 infections in children are asymptomatic. When symptomatic, the symptoms are usually mild and critical illness and hospitalizations are extremely rare. Children account for 1.5% of all COVID hospitalizations. Studies done in the initial stages of the pandemic suggested that children do not participate significantly in the chain of transmission [bib_ref] Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. According to the National Centre for Disease Control data as of 26/2/21, 3.9% of cases occurred in the 0-10 year age group and 7.99% in the 11-20 year age group. The morbidity and mortality of COVID-19 in children are much lower than that seen in adults and the elderly [bib_ref] Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak..., Wu [/bib_ref]. Thus, the assessment of benefit vs risk of COVID vaccination in children is complex. VOLUME 59 __ COVID-19 VACCINATION FOR CHILDREN in the number of cases and hospitalization rates in children in many countries [bib_ref] Hospitalizations associated with COVID-19 among children and adolescents -COVID-NET, 14 States, Delahoy [/bib_ref]. This may be amplified if more transmissible variants predominate in the coming months. This further underscores the need for COVID-19 vaccination in children. In USA, during the peak of the Delta wave, the weekly hospitalization rate among children aged 0-4 years increased nearly 10 times. Nearly one third of adolescents aged 12-17 years hospitalized with COVID-19 during March 2020-April 2021 required intensive care, and 5% of those hospitalized required endotracheal intubation and mechanical ventilation [bib_ref] Hospitalizations associated with COVID-19 among children and adolescents -COVID-NET, 14 States, Delahoy [/bib_ref]. The current surge of COVID-19 in UK, is being primarily driven by high levels of infection in school-age children, with more than a third of all recent cases being reported in those under 15 years of age. In USA, during the period from June 20 to July 31, 2021, the hospitalization rate among unvaccinated adolescents (aged 12-17 years) was 10.1 times higher than that among fully vaccinated adolescents, underlining the utility of vaccines in reducing the morbidity and mortality associated with COVID 19 in adolescents [bib_ref] Hospitalizations associated with COVID-19 among children and adolescents -COVID-NET, 14 States, Delahoy [/bib_ref]. Age distribution data from India revealed that children in the age group 0-10 years accounted for 3.28% of all cases, and individuals 11-20 years accounted for 8.03% of all cases in the first wave. Corresponding figures in the second wave were 3.05% and 8.57%, respectively. Although the proportion remained almost similar in both waves, the second wave involved almost twice the number as in the first wave, with a consequent increase in the absolute numbers of children needing hospitalization and ICU care. In a study conducted in Tamil Nadu and Andhra Pradesh, in the pediatric age group, the case fatality rate was highest in the 0-4 years age group [median (IQR) 0.16% (0, 0.36)], which was comparable to that observed in the 18-29 years age group but lower than that observed in the older age groups [bib_ref] Epidemiology and transmission dynamics of COVID-19 in two Indian states, Laxminarayan [/bib_ref]. A systematic review and meta-analysis of severe COVID-19 infection and pediatric comorbidities concluded that children with comorbidities have a higher risk of severe COVID-19 and associated mortality than children without underlying disease [bib_ref] Severe COVID-19 Infection and pediatric comorbidities: A systematic review and meta-analysis, Tsankov [/bib_ref]. Severe COVID-19 was present in 5.1% of children with comorbidities as compared to 0.2% in children without comorbidities. Children with comorbidities had higher risk of severe COVID-19 [RRR 1.79 (95% CI 1.27-2.51)] and COVID-19-associated mortality [RRR 2.81 (95% CI 1.31-6.02)] as compared to healthy children. Children with obesity had a relative risk ratio of 2.87 (95% CI 1.16-7.07) [bib_ref] Clinical profile and risk factors for severe disease in 402 children hospitalized..., Jat [/bib_ref]. In a multi-centric study done in five major institutions across India, 44% of 402 children had some underlying comorbidity, malignancy (leukemia and other malignancy) followed by cardiac disease was the most common underlying comorbidity. In this study, children with underlying disease had an odds ratio of 8.85 (6.07-12.91) for moderate-severe disease [bib_ref] Clinical profile of children with sars-cov-2 infection from a dedicated covid-19 hospital..., Pande [/bib_ref].In a study done from a dedicated COVID-19 hospital in India, 30 out of 100 admitted children had underlying comorbidities, 60% had severe disease, and the presence of underlying comorbidities and the number of comorbidities were significant predictors of severity of the disease [bib_ref] Clinical profile of children with sars-cov-2 infection from a dedicated covid-19 hospital..., Pande [/bib_ref]. A review of cases till December, 2020, revealed that 91.5% of COVID-19 deaths were reported from low-and middle-income countries (LMICs), and 83.5% of reported pediatric Covid-19 cases from all included countries were from LMICs. The pediatric deaths/1,000,000 children, case fatality rate (CFR) and ICU admission/1,000,000 children were significantly higher in LMICs than in high-income countries [bib_ref] The differential impact of pediatric COVID-19 between high-income countries and lowand middle-income..., Kitano [/bib_ref]. This data underscores the greater need for vaccination of children in LMICs, for the prevention of COVID-19. ## Prevention of complications Multi-Inflammatory syndrome in children (MIS-C) first reported in April, 2020, is generally reported during the weeks following a peak in COVID-19 disease. MIS-C may need hospitalization and ICU care in addition to expensive medications [bib_ref] Updated management protocol for multisystem inflammatory syndrome in children (MIS-C), Takia [/bib_ref]. The burden of MIS-C in our country has previously been documented [bib_ref] Multisystem inflammatory syndrome in children: An international survey, Bautista-Rodriguez [/bib_ref] [bib_ref] A cohort study of COVID-19 related multisystem inflammatory syndrome in children and..., Tiwari [/bib_ref] [bib_ref] COVID-19 associated multisystem inflammatory syndrome in children: A multicentric retrospective cohort study, Mehra [/bib_ref]. By preventing SARS-CoV-2 disease, COVID-19 vaccines may prevent MIS-C. Some patients who have recovered from COVID-19 may experience persisting symptoms after the resolution of acute disease, the so-called long COVID. Estimates in the literature range from 0-27% [bib_ref] Characterising long COVID: a living systematic review, Michelen [/bib_ref] ; however, similar literature regarding long COVID-19 in children is not available from India. Similar to MIS-C, COVID-19 vaccines may prevent long COVID; although, currently there is no data available to support this statement. A report of three children with subacute neuropsychiatric impairment following COVID-19 and the detection of intrathecal anti-SARS-CoV-2 antibodies also raises the spectre of direct involvement of the central nervous system by the SARS-CoV-2 virus [bib_ref] Anti-SARS-CoV-2 and autoantibody profiles in the cerebrospinal fluid of 3 teenaged patients..., Bartley [/bib_ref]. ## Reduction of transmission School-age children and adolescents can efficiently transmit SARS-CoV-2 to household members, which may lead to hospitalization of adults who are secondarily infected [bib_ref] On the effect of age on the transmission of SARS-CoV-2 in households,..., Go Ldstein [/bib_ref]. Recent data suggest that adolescents contribute significantly to household transmission, and rates of transmission by this age group (11-18 years) may be higher than that in adults [bib_ref] Contact tracing during Coronavirus Disease Outbreak, South Korea, Park [/bib_ref] The highest probability of transmission, given exposure, in an Indian study was shown to be within case-contact pairs of similar age, and this association was strongest among children aged 0 to 14 years and among adults aged ≥65 years [bib_ref] Epidemiology and transmission dynamics of COVID-19 in two Indian states, Laxminarayan [/bib_ref].With reopening of schools, outbreaks have been reported from all over the world. High attack rates of 44% have been reported at a youth camp in Georgia, USA suggesting that SARS-CoV-2 can transmit readily in young populations [bib_ref] SARS-CoV-2 transmission and infection among attendees of an overnight camp -Georgia, Szablewski [/bib_ref]. Vaccination of children may reduce transmission. Some of the COVID vaccines in use have been shown to reduce infection and thus transmission. However, during the Delta surge, vaccinated and unvaccinated individuals had similar viral loads in the nasopharynx. Prevention of psychosocial issues due to prolonged school closure: The COVID-19 pandemic has resulted in drastic changes in the lives of children and adolescents. Restrictive measures, such as nationwide lockdown, school closures, online lectures, and quarantines, have resulted in significant adverse psychological effects on children, and adolescents [bib_ref] Impact of COVID -19 on children: Special focus on the psychosocial aspect, Ghosh [/bib_ref] [bib_ref] Psychological impact of COVID-19 on children and adolescents: A systematic review, Chawla [/bib_ref] [bib_ref] Psychological and behavioral impact of lockdown and quarantine measures for COVID-19 pandemic..., Panda [/bib_ref]. COVID-19 associated obesity has become a real issue [bib_ref] Will the COVID-19 pandemic worsen the obesity epidemic?, Clemmensen [/bib_ref]. Children are losing out on their development and learning opportunities, including nutritional deficiencies and delayed immuni-zations. Vaccination and other measures to reduce community transmission may help to avert some of these indirect effects of the pandemic. Although vaccinations and school reopening are not linked, parents will be more confident about sending their vaccinated children to school. Herd immunity: Herd immunity against COVID-19, either through vaccinations or natural infection, is the logical way to terminate the pandemic. Initially, a population immunity of 65-70% was estimated as the threshold for herd immunity [bib_ref] Herd immunity: understanding COVID-19, Randolph [/bib_ref]. However, ongoing vaccine hesitancy and the circulation of more transmissible variants have raised the bar for achieving herd immunity. The goal of attaining herd immunity can never be achieved if children, who constitute 20-35% of the population, are excluded from the vaccination process. If unprotected, children could act as reservoirs of infection and may contribute to the rise of variants in the future. Potential risks of vaccinating children: Myocarditis has been recognized as a rare complication of mRNA vaccines against COVID-19, especially in young adult and older adolescent males [bib_ref] Myocarditis after Covid-19 vaccination in a large health care organization, Witberg [/bib_ref]. Of the 8.9 million U.S. adolescents aged 12-17 years, who had received Pfizer-BioNTech vaccine, up to July 16, 2021, there were 9246 adverse events reported, of which 9.3% were serious adverse events, including myocarditis (4.3%). It should be noted that most of these cases were mild and resolved spontaneously. The risk, if any, in the younger age groups is unknown. Vaccine-induced thrombotic thrombocytopenic purpura (VITT) is a rare but potentially life-threatening adverse effect following adeno-vectored COVID vaccines administered to those >18 years. As this vaccine has not been administered below 18 years of age, the risk, if any, in the younger age groups is unknown. There is also a theoretical risk of COVID-19 vaccines triggering systemic, dysregulated inflammatory response (MIS-C). Post-vaccination surveillance data, with the mRNA vaccines, has not detected any case of MIS-C following vaccination. ## Vaccines available for pediatric population Internationally, only the Pfizer and the Moderna vaccines have received emergency use authorization (EUA) for use in children between 12 and 17 years of age. The Pfizer vaccine has received EUA for use in children 5-11 years. In India, ZyCov-D (Zydus Healthcare) has received EUA in the age group 12-17 years, while Covaxin (Bharat Biotech Ltd) has received EUA for 2-18 years. ## Bnt162b2 (pfizer) vaccine In the 12-15-year-old cohort, the geometric mean titer (GMT) of the serum-neutralizing antibodies one month after BNT162b2 dose 2 was higher as compared to the 16 to 25year-old cohort. This established the non-inferiority and a greater response in adolescents than in young adults [bib_ref] Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents, Frenck [/bib_ref]. The vaccine efficacy (VE) was 100% (78.1 to 100) in the efficacy trial, with 16 cases in the placebo group and none in the vaccine group [bib_ref] Safety, immunogenicity, and efficacy of the BNT162b2 Covid-19 vaccine in adolescents, Frenck [/bib_ref]. EUA was granted by the USFDA, on May 10, 2020, for use in children 12-15 years of age. This vaccine is now in use in children 12-15 years in European countries, Israel, UK, Dubai, UAE, Singapore, Japan, Philippines, Canada, and Chile. Of the 8.9 million doses of the vaccine administered to adolescents 12-17 years (as of July 16, 2021), serious adverse effects were noticed in 9.3% children. Among the serious adverse effects, myocarditis accounted for 40.3% [bib_ref] Psychological impact of COVID-19 on children and adolescents: A systematic review, Chawla [/bib_ref]. The overall rate of myocarditis was 4.3% [bib_ref] COVID-19 vaccine safety in adolescents aged 12-17 years -United States, Hause [/bib_ref]. Trials for children 6 months to 11 years of age, are ongoing. Children ages 5 to 11 years will receive two-doses of 10 µg each while children less than age 5 years will receive a 3 µg dose. The SARS-CoV-2-neutralizing antibody GMT in the 5-11 years was 1197.6 (95% CI, 1106.1, 1296.6), as compared to the 16-25 years cohort [1146.5 (95% CI: 1045.5, 1257.2)], proving non-inferiority in the 5-11 years cohort. The reactogenicity and adverse effects profile was similar to that observed in the 16-25 years age group [bib_ref] Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years..., Walter [/bib_ref]. On 29 October, 2021, EUA was granted by the USFDA for use in children 5-11 years. ## Mrna-1273 vaccine (moderna vaccine) Adolescents aged [bib_ref] Multisystem inflammatory syndrome in children: An international survey, Bautista-Rodriguez [/bib_ref] [bib_ref] Evaluation of mRNA-1273 SARS-CoV-2 vaccine in adolescents, Ali [/bib_ref]. The VE against COVID-19, 14 days after second dose, in the per protocol cohort was 100% (28.9 to NE: not estimated). On 4 September 2021, this vaccine was granted EUA by the USFDA, for adolescent 12-17 years.The phase 2/3 study (KidCove), is being done in three age cohorts, 6-12 years, 2-6 years and 6 months to 2 years, in two parts. Part 1 is a dose-escalation study. In Part 2, participants will receive two intramuscular injections of mRNA-1273, on 0-28 days, at the dose selected from Part 1. This study involves 13275 participants enrolled from 79 centres across USA [bib_ref] A phase 2/3, two-part, open-label, doseescalation, age de-escalation and randomized, observer-blind, placebo-controlled..., Modernatx [/bib_ref]. ## Gam-covid-vac (sputnik) This vaccine is being studied in 12-17 years in two stages, in stage 1 (Phase I-II) 100 volunteers will be included in two dosing groups and in stage 2 (Phase III) 3000 volunteers will be divided in two age groups, 12-14 years and 15-17 years. Recruitment is ongoing in this trial. ## Covaxin in children A Phase II/III, open-label study was conducted in healthy volunteers in three age groups, 2-6 years, 6-12 years and 12-18 years, with 175 subjects in each group. Each participant was administered two doses of Covaxin (6 µg/0.5 mL) on 0-28 days. Based on data provided by the company to the Special Expert Committee, the vaccine was granted EUA by the Government of India, on October 12, 2021 for use in children 2-17 years. So far, no data is available in the public domain and Drugs Controller General of India (DCGI) approval is still pending. ## Zycov-d This vaccine has been granted EUA for use in children 12-17 years. The phase 3 efficacy trial done in 28000 subjects included 1400 subjects between 12-17 years of age. No severe side effects related to the vaccine were seen in the 12-18 years age group. The overall vaccine efficacy has been reported as 66.6% . The company has received approval for phase 3 studies in children 2-17 years. ## Covovax Covovax, a subunit vaccine developed by Novavax received DCGI approval for phase 3 studies in children . A total of 920 eligible children of ≥2 years of age will be enrolled in this study. The schedule is two doses on days 0-22. ## Corbevax Corbevax, an adjuvanted subunit vaccine by Biological E Limited, had received permission from the DCGI to conduct Phase 2 and 3 clinical trials on children aged 5-18 years [40]. ## J & j vaccine Johnson and Johnson has applied to the Indian drug regulator to conduct a study of its COVID-19 vaccine in adolescents aged 12-17 years. ## Iap-acvip recommendations 1. The IAP supports the Government of India's decision to extend the COVID-19 vaccination program to children between 2-18 years of age. Children with highrisk conditions should be immunized on a priority basis, as follows: i) high-risk population in age group 2-18 years ii) children aged 2-18 years living with high-risk individuals iii) all population below 18 years of age (in an age deescalation manner) Although the Fourth All-India sero-survey showed a positivity of 57.2% in the 6-9 years age group and 61.6% in the 10-17 years age group, it should be noted that antibodies and efficacy decline with time. Studies done with the mRNA vaccines have shown that unvaccinated individuals are more than twice as likely to be reinfected with COVID-19 than those who were fully vaccinated after initially contracting the virus. Moreover, the antibody responses were superior in adults hospitalized with COVID-19-like illness, who had prior vaccination with a mRNA vaccine compared to those with prior natural infection [bib_ref] Reduced risk of reinfection with SARS-CoV-2 after COVID-19 vaccination -Kentucky, Cavanaugh [/bib_ref] [bib_ref] Laboratory-confirmed COVID-19 among adults hospitalized with COVID-19-Like illness with infection-induced or mRNA..., Bozio [/bib_ref]. The IAP strongly recommends that its members should be made a part of the process of vaccinating children, either by vaccinating in their clinics or as a part of the government initiative. 2. Pediatricians are well acquainted with cold chain, vaccine administration skills, AEFI (adverse events following immunity) recognition and management, and biomedical waste disposal. They also have the infrastructure to maintain the rigorous protocols for vaccination, as put forth by the regulatory authorities. Their rapport with children and their parents will provide the most reassuring situation for vaccinating the children in the clinics and can lessen vaccine hesitancy and vaccine refusal. Local and district branches of IAP can be involved in the process to disseminate information, education and communication (IEC) activities via print media, social media, radio and television in local languages. This may be important for better acceptance by the parents of COVID-19 vaccines for children. Pediatricians and parents have to be convinced about VOLUME 59 __ INDIAN ACADEMY OF PEDIATRICS 55 the safety and efficacy of COVID-19 vaccines in children. Study data has to be provided to the pediatricians and parents before embarking on any COVID-19 vaccination programs for children. ## The iap supports a school-based vaccination program, as this is the quickest way to achieve maximum immunization coverage. However, this should not be made mandatory, and the parents should be offered a choice of administering the vaccine to their children, in the schools or in the clinics of their pediatricians. 4. School-based centers should have a medical personnel trained to handle emergencies, nursing and administrative staff, emergency medications and equipment, tie-up with the closest hospital for emergency care, and immediate availability of transport to the referral hospitals. 5. The IAP recommends administering currently available COVID-19 vaccines and other scheduled childhood vaccines, either simultaneously or at any interval between them. 6. The IAP recommends the setting up of an active and passive surveillance mechanism for adverse effects of COVID-19 vaccines. This should include surveillance for any link between COVID-19 vaccines and MIS-C, and other adverse effects observed during long-term follow-up. IAP should be a part of this surveillance mechanism. Children have striking differences in their immunological responses to vaccines as compared to adults. Younger children have a more active immune response that may translate into heightened immunological responses and probably reactogenicity. The link, if any, between dysregulated immune responses e.g., MIS-C and vaccination, should be thoroughly studied in the post-marketing surveillance. 7. In children with acute illnesses, the vaccination may be postponed till clinical recovery. 8. Immunodeficiencies due to drugs or diseases are not contraindications for the COVID-19 vaccines to be rolled out for children. The COVID-19 vaccines approved for children are inactivated vaccines. 9. Studies should be initiated to determine the duration of protection and efficacy against variants. This data will be necessary for booster dose recommendations. 10. The government should prioritize research for safer and more effective COVID-19 vaccines for children. # Conclusion India has the largest childhood immunization program in the world, with a well-established and time-tested vaccination network, including cold chain networks. These can be utilized for the COVID-19 vaccination program. India has sufficient manufacturing capability for the vaccine (more than 2.4 billion doses annually), including surgical disposables such as vials, stoppers, syringes, gauze, and alcohol swabs and adequate storage and transportation of the vaccines. Real-time remote temperature monitoring of 29,000 cold-chain points exists through COVID Vaccine Intelligence Network (Co-WIN) vaccine delivery and E-VIN . The vaccination capacity in India has been established with record immunizations of 7-10 million adults in a day. In a span of nine months, India has immunized over a billion individuals with at least one dose of the COVID-19 vaccine. It becomes more important during a pandemic that scarce resources are used efficiently, balancing the principles of equity and justice. The decision to vaccinate healthy children would depend on the availability of one or more suitable vaccines in the quantities enough to immunize the vulnerable population in our country. Funding: None; Competing interests: None stated. ## Effect of mixing the vaccines against covid-19 Vaccines trigger the immune response by imitating an infection, leading to the generation of the memory T-cells and B-cells. This antibody response gets enhanced with the second dose and boosters leading to the generation of antibody levels which will be protective against future infections.But does this response appear / persist, if the type of vaccine has been changed for the second dose? In a recently published paper by Com-COV-2 Study Group -a multicentre survey network of nine institutions in the UK, researchers studied the effect of mixing of different COVID-19 vaccines on the antibody response. In this study, 1072 participants were studied where the participants were inoculated with a dose of the Pfizer-BioNTech mRNA (BNT162b2), Moderna mRNA (mRNA-1273), Astra Zeneca (chimpanzee nonreplicating adenovirus (ChAdOx1 nCoV-19), or Novavax Matrix M-adjuvanted recombinant S protein (NVX-CoV2373) vaccine after an initial dose of Astra Zeneca or Pfizer. Higher levels of binding and neutralizing antibodies were seen with the second dose of Moderna vaccine after a first dose of Astra Zeneca or Pfizer compared to two doses of either Pfizer or Astra Zeneca. Findings of the present study, provide the data to support the mix and match of COVID-19 vaccines in primary immunization schedules. This will provides the much needed flexibility required to vaccinate the large unvaccinated population in low income countries. With the emergence of new variant Omicron, it is the need of hour to vaccinate as many people as possible (BMJ 07 December, 2021) ## Finally something against childhood dental caries Exact burden of dental caries in India is not known due to poor awareness among the general public about its long term impact on health affecting the growth, early childhood development, learning and limited published literature. A recent meta-analysis estimated that the approxi-mately 52% of children aged 3-18 years have caries in India. In the absence of a validated risk determining tool, prevention and screening are the best modalities. Recently, United States Preventive Services Task Force (USPSTF) has recommended that the primary care physicians must prescribe oral fluoride supplements to all asymptomatic children aged 6 months to 5 years, living in areas having lesser than 0.6 ppm fluoride levels (fluoride deficient areas). Use of fluoride varnish containing 5% sodium fluoride is also recommended to all childrenaged 6 months to 5 years after the eruption of primary teeth. These recommendations are beyond the routine dental evaluation and referral to the dental health professionals. More Indian data is needed before recommendations in Indian context are produced to reduce the potentially preventable burden of dental caries in Indian children. (JAMA 07 December, 2021) ## Microfluidics: future of treatment of neonatal jaundice Neonatal jaundice is the most common morbidity in the first week of life after birth. Almost 60% of term and 80% of preterm babies develop jaundice. Approximately 5-8% of these babies require one or another modality to lower the serum bilirubin levels, in order to prevent neurological damage. Beyond particular levels or in the presence of features suggestive of bilirubin encephalopathy, double volume exchange transfusion (DVET) rapidly lowers the bilirubin levels but in VLBW/ELBW babies it can cause hemodynamic instability. Researchers at Oregon State University College of Engineering has led to a promising potential therapy for the treatment of neonatal jaundice using microfluidics. Microfluidics is the branch of science which study the behavior of fluids, as they travel through or are confined in microminiaturized devices equipped with channels and chambers. The team has found a simpler and safer alternative to DVET, by treating the patient's blood by circulating it through an external device known as a microfluidic photoreactor. The basic principle is same as that of phototherapy but using the microfluidics helps in lowering the bilirubin at faster rates. Preclinical studies in Gunn rats, using high-intensity light at 470 nm for 4 hours demonstrates a significant reduction in the bilirubin levels without causing an appreciable DNA damage. The rates of bilirubin reduction were similar to those observed with exchange transfusion and on a similar time scale. Mathematical prediction model for the human newborn, suggested that this newer modality will outperform the exchange transfusion at the clinical scale. Use of microfluidics is a potential promising approach for the treatment of neonatal jaundice, especially in the VLBW/ ELBW, babies without the use of donor blood.	None	https://link.springer.com/content/pdf/10.1007/s13312-022-2421-9.pdf	None
17fa1d649a932892ea33a5ffd757a4e339586960	pubmed	Corticosteroid therapy for sepsis: a clinical practice guideline	Corticosteroid therapy for sepsis: a clinical practice guideline Do corticosteroids reduce death or improve recovery in people with sepsis or septic shock? Our panel make a weak recommendation to give corticosteroids to people with all types and severity of sepsis, based on new evidence. Because we are not certain that they are beneficial, it is also reasonable not to prescribe them. Patients' values and preferences may guide this decision-making process.This rapid recommendation was triggered by two trials, with differing conclusions whose results might change practice: - APROCCHSS (1241 patients who had septic shock) found that hydrocortisone plus fludrocortisone reduced 90 day mortality. [bib_ref] Hydrocortisone plus fludrocortisone for adults with septic shock, Annane [/bib_ref] The trials are incorporated into a linked systematic review comparing corticosteroids with placebo. [bib_ref] Corticosteroids in sepsis: an updated systematic review and meta-analysis, Rochwerg [/bib_ref] This BMJ Rapid Recommendation promptly and transparently translates this evidence using GRADE methodology for trustworthy guidelines. Sepsis is a life threatening organ dysfunction from infection. C urrently most guidelines advise against giving corticosteroids in sepsis in the absence of refractory shock, but these guidelines have not taken into account the new evidence. We do not anticipate that new clinical trials will substantively alter the evidence suggesting a small but uncertain mortality reduction. The box below shows publications linked in this Rapid Recommendation package. The main infographic provides an overview of the absolute benefits and harms. The table at the end of the article shows any evidence that has emerged since the publication of this guideline. ## Current understanding Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection. [bib_ref] The third international consensus definitions for sepsis and septic shock (Sepsis-3), Singer [/bib_ref] In practice, a sepsis-related organ failure assessment (SOFA) score of ≥2 in patients with infections is sepsis (table 1). Worldwide, about 30 million people are hospitalised with sepsis every year and up to six million of them die. [bib_ref] International Forum of Acute Care Trialists. Assessment of global incidence and mortality..., Fleischmann [/bib_ref] Clinicians typically manage sepsis with early, broad spectrum antibiotics. They may provide supportive treatment such as vasoactive drugs and mechanical ventilation. They track and adjust treatment based on clinical signs and laboratory data. [bib_ref] Surviving Sepsis campaign: international guidelines for management of sepsis and septic shock, Rhodes [/bib_ref] Septic shock is the most severe form of sepsis. These patients experience profound circulatory, metabolic, and cellular abnormalities. [bib_ref] The third international consensus definitions for sepsis and septic shock (Sepsis-3), Singer [/bib_ref] Disclaimer: This infographic is not a clinical decision aid. This information is provided without any representations, conditions or warranties that it is accurate or up to date. BMJ and its licensors assume no responsibility for any aspect of treatment administered with the aid of this information. Any reliance placed on this information is strictly at the user's own risk. For the full disclaimer wording see BMJ's terms and conditions: http://www.bmj.com/company/legal-information/ Those who place more value on avoiding functional deterioration and maximising quality of life than on avoiding death may be more likely to choose not to use corticosteroids ## Preferences and values Patients at greatest risk of death (e.gs. those with shock, high qSOFA/SOFA scores) will probably have the greatest reduction in risk of death with corticosteroids ## Risk of death There are no clear differences in efficacy or adverse effects between different corticosteroids or corticosteroid combinations. Most studies used hydrocortisone It is possible that corticosteroids help improve the dysregulated immune response caused by sepsis [bib_ref] Glucocorticoids and inflammation revisited: the state of the art. NIH clinical staff..., Franchimont [/bib_ref] and increase blood pressure if it is low. [bib_ref] A systematic review of vasopressor blood pressure targets in critically ill adults..., Hylands [/bib_ref] Some clinicians have found this biological rationale, and results of early studies, compelling. Others disagree and do not use corticosteroids. [bib_ref] US practitioner opinions and prescribing practices regarding corticosteroid therapy for severe sepsis..., Bruno [/bib_ref] Most professional organisations recommend against corticosteroid use in the absence of refractory shock. [bib_ref] Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI)..., Annane [/bib_ref] [fig_ref] Table 2 \|: Current recommendations for corticosteroid therapy in patients with sepsis SCCM = Society... [/fig_ref] summarises current professional society guidelines. ## The evidence The linked systematic review identified 42 randomised controlled trials (RCTs) comparing corticosteroids with no corticosteroids (typically placebo). [bib_ref] Corticosteroids in sepsis: an updated systematic review and meta-analysis, Rochwerg [/bib_ref] [fig_ref] Fig 2 \|: Characteristics of patients and trials included in systematic review of the use... [/fig_ref] provides an overview of the trials and participants. The systematic review includes total of 10 194 patients who had sepsis. Of the 42 trials included, 24 restricted enrolment to patients who had septic shock. The typical patient was critically ill-a median of 32% of participants died within the first month. The most common sources of sepsis were pulmonary infections (median 44%) and abdominal infections (median 17%). Most of the RCTs used hydrocortisone alone (n=26), others used hydrocortisone plus fludrocortisone (n=2), methylprednisolone (n=6), prednisolone (n=3), or dexamethasone (n=3) (see [fig_ref] Fig 2 \|: Characteristics of patients and trials included in systematic review of the use... [/fig_ref]. Although most of the clinical trials included patients who had septic shock, many included patients who did not (16 trials, 2241 patients). The linked systematic review provides detailed trial descriptions, including risk of bias assessments and patient characteristics. 3 ## Subgroups of patients Corticosteroids did not seem to be more or less effective in particular clinical subgroups, for example: Older studies tended to use much higher doses of corticosteroids for a shorter time than are typically used now; the pooled evidence from these older studies is imprecise (few events), and the linked meta-analysis was underpowered to detect important subgroup differences such as by dose. All tests for relative subgroup effects may be underpowered to detect true differences because the effect sizes are small, especially for mortality. Therefore, we cannot be certain that a true subgroup effect does not exist. Future meta-analyses of individual patient data may help to identify populations that benefit more or less from corticosteroids. Until such time, we can only conclude that the evidence applies to all subgroups. [formula] - [/formula] ## Understanding the recommendation The main infographic provides an overview including the benefits and harms, and our certainty in the evidence for each outcome. ## Absolute benefits and harms There was better survival in the group taking corticosteroids, but this was not certain. This drives the weak rather than strong recommendation. ## Mortality Corticosteroids may reduce mortality in the first month after admission to an intensive care unit (ICU) by approximately 2%. However, the panel had low certainty that this is true. The confidence interval crosses the line of no difference, and the results were inconsistent, with some RCTs showing a mortality reduction and others showing none. The effect on longer term mortality (from 60 days to 1 year) was similar. Fewer studies reported this outcome, so, although the results were consistent in the RCTs that did report this outcome, the panel also had low certainty that corticosteroids reduce longer term mortality. ## Quality of life No RCT reported quality of life outcomes at any time point. The ADRENAL study investigators are collecting quality of life data at six months, but these data have not been published. [bib_ref] ANZICS CTG investigators. The ADRENAL study protocol: adjunctive corticosteroid treatment in critically..., Venkatesh [/bib_ref] Outcomes of some interest Corticosteroids may reduce the length of ICU and hospital stay by less than a day each (moderate quality evidence). The impact of corticosteroids on other patient-important outcomes such as stroke and myocardial infarction was extremely uncertain. They may increase the risk of neuromuscular weakness by a small amount (low quality evidence from seven RCTs). Possible explanations include the toxic effects on nerve and muscle cells, and hyperglycaemia from corticosteroid use. [bib_ref] Corticosteroids and neuromuscular blockers in development of critical illness neuromuscular abnormalities: A..., Wilcox [/bib_ref] Weakness may compromise patients' ability to function independently [bib_ref] Early physical and occupational therapy in mechanically ventilated, critically ill patients: a..., Schweickert [/bib_ref] and delay recovery. [bib_ref] RECOVER Program Investigators (Phase 1: towards RECOVER) Canadian Critical Care Trials Group...., Herridge [/bib_ref] In two of the seven RCTs evaluating weakness, it was prospectively evaluated one month after enrolment. Evaluations of neuromuscular weakness, especially in RCTs that relied on investigator identification, were unreliable. The panel therefore believed that the RCTs probably underestimated the risk of neuromuscular weakness. ## Outcomes of less importance Corticosteroids probably increase the risk of hyperglycaemia and hypernatraemia. Corticosteroids probably improve organ function at day 7 and the chance of shock reversal at day 7. ## Patient subgroups Our recommendation applies to all patients with sepsis. There was no meaningful difference in the efficacy of corticosteroids in different groups of patients including those with septic shock, pneumonia, acute respiratory distress syndrome, or other sources of sepsis, or those who were sicker. However, the absolute reduction in mortality from corticosteroids will be greater in patients with a higher risk of death. The absolute harm (such as neuromuscular weakness) will also be greater in sicker patients. The analysis of a subgroup effect showed no convincing evidence of such an effect. Based on published criteria for credible subgroup effects, [bib_ref] How to use a subgroup analysis: users' guide to the medical literature, Sun [/bib_ref] in the absence of a subgroup Several trials of corticosteroids for pneumonia or acute respiratory distress syndrome have enrolled patients who did not have sepsis; we did not consider these trials. Therefore, clinicians treating these conditions should also consider evidence and guidelines 12 applicable to patients who have pneumonia and acute respiratory distress syndrome. ## Patient values and preferences Fully informed patients who place a higher value on avoiding death than on quality of life and function would be more likely to choose to receive corticosteroids. We heard from our patient partners that most patients will want to reduce their risk of death, even if this reduction is small and uncertain. This view is consistent with the experiences of the rest of the panel. Most patients will likely be willing to accept a small increased risk of weakness. Patients (or their care givers and surrogate decisionmakers) will probably vary in how they would weigh the balance of expected desirable and undesirable consequences from corticosteroids. We assume that most patients want to avoid death and will value even a small, uncertain reduction in mortality. We judge that they will be less concerned about the possible increase in weakness among survivors. There is also likely to be a sizeable minority of patients who would place a large value on avoiding a very uncertain but possible decline in quality of life and functional abilities even at the cost of a small increase in risk of death. [bib_ref] Understanding patient-centredness: contrasting expert versus patient perspectives on vasopressor therapy for shock, Lamontagne [/bib_ref] Shared decision making conversations about specific interventions in patients with sepsis may not always be feasible, and could delay care. However, clinicians should do their best to elicit each patient's values and preferences. For example, they could talk about the patient's goals of care with the patient, their family, and friends. [fig_ref] Fig 3 \|: Practical issues about use of corticosteroids for treatment of sepsis on 30... [/fig_ref] outlines the key practical issues for patients and clinicians discussing corticosteroid treatment for sepsis. ## Practical considerations The optimal corticosteroid drug, dose, and duration of treatment are uncertain. Hydrocortisone was the most commonly used corticosteroid in the RCTs and is therefore a reasonable choice. Differences among corticosteroids, if they do exist, are probably small; dexamethasone, methylprednisolone, and prednisolone were also studied and produced similar results. Adding an agent that has additional mineralocorticoid activity, such as fludrocortisone, could be helpful, but that is highly speculative. The typical hydrocortisone dose for an adult in the RCTs was 200-300 mg/day, given either as an infusion or as boluses every six hours. [bib_ref] Effect of mode of hydrocortisone administration on glycemic control in patients with..., Loisa [/bib_ref] If an infusion is chosen, a bolus of 50-100 mg can be given before the infusion. In the RCTs the duration of treatment was typically 7-14 days, or less for those who were rapidly improving. Inflammation may recur after discontinuing corticosteroid therapy, 27 especially when it is stopped abruptly. 28 Clinicians should carefully monitor all patients after discontinuing corticosteroids. In patients who deteriorate after stopping corticosteroids (such as development of shock or need for mechanical ventilation), reinitiating corticosteroid therapy could be helpful, although this is highly speculative. Whether corticosteroids should be tapered rather than stopped abruptly is unclear. Corticosteroid induced adrenal suppression is probably duration dependent, and so patients who receive longer courses of corticosteroids (such as >14 days) might be particularly likely to benefit from a taper before discontinuing and an evaluation of hypothalamo-pituitary-adrenal axis function if in doubt. [bib_ref] Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI)..., Annane [/bib_ref] ## How this recommendation was created Our international panel included sepsis survivors, family caregivers of patients who had sepsis, intensivists, internists, nurses, an endocrinologist, physiotherapists, trialists, and methodologists (see appendix 1 on bmj.com). They decided on the scope of the recommendation and the outcomes that are most important to patients. The panel judged death and quality of life to be the most important outcomes. Myocardial infarction, stroke, duration of stay in hospital and in the intensive care unit (ICU), superinfections, and neuromuscular weakness (such as ICU-acquired weakness) were also identified as important outcomes for patients. Surrogate outcomes such as time to shock reversal, organ dysfunction measured by the sepsis-related organ failure assessment (SOFA) score, hyperglycaemia, and hypernatraemia were less important to the panel. This view is consistent with GRADE recommendations to focus on patient-important outcomes rather than surrogates. [bib_ref] GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes, Guyatt [/bib_ref] Subgroups of interest-The panel wanted to know whether the effect of corticosteroids differed in people with sepsis, compared with people who had septic shock, pneumonia, acute respiratory distress syndrome, or were at higher risk of death. They also wanted to know whether the type of corticosteroid or its dose influenced outcomes. The panel met by videoconference to discuss the evidence and formulate a recommendation. No panel member had financial conflicts of interest; intellectual and professional conflicts were minimised and managed (see appendix 2 on bmj.com). The panel requested a systematic review of randomised controlled trials on the impact of corticosteroid therapy for patients who have sepsis, including those who have septic shock. [bib_ref] Corticosteroids in sepsis: an updated systematic review and meta-analysis, Rochwerg [/bib_ref] This review examines the two latest, as well as previous studies, on corticosteroids in sepsis. The aim was to resolve apparently conflicting evidence. The panel followed the BMJ Rapid Recommendations procedures for creating a trustworthy recommendation, [bib_ref] Introduction to BMJ Rapid Recommendations, Siemieniuk [/bib_ref] including using the GRADE approach to critically appraise the evidence and create recommendations (see appendix 3 on bmj.com). [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] The panel considered the balance of benefits, harms, and burdens of corticosteroids, the quality of the evidence for each outcome, expected variations in patient values and preferences, and acceptability of corticosteroids. [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref] Determining patient values and preferences occurred before the panel received the results of the meta-analysis to reduce the risk that opinions regarding outcome importance will be data driven. According to the GRADE approach, recommendations can be strong or weak and for or against a course of action. [bib_ref] GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction..., Andrews [/bib_ref] High quality evidence of an effect on surrogate outcomes do not trigger strong recommendations. ## Costs Corticosteroids are typically inexpensive and widely available. The impact of corticosteroids on the overall costs to patients and to health systems is uncertain and would be driven mostly by ICU and hospital lengths of stay or prolonged periods of rehabilitation. # Future research With the exception of the awaited analysis of quality of life in the ADRENAL trial, there are currently no planned or ongoing RCTs in patients who have sepsis that are likely to substantively change the overall effect estimates for the key outcomes. Given remaining u ncertainty regarding the effect of corticosteroids in different subgroups, additional analyses of existing data to explore heterogeneity of treatment effects are logical next steps before more patients are enrolled in similar trials. Such work mandates individual patient-data meta-analyses that rely on investigators sharing the data from their RCTs and cooperation among research networks. It is possible that additional adaptive RCTs could help to resolve remaining uncertainty. Key research questions to inform decision makers and future guidelines are: - What is the impact of corticosteroid therapy on quality of life in the short and long term? - What is the impact of corticosteroid therapy on functional recovery? - What is the impact of corticosteroid therapy on healthcare costs? - Are there subgroups of patients with sepsis who benefit more or less from corticosteroid therapy? - Are there differences between bolus and infusion dosing? - Does the addition of fludrocortisone improve outcomes? ## Updates to this article The final table shows evidence that has emerged since the publication of this article. As new evidence is published, a group will assess the new evidence and make a judgment on to what extent it is expected to alter the recommendation. Competing interests: All authors have completed the BMJ Rapid Recommendations interests disclosure form, and a detailed description of all disclosures is reported in appendix 2 on bmj.com. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions. Funding: This guideline was not funded. Transparency: R A C Siemieniuk affirms that the manuscript is an honest, accurate, and transparent account of the recommendation being reported; that no important aspects of the recommendation have been omitted; and that any discrepancies from the recommendation as planned (and, if relevant, registered) have been explained. [fig] Fig 2 \|: Characteristics of patients and trials included in systematic review of the use of corticosteroids for treating sepsis 3 CAP = community acquired pneumonia. ARDS = acute respiratory distress syndrome. [/fig] [fig] Fig 3 \|: Practical issues about use of corticosteroids for treatment of sepsis on 30 July 2022 by guest. Protected by copyright. http://www.bmj.com/ BMJ: first published as 10.1136/bmj.k3284 on 10 August 2018. Downloaded from [/fig] [table] 8: They require vasopressors to maintain perfusion pressure and have elevated serum lactate concentrations despite adequate fluid repletion. WHAT YOU NEED TO KNOW • Sepsis is a syndrome of life threatening infection with organ dysfunction, and most guidelines do not advise use of corticosteroids to treat it in the absence of refractory shock • Two new trials of corticosteroid treatment for sepsis came to differing conclusions • Corticosteroids may reduce the risk of death by a small amount and increase neuromuscular weakness by a small amount, but the evidence is not definitive • This guideline makes a weak recommendation for corticosteroids in patients with sepsis; both steroids and no steroids are reasonable management options • Fully informed patients who value avoiding death over quality of life and function would likely choose corticosteroids Cite this as: BMJ 2018;362:k3284 doi: 10.1136/bmj.k3284This BMJ Rapid Recommendation article is one of a series that provides clinicians with trustworthy recommendations for potentially practice changing evidence. BMJ Rapid Recommendations represent a collaborative effort between the MAGIC group (http:// magicproject.org/) and The BMJ. A summary is offered here and the full version including decision aids is on the MAGICapp (https://app.magicapp.org), for all devices in multilayered formats. Those reading and using these recommendations should consider individual patient circumstances, and their values and preferences and may want to use consultation decision aids in MAGICapp to facilitate shared decision making with patients. We encourage adaptation and contextualisation of our recommendations to local or other contexts. Those considering use or adaptation of content may go to MAGICapp to link or extract its content or contact The BMJ for permission to reuse content in this article. articles in the BMJ Rapid Recommendation cluster [/table] [table] Table 1 \|: Sepsis-related organ failure assessment (SOFA) score to help diagnose sepsis (adapted from Vincent et al 5 )* [/table] [table] Table 2 \|: Current recommendations for corticosteroid therapy in patients with sepsis SCCM = Society of Critical Care Medicine. ESICM = European Society for Intensive Care Medicine. CIRCI = critical illness-related corticosteroid insufficiency. CAEP = Canadian Association of Emergency Physicians. NICE = National Institute for Health and Care Excellence (UK). JSICM = Japanese Society for Intensive Care Medicine. [/table]	None	https://www.bmj.com/content/bmj/362/bmj.k3284.full.pdf	### What you need to know Do corticosteroids reduce death or improve recovery in people with sepsis or septic shock? Our panel make a weak recommendation to give corticosteroids to people with all types and severity of sepsis, based on new evidence. Because we are not certain that they are beneficial, it is also reasonable not to prescribe them. Patients’ values and preferences may guide this decision-making process. This rapid recommendation was triggered by two trials, with differing conclusions whose results might change practice: The trials are incorporated into a linked systematic review comparing corticosteroids with placebo.3 This BMJ Rapid Recommendation promptly and transparently translates this evidence using GRADE methodology for trustworthy guidelines. Sepsis is a life threatening organ dysfunction from infection. Currently most guidelines advise against giving corticosteroids in sepsis in the absence of refractory shock, but these guidelines have not taken into account the new evidence. We do not anticipate that new clinical trials will substantively alter the evidence …
9161821b6de7e78b8eea86de71c99d1c5163ccaf	pubmed	JPN Guidelines for the management of acute pancreatitis: severity assessment of acute pancreatitis	JPN Guidelines for the management of acute pancreatitis: severity assessment of acute pancreatitis Key words Severity assessment · Acute pancreatitis · JPN score · APACHE II score Clinical questions CQ1. Is severity assessment necessary in the management of acute pancreatitis? CQ2. Are severity scoring systems (JPN score, Acute Physiology and Chronic Health Evaluation [APACHE] II score) useful for assessing the severity of acute pancreatitis? CQ3. Are clinical symptoms and signs useful for severity assessment of acute pancreatitis? CQ4. Are blood tests useful for severity assessment of acute pancreatitis? CQ5. Is diagnostic imaging useful for severity assessment of acute pancreatitis? CQ6. What are the indications for transferring patients with acute pancreatitis to a specialist unit?AbstractThis article addresses the criteria for severity assessment and the severity scoring system of the Ministry of Health and Welfare of Japan; now the Japanese Ministry of Health, Labour, and Welfare (the JPN score). It also presents data comparing the JPN score with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Ranson score, which are the major measuring scales used in the United States and Europe. The goal of investigating these scoring systems is the achievement of earlier diagnosis and more appropriate and successful treatment of severe or moderate acute pancreatitis, which has a high mortality rate. This article makes the following recommendations in terms of assessing the severity of acute pancreatitis:(1) Severity assessment is indispensable to the selection of proper initial treatment in the management of acute pancreatitis (Recommendation A). (2) Assessment by a severity scoring system (JPN score, APACHE II score) is important for determining treatment policy and identifying the need for transfer to a specialist unit (Recommendation A).(3) C-reactive protein (CRP) is a useful indicator for assessing severity (Recommendation A). (4) Contrast-enhanced computed tomography (CT) scanning and contrast-enhanced magnetic resonance imaging (MRI) play an important role in severity assessment (Recommendation A). (5) A JPN score of 2 or more (severe acute pancreatitis) has been established as the criterion for hospital transfer (Recommendation A). (6) It is preferable to transfer patients with severe acute pancreatitis to a specialist medical institution where they can receive continuous monitoring and systemic management. # Introduction There is wide variation in the severity of acute pancreatitis. Mild acute pancreatitis tends towards spontaneous remission, but once acute pancreatitis becomes severe, there is a great risk of death from fatal complications, such as circulatory failure, vital organ failure, and infection. Because acute pancreatitis, although benign, has a poor prognosis, it has been designated as an intractable disease by the Japanese Ministry of Health, Labour, and Welfare. To improve prognosis, it is important to assess accurately the severity of the disease in order to select proper initial treatment. Thus, accurate severity assessment and determination of a proper disease management policy are crucial. The severity scoring system most widely used in Japan (JPN score) allows sequential scoring of severity and is useful for the selection of proper initial treatment. The JPN scoring system is based on clinical signs, blood test data, and imaging findings, and it is used to decide on the treatment strategy. Because acute pancreatitis that is initially diagnosed as mild or moderate can progress to severe, or become fatal, during treatment, even mild acute pancreatitis should be continuously monitored with the greatest care. Serial assessments of severity should be performed as early as possible to detect signs of a poor outcome. This article reviews the JPN score, various severity evaluation systems used in the United States and Europe, and severity assessment methods that are based on clinical signs and blood tests. Practical recommendations were also graded according to suggestions in previous reports. [bib_ref] Evidence-baced clinical practice guidelines for acute pancreatitis: proposals, Mayumi [/bib_ref] [bib_ref] Guide to development of practice guidelines, Kish [/bib_ref] Necessity for severity assessment Clinical question (CQ) 1. Is severity assessment necessary in the management of acute pancreatitis? ## Severity assessment is essential to the selection of appropriate initial treatment. even acute pancreatitis that is initially diagnosed as mild or moderate may quickly progress to severe, and continuous assessment is required, particularly during the first 3 days after onset (recommendation a) To improve the survival rate in patients with acute pancreatitis, severity assessment during the initial examination is extremely important to ensure the quick and accurate diagnosis of severe cases (which have a high mortality rate), to commence appropriate initial treatment, and, if necessary, to transfer the patient to an advanced specialist medical institution. Because quite a few cases initially diagnosed as mild acute pancreatitis may progress to severe acute pancreatitis, serial assessments of severity should be performed. It is also impor-tant to monitor the effects of treatment by serial assessments of severity. When deciding on an appropriate system of criteria to assess the severity of pancreatitis, it is important to establish whether the assessment (1) depends on an examination method that is available at most medical institutions, [bib_ref] Guide to development of practice guidelines, Kish [/bib_ref] can be used to assess severity shortly after admission to the hospital, and (3) can be used to monitor the course of the disease, and can be preformed repeatedly. ## Severity scores CQ2. Are severity scoring systems (JPN score, Acute Physiology and Chronic Health Evaluation [APACHE] II score) useful for assessing the severity of acute pancreatitis? ## Assessment by a severity scoring system is important when deciding on treatment policy and the need for transfer to a specialist unit. use of the jpn score is recommended for severity assessment in japan (recommendation a) ## Historical progress Because acute pancreatitis is manifested by a wide range of clinical signs, it is difficult to evaluate those signs objectively as parameters for severity assessment. With this feature in mind, severity assessment criteria, in the form of the Ranson score, were proposed in 1974 in the United States. Of 43 total criteria, Ranson et al. [bib_ref] Prognostic signs and the role of operative management in acute pancreatitis, Ranson [/bib_ref] selected those 11 that showed statistical significance, consisting mainly of examination findings (Level 1b). [bib_ref] Prognostic signs and the role of operative management in acute pancreatitis, Ranson [/bib_ref] The criteria were not suitable for patients with gallstone pancreatitis and so were evaluated only for patient groups containing a higher percentage of patients with alcoholic pancreatitis; subsequently, in 1982, new separate assessment criteria, classified according to gallstone, alcoholic, and other types of pancreatitis, were prepared (the Ranson score will be detailed later). [bib_ref] Etiological and prognostic factors in human acute pancreatitis: a review, Ranson [/bib_ref] In 1978, 9 severity assessment criteria, comprised mainly of examination findings, were developed in the United Kingdom (Level 1b). [bib_ref] A single-centre double-blind trial of Trasylol therapy in primary acute pancreatitis, Imrie [/bib_ref] After two revisions, 6,7 these criteria are currently being used as the Glasgow score. These two sets of severity assessment criteria (i.e., the revised Rarson score 4 and the Glasgow score 6,7 ) are used widely throughout the world. The scoring system of Bank et al. [bib_ref] Risk factors in acute pancreatitis, Bank [/bib_ref] which uses clinical symptoms as important criteria, is also used. In 1964, [bib_ref] Die konservative Behandlung der Pankreaserkrankungen, Forell [/bib_ref] in Germany, reported clinical and examination items that he considered indicative of severe pancreatitis, and Damman et al. [bib_ref] Die Beurteilung der Fruhprognose der akuten Pankreatitis, Dammann [/bib_ref] reported assessment criteria consisting of eight indicators in 1981. In Japan, assessment criteria consisting of symptoms and blood tests and computed tomography (CT) scan findings were developed in 1990 by the then Research Committee for Intractable Diseases of the Pancreas, which was sponsored by the then Japanese Ministry of Health and Welfare, and these criteria have been applied clinically. In 1998, the severity scoring system (JPN score) was developed and the 2002 version 11 is summarized in [fig_ref] Table 1: Standardized criteria for severity grading of acute pancreatitis A [/fig_ref]. For a long time, various severity assessment criteria were based on the analysis of clinical data, but they have now been modified to take into account the etiology, the age and sex of the patient, examination and treatment methods, and all other applicable factors. In 1981, the APACHE score was developed as a method for assessing the severity of acute diseases from the standpoint of emergency treatment. The APACHE II score (see below), renamed after modification in 1985, 12 enjoys a good reputation as a tool for assessing the severity of acute pancreatitis. ## Evaluation of severity scores Ranson score and Glasgow score The Ranson and Glasgow scoring systems are based mainly on examination findings and have a sensitivity of between 70% and 80% for predicting a poor outcome (Levels 1b-2b). [bib_ref] Prognostic signs and the role of operative management in acute pancreatitis, Ranson [/bib_ref] [bib_ref] Etiological and prognostic factors in human acute pancreatitis: a review, Ranson [/bib_ref] [bib_ref] Prognostic factors in acute pancreatitis, Blamey [/bib_ref] [bib_ref] Prognostic signs and nonoperative peritoneal lavage in acute pancreatitis, Ranson [/bib_ref] [bib_ref] Comparison of three Glasgow multifactor prognostic scoring systems in acute pancreatitis, Leese [/bib_ref] Metaanalysis (prediction of a poor outcome) suggested that the Ranson and Glasgow scores were almost equal as assessment criteria, but neither of them were satisfactory (Level 1a). 14,15 Both require 48 h to complete assessments. ## Apache ii score The APACHE II score is based on 12-item findings in the medical examination, plus the presence of chronic complications and age; it is considered to be a useful tool for assessing severity in 24 h (Levels 2a-2b). [bib_ref] Assessment of severity and prognosis in acute pancreatitis, Larvin [/bib_ref] [bib_ref] Prediction of outcome in acute pancreatitis: a comparative study of APACHE II,..., Wilson [/bib_ref] Daily scoring enables monitoring of the course of pancreatitis. The Atlanta Symposium in 1992 18 concluded that a score of 8 or more indicated severe pancreatitis, while the Santorini Consensus Conference, in 1999, [bib_ref] Diagnosis, objective assessment of severity, and management of acute pancreatitis, Dervenis [/bib_ref] concluded that a score of 6 or more indicated severe pancreatitis; both gatherings rated the APACHE II score as the best assessment tool, because the results can be obtained so quickly. The British Society of suggests that the APACHE II score is useful for early diagnosis and monitoring of the clinical course, citing a report (Level 2a) [bib_ref] Prediction of outcome in acute pancreatitis: a comparative study of APACHE II,..., Wilson [/bib_ref] stating that Standardized criteria Severe, If at least one item in prognostic factor I is present, or if more than two items in prognostic factor II are present, the case is considered severe. Moderate, if none of the items in prognostic factor I and only one item in prognostic factor II is present, the case is considered moderate. Mild, if none of the items in prognostic factor I or II are present, the case is considered mild Severity score The sum of the points for the positive prognostic factors is defined as the severity score Data are from reference 9 a If diffuse, uneven density is present in the pancreatic parenchyma, or if extrapancreatic inflammatory changes extend away from the pancreas, the case is considered as Grade IV or Grade V on CT when an APACHE II score of 6 or more is used as a criterion for severe disease, the positive predictive value is 40% (sensitivity, 95%). JPN score [fig_ref] Table 1: Standardized criteria for severity grading of acute pancreatitis A [/fig_ref] [bib_ref] Development and use of a new staging system for severe acute pancreatitis..., Ogawa [/bib_ref] The criteria for the JPN score were developed based on an analysis of the results of nationwide surveillance. Five clinical sign items, ten blood test items, CT findings, the presence of systemic inflammatory response syndrome (SIRS), and age were all scored as prognostic factors. The highest possible total score is 27, and severity is classified into five stages (Stages 0 to 4). [bib_ref] Development and use of a new staging system for severe acute pancreatitis..., Ogawa [/bib_ref] Examination of about 1100 patients showed that the scores were correlated with outcome (Level 3b). [bib_ref] Mortality and deterioration factors of acute pancreatitis -the multicenter analysis of death..., Otsuki [/bib_ref] Examination of the results of a nationwide survey of 1240 patients conducted between 1995 and 1998 showed that the JPN score had almost the same value for assessment as the APACHE II score and the Ranson score (Level 3b).However, because the currently used severity assessment criteria involve too many evaluation items and it is difficult to interpret data obtained during oxygen administration or transfusion, new severity assessment criteria, based on nine evaluation items, are now being developed. ## Clinical symptoms and signs ## Cq3. are clinical symptoms and signs useful for severity assessment of acute pancreatitis? ## Because acute pancreatitis is manifested by a wide range of clinical signs, it is difficult to evaluate them objectively as parameters for use in severity assessment. Patients exhibiting manifestations of vital organ failure, such as shock, psychoneurotic symptoms, and abdominal distention (ileus, ascites), are assessed as having severe acute pancreatits, and these manifestations have been used as parameters for reported severity assessment criteria. [bib_ref] A single-centre double-blind trial of Trasylol therapy in primary acute pancreatitis, Imrie [/bib_ref] [bib_ref] Risk factors in acute pancreatitis, Bank [/bib_ref] [bib_ref] Die konservative Behandlung der Pankreaserkrankungen, Forell [/bib_ref] Five conditions -shock, dyspnea, neurotic symptoms, severe infection, and bleeding tendency (including that manifested by Grey-Turner's sign and Cullen's sign) -are considered to be associated with a prognosis for survival. [bib_ref] Development and use of a new staging system for severe acute pancreatitis..., Ogawa [/bib_ref] Analysis of different severity assessment criteria has revealed that criteria based on clinical findings have a sensitivity of 54.7%, a specificity of 93.0%, and a positive predictive value of 59.2%, while criteria based on examination findings have a sensitivity of 69.3%, a specificity of 79.5%, and a positive predictive value of 77.1% (Level 1a). [bib_ref] Discriminant power and information content of Ranson's prognostic signs in acute pancreatitis:..., Bernardinis [/bib_ref] This suggests that clinical findings alone are not reliable for severity assessment, and that further investigation is required, because both clinical and examination findings have advantages and disadvantages. Abdominal findings in the form of color marks on the skin, e.g., Grey-Turner's sign, Cullen's sign, and Fox's sign, are indicative of a poor outcome and high mortality, 23,24 but they do not necessarily reflect severity. [bib_ref] Diagnosis, objective assessment of severity, and management of acute pancreatitis, Dervenis [/bib_ref] The value of the color marks for severity assessment remains obscure, and, because they often appear 48 to 72 h after the onset of pancreatitis, their significance as an early predictor of poor outcome is low. The 1992 Atlanta Symposium, [bib_ref] A clinically based classification system for acute pancreatitis, Bradley [/bib_ref] an international conference that examined severity assessment of acute pancreatitis, suggested that clinical organ failure (respiration, circulatory, and kidney failure) was an indicator of severe pancreatitis, while the guidelines of the British Society of Gastroenterology 20 state that clinical assessment alone is unreliable and will misclassify around 50% of patients (Level 2b). [bib_ref] Prediction of severity in acute pancreatitis: prospective comparison of three prognostic indices, Corfield [/bib_ref] The Santorini Consensus Conference in 1999 [bib_ref] Diagnosis, objective assessment of severity, and management of acute pancreatitis, Dervenis [/bib_ref] suggested that skin findings such as Grey-Turner's sign and Cullen's sign were signs of severity. ## Severity assessment based on blood tests ## Cq4. are blood tests useful for severity assessment of acute pancreatitis? ## Serum c-reactive protein (crp) values ## Serum crp values are useful for severity assessment, but they may not reflect severity within the first 48 h after onset (recommendation a) Serum CRP values are a sensitive predictor of the progression of severity from moderate to severe. The time of measurement and the CRP values vary with different investigations and researchers. In one report, the cutoff value within the first 48 h of onset was greater than 30 mg/dl (Level 1c), [bib_ref] Inflammatory response in the early prediction of severity in human acute pancreatitis, Viedma [/bib_ref] whereas it was greater than 15 mg/dl in other reports (Level 2b). [bib_ref] Serum interleukin-6, interleukin-8, and beta 2-microglobulin in early assessment of severity of..., Pezzilli [/bib_ref] [bib_ref] Changes in plasma levels of acute phase proteins in pancreatitis, Uchikov [/bib_ref] The Santorini Consensus Conference in 1999 19 recommended a cutoff value of greater than 15 mg/dl. There is one report that shows the peak CRP in patients with severe cases at more than ten times above normal (less than five times above normal in mild cases; P < 0.001; Level 2b), [bib_ref] C-reactive protein, antiproteases and complement factors as objective markers of severity in..., Wilson [/bib_ref] and another report has suggested that peak CRP greater than 21 mg/dl within the first 4 days after onset (greater than 12 mg/dl after 7 days) can be used as a predictor of progression to severity, with a sensitivity of about 80% (Level 2b). [bib_ref] Prospective comparison of C-reactive protein level, Ranson score and contrast-enhanced computed tomography..., Vesentini [/bib_ref] Still another report (Level 1c) [bib_ref] Inflammatory response in the early prediction of severity in human acute pancreatitis, Viedma [/bib_ref] shows that combining CRP with other diagnostic criteria further improves sensitivity. However, it should be noted that the CRP values may not reflect severity before 48 h after onset. There is a report (Level 2b) [bib_ref] High, not low, amylase and lipase levels indicate severe acute pancreatitis!, Lankisch [/bib_ref] stating that CRP values are correlated with the CT severity index (Level 1c) [bib_ref] Acute pancreatitis: value of CT in establishing prognosis, Balthazar [/bib_ref] when the maximum CRP (within 72 h of onset) is greater than ten times the normal value. CRP values are of little use as a diagnostic indication for infected pancreatic necrosis, but if CRP measured on admission is greater than 8.5 mg/dl, sepsis can be diagnosed with a sensitivity of 100%, a specificity of 53%, a positive predictive value of 50%, and a true positive rate of 68% (Level 1b). [bib_ref] Prospective comparison of C-reactive protein level, Ranson score and contrast-enhanced computed tomography..., Vesentini [/bib_ref] This suggests that CT should be used for the diagnosis of infected pancreatic necrosis (true positive rate, 81%). ## Hematocrit (hct) Hemoconcentration caused by dehydration is a predictor of pancreatic necrosis and organ failure (Level 2b). [bib_ref] Hemoconcentration is an early marker for organ failure and necrotizing pancreatitis, Brown [/bib_ref] [bib_ref] Hemoconcentration as an early risk factor for necrotizing pancreatitis, Baillargeon [/bib_ref] If the Hct on admission is 47% or more, or if no improvement is observed within the first 24 h, there is a strong possibility that pancreatic necrosis has begun (sensitivity, 81%; specificity, 88%). 34 ## Serum phospholipase a 2 (pla 2 ) The serum PLA 2 level in severe pancreatitis is already significantly higher on the day of onset than it is in moderate pancreatitis, and the degree of elevation is much greater than the degree of amylase elevation or the degree of trypsin elevation (Level 2b). [bib_ref] Usefulness of determination of serum immunoreactive pancreatic phospholipase A 2 content for..., Matsuda [/bib_ref] Type IB secretory PLA 2 (sPLA 2 ) (a digestive enzyme present in pancreatic juice) and type IIA sPLA 2 (produced by various cells in response to inflammatory stimuli) are both low-molecular-weight PLA 2 , while cytosolic PLA 2 (cPLA 2 ) (contained in the cytoplasm and involved in arachidonic acid metabolism) is a high-molecularweight PLA 2 ; all have been identified as isoenzymes. The serum type II (IIA) PLA 2 level is markedly elevated in patients with severe acute pancreatitis (Level 3b). [bib_ref] Pancreatic and synovial type phospholipases A 2 in serum samples from patients..., Nevalainen [/bib_ref] SIRS-positive patients have significantly higher PLA 2 levels (Level 2b), [bib_ref] Extracellular phospholipases A 2 in relation to systemic inflammatory response syndrome (SIRS)..., Hietaranta [/bib_ref] and the PLA 2 level is even higher in patients with more SIRS-positive items (Level 2b). [bib_ref] Extracellular phospholipases A 2 in relation to systemic inflammatory response syndrome (SIRS)..., Hietaranta [/bib_ref] Increases in the PLA 2 level are considered to be evidence of systemic inflammation leading to multiple organ failure. However, no significant association between serum PLA 2 values and severity or mortality has been demonstrated. ## Diagnostic imaging ## Cq5. is diagnostic imaging useful for severity assessment of acute pancreatitis? ## The presence and range of pancreatic necrosis and the extent of inflammatory change are correlated with severity. accurate diagnosis of the presence and range of pancreatic necrosis requires contrast-enhanced ct or contrast-enhanced magnetic resonance imaging (mri). however, it should be noted that the use of contrast medium may involve adverse reactions (recommendation a) ## Computed tomography (ct) It is important to diagnose accurately the presence of pancreatic necrosis and the extent of inflammatory change, both of which are closely associated with various complications and prognosis (Levels 1b-3b) [bib_ref] Changes in plasma levels of acute phase proteins in pancreatitis, Uchikov [/bib_ref] [bib_ref] Early localization of necrosis by contrast-enhanced computed tomography can predict outcome in..., Kemppainen [/bib_ref] [bib_ref] Prediction of pancreatic necrosis by dynamic pancreatography, Bradley [/bib_ref] and affect treatment policy, such as the administration of an antibacterial agent to prevent infection. Plain CT scans allow for an evaluation of peripancreatic inflammatory change, but they can not be used to diagnose pancreatic necrosis in general. Contrast-enhanced CT is required for the accurate diagnosis of the presence and range of pancreatic necrosis (Level 1c). [bib_ref] Dynamic contrastenhanced computed tomography: a precise technique for identifying and localizing pancreatic..., Larvin [/bib_ref] One report (Level 2b) [bib_ref] Contrast-enhanced dynamic computed tomography does not aggravate the clinical severity of patients..., Hwang [/bib_ref] has shown that the use of a contrast medium does not aggravate the morbidity of pancreatitis, while another (Level 2b) [bib_ref] Potential harmful effect of iodinated intravenous contrast medium on the clinical course..., Carmona-Sanchez [/bib_ref] argues that it exacerbates pancreatitis. As the contrast medium may probably aggravate kidney disorders associated with severe acute pancreatitis, contrast-enhanced CT should be used only when the value of the information obtained exceeds the disadvantages, such as impairment of renal function and allergic reactions. Contrast-enhanced CT has various other advantages besides the visualization of pancreatic necrosis. It provides useful information for evaluating the need for surgical procedures and drainage, and it visualizes pseudoaneurysms. There is also an opinion that contrast-enhanced CT should only be used when a case has been diagnosed as severe by plain CT (Level 2b). [bib_ref] Prognostic value of CT in the early assessment of patients with acute..., Casas [/bib_ref] The CT severity index (Level 2b), [bib_ref] Acute pancreatitis: value of CT in establishing prognosis, Balthazar [/bib_ref] which is based on CT findings, is also used for severity assessment. It scores severity based on a combination of the presence and extent of pancreatic necrosis and the extent of peripancreatic inflammatory change, all of which are closely associated with outcome. A modified CT severity index (Level 2b), [bib_ref] A modified CT severity index for evaluating acute pancreatitis: improved correlation with..., Mortele [/bib_ref] which simplifies the evaluation of pancreatic necrosis and inflammatory changes in and around the pancreas and evaluates the presence of extrapancreatic complications, has also been proposed. In Japan, Matsuno et al. [bib_ref] CT staging of the severity of acute pancreatitis: analysis of data collected..., Matsuno [/bib_ref] proposed a severity assessment method, using contrast-enhanced CT, from a similar standpoint, and they also reported on its usefulness (Level 2b). It is desirable to use contrast-enhanced CT in patients with a high JPN score, APACHE II score, and Ranson score (see below), and in those patients with organ failure. Contrast-enhanced CT is the most useful method for differentiating edematous from necrotizing pancreatitis (Level 1c). [bib_ref] Dynamic contrastenhanced computed tomography: a precise technique for identifying and localizing pancreatic..., Larvin [/bib_ref] A small unenhanced area on contrast-enhanced CT scans indicates edematous change in the pancreatic parenchyma. A large unenhanced area indicates pancreatic necrosis. At the Atlanta Symposium in 1992, [bib_ref] A clinically based classification system for acute pancreatitis, Bradley [/bib_ref] poorly perfused area (having an increase in density after enhancement of less than 30 Hounsfield units [Level 1c] 41 ) covering more than 30% of the pancreas or measuring 3 cm or more in diameter was defined as diagnostic evidence of pancreatic necrosis. However, recently, smaller unenhanced areas are often being evaluated as a sign of pancreatic necrosis. There is no clear criterion for distinguishing edematous changes from pancreatic necrosis in a small area. The Guidelines of the British Society of Gastroenterology 20 recommend that dynamic contrast-enhanced CT in patients with severe acute pancreatitis should be performed between the third and tenth days of hospital admission. This is based on the findings that necrosis is often not evident in the initial stage and that it is better to perform CT scanning after initial treatment. Contrast-enhanced CT between the fourth and tenth days after onset enables diagnosis of pancreatic necrosis to almost 100% accuracy . [bib_ref] Changes in plasma levels of acute phase proteins in pancreatitis, Uchikov [/bib_ref] [bib_ref] Early localization of necrosis by contrast-enhanced computed tomography can predict outcome in..., Kemppainen [/bib_ref] [bib_ref] Dynamic contrastenhanced computed tomography: a precise technique for identifying and localizing pancreatic..., Larvin [/bib_ref] [bib_ref] Rapid-bolus contrastenhanced dynamic computed tomography in acute pancreatitis: a prospective study, London [/bib_ref] However, some studies in Europe have reported that contrastenhanced CT on admission (within the first 36 to 48 h) is useful for assessing the severity of acute pancreatitis (Level 2b). [bib_ref] Prognostic value of early computed tomographic scans in severe acute pancreatitis, Rotman [/bib_ref] [bib_ref] Value of contrastenhanced computerized tomography in the early diagnosis and prognosis of..., Clavien [/bib_ref] CT is often performed on the day of admission in order to determine whether there is an indication for continuous regional arterial infusion therapy. Even after the initial examination, CT scanning needs to be applied regularly and whenever any infection or other complications are suspected. The best time to perform CT should be determined by further investigations, so as to resolve the differences in opinion between researchers in Japan, the United States, and Europe. ## Magnetic resonance imaging (mri) Contrast-enhanced MRI can be used to diagnose the presence of pancreatic necrosis and inflammatory changes in and around the pancreas, and it is also useful for assessing severity (Level 2b). [bib_ref] Visualization of the heterogeneous internal structure of so-called pancreatic necrosis by magnetic..., Hirota [/bib_ref] [bib_ref] T2-weighted and dynamic enhanced MRI in acute pancreatitis: comparison with contrast enhanced..., Ward [/bib_ref] [bib_ref] Acute pancreatitis: interobserver agreement and correlation of CT and MR cholangiopancreatography with..., Lecesne [/bib_ref] [bib_ref] Computed tomography and magnetic resonance imaging in the assessment of acute pancreatitis, Arvanitakis [/bib_ref] MRI has the advantages of (1) less nephrotoxicity of the contrast medium, (2) no X-ray exposure, (3) allowing evaluation of damage to the pancreatic duct, and (4) providing information on the biliary system. MRI is useful for identifying the etiology of acute pancreatitis and is not merely an alternative procedure for use in patients who cannot undergo CT scanning. However, MRI also has disadvantages. For example: (1) because metal objects cannot be brought into the scanning area, MRI cannot be used in patients who are on a respirator; (2) timeconsuming procedures, including the removal of transfusion pumps, must be completed before MRI can be performed; and (3) no emergency MRI system has been properly established. ## Plain x-rays of the chest and abdomen It has been reported that early pleural effusion in patients with acute pancreatitis is a sign of widespread inflammation and that pleural effusion in one or both sides of the chest is associated with a poor outcome (Level 2b). [bib_ref] Risk of death from acute pancreatitis. Role of early, simple "routine" data, Talamini [/bib_ref] [bib_ref] Ascites, pleural, and pericardial effusions in acute pancreatitis. A prospective study of..., Maringhini [/bib_ref] [bib_ref] Sign of severe acute pancreatitis, Lankisch [/bib_ref] Because ileus found by plain abdominal x-rays may be a sign of organ failure, its association with severity should be investigated in further research. ## Angiography Diagnosis of acute pancreatitis itself does not require angiography. However, in Japan, angiography is sometimes carried out in the acute phase of acute pancreatitis before the performing of continuous regional arterial infusion of protease inhibitors and antibacterial drugs. The angiographic findings may be helpful in diagnosing the severity of the disease. Arterial constriction observed by angiography suggests the presence of splanchnic ischemia of the pancreas and other intraperitoneal organs, and is correlated with severity (Level 2b). [bib_ref] Angiographic features in acute pancreatitis: the severity of abdominal vessel ischemic change..., Inoue [/bib_ref] [bib_ref] Pancreatic ischemia associated with vasospasm in the early phase of human acute..., Takeda [/bib_ref] ## Severity assessment based on other factors Obesity Obesity has been found to have a major negative impact on prognosis and the progression of severity of acute parcreatitis in the United States and Europe (Level 1a). [bib_ref] Is obesity a risk factor in acute pancreatitis? A meta-analysis, Martinez [/bib_ref] The number of patients with severe pancreatitis with abscess formation and the number of deaths are significantly higher among patients with acute pancreatitis who are obese, particularly those with a body mass index (BMI; body weight [kg] / height 2 [m 2 ]) of 30 kg/m 2 or more (Level 1c-2c). [bib_ref] Obesity: an important prognostic factor in acute pancreatitis, Funnell [/bib_ref] [bib_ref] Obesity: a prognostic factor of severity in acute pancreatitis, Martinez [/bib_ref] This is explained by local complications caused by obesity (Level 2b) [bib_ref] Is obesity a significant prognostic factor in acute pancreatitis?, Tsai [/bib_ref] and the higher probability of respiratory complications from obesity (Level 3b). [bib_ref] Obesity as a predictor of severity in acute pancreatitis, Porter [/bib_ref] ## Gastric intramucosal ph (phi) The lowering of pHi is based on the rapid reduction of circulating plasma volume at the onset of acute pancreatitis and accompanying acute circulation failure. pHi is measured with a tonometer inserted transnasally within 12 to 48 h after the onset of acute pancreatitis. A study (Level 1c) 64 of 17 patients with severe pancreatitis revealed a significantly higher mortality rate among those with the lowest pHi within the first 48 h after admission, with a pHi of 7.25 as a cutoff value (sensitivity, 100%; specificity, 77%; and positive predictive value, 82%). The number of failed organs was higher among patients with lower pHi (Level 2b). [bib_ref] Intramucosal pH and endotoxin and cytokine release in severe acute pancreatitis, Hynninen [/bib_ref] There are significant corre-lations of pHi with the serum levels of various cytokines (Level 2b), [bib_ref] Intramucosal acidosis and the inflammatory response in acute pancreatitis, Soong [/bib_ref] but pHi cannot be used to differentiate between severe and moderate cases (Level 2b). [bib_ref] Gastric tonometry in assessing splanchnic tissue perfusion in acute pancreatitis, Juvonen [/bib_ref] ## Molecular markers The blood concentrations of interleukin-6 (Level 2b), [bib_ref] Serum interleukin-6, interleukin-8, and beta 2-microglobulin in early assessment of severity of..., Pezzilli [/bib_ref] interleukin-8 (Level 2b), [bib_ref] Serum concentrations of inflammatory mediators related to organ failure in patients with..., Beaux [/bib_ref] soluble tumor necrosis factor-receptor (sTNF-R; Level 2b), 68,69 granulocyte esterase (Levels 1c-2b), [bib_ref] Inflammatory response in the early prediction of severity in human acute pancreatitis, Viedma [/bib_ref] [bib_ref] Granulocyte elastase in assessment of severity of acute pancreatitis. Comparison with acute-phase..., Gross [/bib_ref] [bib_ref] PMN-elastase in comparison with CRP, antiproteases, and LDH as indicators of necrosis..., Uhl [/bib_ref] cytochrome c (Level 2b), [bib_ref] Serum cytochrome c level as a prognostic indicator in patients with systemic..., Adachi [/bib_ref] creatine phosphokinase (CPK; Level 2b), [bib_ref] Non-occlusive mesenteric ischemia and its associated intestinal gangrene in acute pancreatitis, Hirota [/bib_ref] activation peptide of procarboxypeptidase B (CAPAP), 74,75 methemalbumin, [bib_ref] Methemalbumin in acute pancreatitis: an evaluation of its prognostic value and comparison..., Lankisch [/bib_ref] procalcitonin, 77 pancreatitis-associated protein (PAP), [bib_ref] Serum levels of pancreatitis-associated protein as indicators of the course of acute..., Iovanna [/bib_ref] ribonuclease, [bib_ref] Serum ribonuclease elevation and pancreatic necrosis in acute pancreatitis, Warshow [/bib_ref] and endothelin-1 80 all reflect the severity of acute pancreatitis. Urine trypsinogen activation peptide (TAP; Level 2b), 74,81 ascites TAP (Level 1b), [bib_ref] Trypsinogen activation peptides (TAP) concentrations in the peritoneal fluid of patients with..., Heath [/bib_ref] and urine trypsinogen-2 (Level 1b) [bib_ref] Trypsinogen-2 and trypsinogen activation peptide (TAP) in urine of patients with acute..., Lempinen [/bib_ref] are also reported to reflect the severity of pancreatitis. In view of their high sensitivity and specificity, these markers are expected to be useful in the future for assessing severity and predicting progression to a poor outcome. Elevation of blood amylase and lipase concentrations is an important factor for the diagnosis of acute pancreatitis, but it does not necessarily reflect severity. ## Transfer criteria CQ6. What are the indications for transferring patients with acute pancreatitis to a specialist unit? ## It is desirable to transfer patients with severe acute pancreatitis (jpn score of 2 or more) to a medical institution where monitoring and systemic management are available (recommendation a) Inpatient treatment is very important with acute pancreatitis. The guidelines of the British Society of Gastroenterology (1998) 20 recommend that multiple acute fluid collections, contrast-enhanced CT findings that indicate pancreatic necrosis of greater than 50%, and organ failure be used as indications for transfer to a specialist medical institution. The Santorini Consensus Conference in 1999 [bib_ref] Diagnosis, objective assessment of severity, and management of acute pancreatitis, Dervenis [/bib_ref] recommended that obesity (BMI, >30 kg/m 2 ), pleural effusion, an APACHE II score of 6, or more, an APACHE-O score ("O" stands for obesity) of 6 or more (APACHE II score + 1, if BMI is 25-30 kg/ m 2 ; or + 2, if BMI is >30 kg/m 2 ), or CRP of more than 15 mg/dl be used as indications of a severe case in which the patient needs referral to a specialist medical institution. In Japan, the JPN score 11 is widely used as the criterion for assessing the severity of acute pancreatitis, and it is desirable to transfer patients diagnosed with severe pancreatitis (based on the JPN score) to a medical institution with full-time physicians and surgeons specializ-ing in digestive diseases. Because the mortality rate for patients with a JPN score of 8 or more within the first 24 to 48 h of onset and an APACHE II score of 13 or more is significantly higher than that in patients with JPN scores of less than 8 and APACHE II scores of less than 13, such patients should be transferred to a specialist medical institution with physicians specializing in intensive care, endoscopic treatment, radiological intervention, and biliary-pancreatic surgery (advanced medical unit; Level 3b). Because acute pancreatitis diagnosed as moderate may become severe, the progress of the disease should be carefully monitored (with sufficient fluid replacement) to examine for indications for transfer to a specialist medical institution. The decision to transfer patients should be made after taking into consideration the possible effect of a long road trip on the patient's morbidity. It is desirable to transfer patients with severe acute pancreatitis (JPN score of 2 or more) to a specialist medical institution where they can receive adequate monitoring and systemic management. [table] Table 1: Standardized criteria for severity grading of acute pancreatitis A. Standardized criteria for grading the severity of acute pancreatitis [/table]	None	https://link.springer.com/content/pdf/10.1007%2Fs00534-005-1049-1.pdf	None
ea30238657bab8454771a71db3f168ccef8a08b4	pubmed	IAP Guideline on Practicing Safely During COVID-19 Era: Clinics and Small Establishments	IAP Guideline on Practicing Safely During COVID-19 Era: Clinics and Small Establishments Justification:The unprecedented COVID-19 pandemic has had a formidable impact on Indian health care. With no sight of its end as yet, various establishments including the smaller clinics and nursing homes are restarting full operations. Hence, there is the need for recommendations to allow safe practice ensuring the safety of both the heath care worker (HCW) and patients. Process: Indian Academy of Pediatrics organized an online meeting of subject experts on 27 July, 2020. A committee was formed comprising of pediatricians, pediatric and neonatal intensivists, and hospital administrators. The committee held deliberations (online and via emails) and a final consensus was reached by November, 2020. Objectives: To develop recommendations to provide a safe and practical healthcare facility at clinics and small establishments during COVID times. Recommendations: The key recommendation to practise safely in this setting are enumerated. Firstly, organizing the out-patient department (OPD). Secondly, appropriate personal protective equipment (PPE) to provide protection to the individual. Thirdly, decontamination/disinfection of various common surfaces and equipment to prevent transmission of infection from fomites. Next, maintaining the heating ventilation and air conditioning (HVAC) to provide a stress-free, comfortable, and safe environment for patients and HCWs. Finally, steps to effectively manage COVID-19 exposures in a non-COVID-19 facility. All these measures will ensure safe practice during these unprecedent times in clinics and smaller establishments. ## R r r r r e e e e e c c c c c o o o o o m m m m m m m m m m e e e e e n n n n n d d d d d a a a a a t t t t t i i i i i o o o o o n n n n n s s s s s T he healthcare industry not only bears the brunt of the coronavirus disease (COVID-19) epidemic, but has also to mitigate its spread too. In this regard, putting strict practices and processes in place that are suitable to the local needs and resources will be paramount in fighting this disease effectively. The Indian Academy of Paediatrics (IAP) has therefore come out with the following guidelines on practicing safely in clinics and small establishments during these unprecedented times. ## Objectives To develop recommendations to provide a safe and practical health care facility at clinics and small establishments during COVID times, and to ensure safety of the healthcare workers (HCW), and patients at clinics and small establishments. ## Process The Indian Academy of Pediatrics organized an online meeting of subject experts on 27 July, 2020. A committee was formed comprising of pediatricians, pediatric and neonatal intensivists, and hospital administrators. The committee held various deliberations (online and via emails) and a final consensus was reached by November, 2020. ## Recommendations The guidelines are applicable for clinics, polyclinics, and level 1 hospitals. A clinic is defined as a clinical establishment providing examination, consultation, and prescription to outpatients, including dispensing medicines by a single doctor, general practitioner, specialist, or a super-specialist doctor. A polyclinic is similar but managed by more than one doctor, VOLUME 58 __ APRIL 15, 2021 INDIAN ACADEMY OF PEDIATRICS PRACTISING SAFELY DURING COVID-19 general practitioner, specialist, or a super-specialist doctor.A Level 1 (A) hospital is a general medical service with an indoor admission facility, provided by recognized allopathic medical graduate(s) and may also include general dentistry services offered by recognized BDS graduates. Example: Primary Health Care Centre (PHC), government and private hospitals, and nursing homes run by MBBS doctors. A Level 1 (B) hospital shall include all the general medical services provided at level 1(A) and indoor and OPD specialist medical services provided by doctors from one or more basic specialties, namely general medicine, general surgery, pediatrics, obstetrics and gynecology, and dentistry.The guideline will be discussed under these broad subheadings ## Patient Segregation -It is prudent to cohort children who are ill from the well-baby visits. Many clinics are operated only by the practicing doctor. However, it is recommended to have a helper who will assist in triaging, maintaining decorum, and educating patients. Preferably an initial screening should be followed by separation of those suspected of COVID-19 from others. These cases should not spend time in the waiting area and should be seen immediately. A separate entry, consultation place & exit, if feasible, will help.As not all clinics have the facilities mentioned above, alternate precautions should be followed: - Telephonic triaging and schedule appointments for all suspect cases after routine OPD- Exclusive days should be allotted for 'Well baby' & Immunization checks once or twice a week. This may even boost parents' morale who otherwise would be scared to come to clinics for vaccinations.. Patient Education and Awareness -All patients should follow respiratory hygiene and cough etiquette. Patients should be provided with tissues, contactless bins, contactless sanitizers, and wash areas. Display these instructions in prominent locations. Patient education is also the physician's responsibility, hence putting educative posters, multimedia information at strategic points is useful.7. One Attendant and Personal Protection -Allow only one parent or guardian with the child.Everybody, including children above two years, should wear a mask. 8. Well Ventilated -Follow the ventilation guidelines provided in this document. [bib_ref] Comparative accuracy testing of non-contact infrared thermometers and temporal artery thermometers in..., Khan [/bib_ref]. Avoid Fomites -Remove toys, magazines, and any items that are likely to be shared between patients in the waiting area or consultation chambers.10. Novel Techniques -Innovative methods have been tried by various doctors and can be utilized. - Using transparent physical barriers between the patient and doctors can help in decreasing direct exposure to droplets. - Virtual detailed video interaction followed by a rapid, focused examination of the patient in another chamber minimizes the patient contact time. - Non-Contact Thermal scanners-These are convenient non-contact devices ideally suited for mass screening in a pandemic and have wide acceptability. However, they lack robust evidence. A recent systematic review VOLUME 58 __ APRIL 15, 2021 [formula] INDIAN ACADEMY OF PEDIATRICS PRACTISING SAFELY DURING COVID-19 [/formula] showed reasonable diagnostic accuracy in fever detection but may vary with patient characteristics, setting, index test, and the reference standard used. These have an excellent negative predictive value. [bib_ref] Comparative accuracy testing of non-contact infrared thermometers and temporal artery thermometers in..., Khan [/bib_ref] However, there are more recent studies doubting its accuracy during screening in a pandemic.Hence, no specific recommendations are available for or against the use of these devices. ## Personal protective equipment [11] PPE, along with other measures like engineering and administrative protocols, reduces the exposure of HCW to infectious agents, including the SARV-CoV2 virus. HCW has 11-fold higher chances of getting infected with the SARS-CoV2 virus than the general population. The use of PPE can reduce that risk by 60-80% when exposed to COVID-19 suspected or proven cases. Various components of PPE and its benefits are given in [fig_ref] Table I: Decontamination and Disinfection GuideCare of Mop -Clean with hot water and detergent... [/fig_ref]. ## Donning and doffing ppe An essential part of PPE is the proper way of putting it on (Donning) and removing (Doffing) as the maximum chances of contamination and infection occur during doffing. The steps and sequence of donning and doffing of N-95 masks and PPE are given in [fig_ref] Table I: Decontamination and Disinfection GuideCare of Mop -Clean with hot water and detergent... [/fig_ref]. All PPE components, especially face masks are effective only when used in combination with frequent hand hygiene. ## Type of exposure and use of ppe for hcw Every patient should be taken as a COVID-19 suspect unless proven otherwise. Appropriate PPE should be universally worn when attending to any patient, even in a non-COVID-19 centre. - In non-aerosol generation areas -head cap, face mask, goggles, and gloves. - For aerosol generation areas and procedures -In addition, wear body gowns, shoe cover, and face shield. - While attending a proven COVID-19 patient -Full Hazmat suit PPE. - Nonmedical staff not in direct contact with patientstriple-layer surgical masks and gloves inside the clinic. They must maintain physical distancing and frequently use hand hygiene. ## Patient ppe - All patients and their attendants should wear a mask. - Using a triple layer surgical mask or N-95, if possible, significantly reduces the risk of transmission. ## Adjuncts to ppe - Patients often complain that the doctor is not audible with PPE. One adjunct is to use a wireless or wired mini personal voice amplifier - The use of the mobile phone is inevitable but often results in the breach of PPE. Hence, using a blue tooth device, preferably with bone conduction that doesn't plug the ear, is advised. - Rexene covers or disposable paper covers/sheets for the patient sitting/lying areas. - Contactless/foot operated dispensers for soap/ sanitizer/water in washbasins. ## Sanitization recommendations Despite consistent evidence of contamination of various surfaces with SARS CoV 2 virus, especially in the hospital setting, there is no direct evidence of fomites being a cause of transmission.However, it is imperative to follow some necessary sanitization precautions for the decontamination/disinfection of COVID-19, as given in [fig_ref] Table I: Decontamination and Disinfection GuideCare of Mop -Clean with hot water and detergent... [/fig_ref]. These are based on the Hospital Infection Prevention and Control guidelines drafted by the National Centre for Disease Control and the WHO.Spraying and Fogging Spraying, fogging, misting, or fumigation of rooms or surfaces is not recommended for COVID-19. Spraying of chemicals is harmful, affecting the mucus membrane, skin, and respiratory system. The recommended method is to wipe with a disinfectant soaked cloth ## Hand hygiene Patients, attendants, and HCW's are advised to wash hands with soap and water in a washbasin with footoperated or motion sensor adapted taps. Everyone should use Foot-operated hand sanitizer dispensers before entering the clinic. ## Sanitizers The composition of sanitizers is 60-70% ethanol or isopropyl alcohol. Avoid methanol containing or nonalcohol based sanitizers. Foot operated and Contactless sanitizer delivery systems are safe and effective. ## Heating ventilation and air conditioning (hvac) Maintaining the HVAC plays a vital role in providing a stress-free, comfortable, and safe environment for patients and health care workers. Maintaining indoor air quality is very important to prevent cross-contamination and hospital-acquired infections. VOLUME 58 __ APRIL 15, 2021 INDIAN ACADEMY OF PEDIATRICS PRACTISING SAFELY DURING COVID-19 2) It is a misconception that if we maintain moderate humidity, the virus growth and propagation can be prevented. Unfortunately, this virus seems to be very resistant to environmental changes like temperature and humidity. It requires an extreme relative humidity of more than 80 percent and a temperature of more than 50 degrees Centigrade to control. These conditions are neither attainable nor acceptable.Air changes per hour (ACR) Air changes per hour (ACR) are the number of total replacements of any room's air in one hour. If the air supply by the HVAC system in one hour is equal to the volume of the space, then it is called one air change per hour. The number of air exchanges required to clean the air depends on the quantum of infected aerosol production. For example, a minimum of 12 ACR is needed in the Intensive Care Unit (ICU). In contrast, only 4 ACR is required for general wards, as the expected amount of aerosol production is different in both areas. There are two ways to reduce the quantum of infection in contaminated air, either by 'diluting' the pathogen (dilution ventilation) or by removing the pathogen (exhaust ventilation). Dilution Ventilation is also called positive pressure isolation, required to prevent infection in an immunocompromised patient. Exhaust Ventilation is called negative pressure isolation and is used primarily to avoid a contaminated patient's airborne disease [15] [fig_ref] Figure 1: Principle of HVAC to prevent airborne spread [/fig_ref]. ## Ways to create air exchanges via exhaust Ventilation: ## 1) cross ventilation by opening up doors and windows: This is the cheapest way, but by this method, we cannot control the thermal and pollution level. 2) Exhaust Fan: The exhaust fan creates a negative pressure in the room, which sucks the dirty and contaminated air out of the room, and fresh air is pulled to replace it. 3) Fully Controlled Air: Air inlet, as well as exhaust air, is fully controlled, including the temperature and filtration. This requires a lot of resources, including technology, and is best suited for negative pressure isolation wards and ICUs. ## 4) air purifying systems: This cleans the air either via filtration (e.g., HEPA) or via other techniques like ultraviolet rays. Recirculation of air has to be prevented for this system to be effective. The airflow should be in the direction of clean to dirty and should not be directed towards the patient as it causes turbulence. [fig_ref] Figure 2: Clinic setting -Placement of exhaust fan, one feet above the ground [/fig_ref] ## Plasma purifiers Plasma purifiers are specialized newer technology air purifiers. Originally these purifiers were very large and cumbersome, however, with significant advancements in technology, they have become compact and a part of the HVAC with the ionization tubes mounted in the air conditioning, either in the unit itself or in the ductwork. These ionization tubes form ions (negatively or positively charged particles) as air circulates over them. The ions that are produced act in three ways to purify the air: 1) Sterilize bacteria and mould. When bacteria, virus and spores of mould come in contact with the ions, they are oxidized and destroyed. They can no longer multiply and are eliminated from the air. 2) Reduce particles in the air. The ions produced by the system bond with the toxins in the air, causing these particles to become larger. That makes them easier to be capture in the filters, reducing the number of toxin particles in the air. 3) Control odors. Odors associated with household aerosols or cleaning products are "captured" by the ions, oxidized, and eliminated. The viricidal properties of the Plasma purifiers may be used while installing the HAVAC in the clinics and small establishments. However further evidence is required regarding its efficacy during this pandemic. ## Recommended hvac modifications for healthcare facilities: Different recommendations for HVAC for various healthcare facilities are given in [fig_ref] Table I: Decontamination and Disinfection GuideCare of Mop -Clean with hot water and detergent... [/fig_ref] and [fig_ref] Figure 1: Principle of HVAC to prevent airborne spread [/fig_ref]. ## Covid-19 exposure in a non-covid health facility There are various situations where a Non-COVID-19 facility is faced with a COVID-19 challenge. The possible problems and recommendations are enumerated. When patients admitted for unrelated/non-respiratory illness turn out to be COVID-19 positive ## Definition of contacts A contact is a person who is likely to get the infection from a positive case through any of the following modes of transmission - Anyone exposed to a COVID -19 positive case 2 days before and 14 days after the onset of symptoms or date of testing The risk assessment of close contacts with COVID-19 patients is given in [fig_ref] Table I: Decontamination and Disinfection GuideCare of Mop -Clean with hot water and detergent... [/fig_ref]. ## Recommendations for monitoring based on covid-19 exposure risk [17] ## High-and medium-risk exposure category - HCW in the high-or medium-risk category should undergo active monitoring, including restriction from work in any healthcare setting until seven days after their last exposure. [18] - High-risk contacts will be quarantined for seven days - Test for COVID-19 done on day 0 of exposure and if negative day 7 of exposure - If they test positive but are asymptomatic, they will follow the protocol for mild/pre-symptomatic cases - If they test negative and are asymptomatic, they should complete a 7-day quarantine from the last date of exposure and then return to work. Further, they should be in self-reporting observation at work for another minimum of 7 days and strictly abide by the mask and physical distancing rules. - If they develop a fever (measured temperature > 100F or subjective fever) OR respiratory symptoms consistent with COVID-19 (e.g., cough, shortness of breath, sore throat), they should immediately test and self-isolate and notify the senior staff to take further action. ## Low-risk exposure category - HCW in the low-risk category should perform selfmonitoring with delegated supervision until 14 days after the last potential exposure. - Asymptomatic HCW in this category are not restricted from work. - They should check their temperature twice daily and remain alert for respiratory symptoms consistent with COVID-19 (e.g., cough, shortness of breath, sore throat) - Test for COVID-19 between day 5 and 14 of exposure - Suppose they develop a fever (measured temperature > 100F or subjective fever) OR respiratory symptoms. In that case, they should immediately self-isolate (separate themselves from others) and notify the staff physician promptly so that they can coordinate consultation and referral to a healthcare provider for further evaluation. Disclaimer: This practice guideline is intended to assist pediatricians and their support staff in safely practicing during the COVID-19 pandemic. The guideline at best serves as a quick reference providing practical advice on continuing medical practice in a safe way in clinics and small establishments. This is a broad advisory and is not intended to override any local or national government policies. This guideline is based on the currently available evidence on COVID-19 and its applicability in the Indian context. With any further developments, the guideline will be subjected to change. Contributors: SC, DG, AB, GVB: conception and design of the work and drafting the work; BJP, SSK, SD, PN, NS, AB, AJC: substantial contributions to the acquisition and interpretation of data for the work, and revising it critically for important intellectual content. All authors provided approval for the final version to be published. Funding: None; Competing Interests: None stated. [fig] Figure 1: Principle of HVAC to prevent airborne spread. [/fig] [fig] Figure 2: Clinic setting -Placement of exhaust fan, one feet above the ground. Direction of air should be from clean to dirty (patient side). Flow of AC air should be directed towards celling. VOLUME 58 __ APRIL 15, 2021 INDIAN ACADEMY OF PEDIATRICS PRACTISING SAFELY DURING COVID-19 [/fig] [table] Table I: Decontamination and Disinfection GuideCare of Mop -Clean with hot water and detergent solution, disinfect it with sodium hypochlorite and keep for drying upside down Drying the floors with a separate drying mop should be done a NaClO = Sodium hypochlorite, b ABR=Alcohol based rub. VOLUME 58 __ APRIL 15, 2021 [/table]	None	https://link.springer.com/content/pdf/10.1007/s13312-021-2201-y.pdf	None
07217b4be53cb035717449c7aa41895ecafc9bcd	pubmed	Details of a prospective protocol for a collaborative meta-analysis of individual participant data from all randomized trials of intravenous rt-PA vs. control: statistical analysis plan for the Stroke Thrombolysis Trialists' Collaborative meta-analysis	Details of a prospective protocol for a collaborative meta-analysis of individual participant data from all randomized trials of intravenous rt-PA vs. control: statistical analysis plan for the Stroke Thrombolysis Trialists' Collaborative meta-analysis Details of a prospective protocol for a collaborative meta-analysis of individual participant data from all randomized trials of intravenous rt-PA vs. control: statistical analysis plan for the Stroke Thrombolysis Trialists' Collaborative meta-analysisThe Stroke Thrombolysis Trialists' Collaborative Group 1 * Rationale Thrombolysis with intravenous alteplase is both effective and safe when administered to particular types of patient within 4·5 hours of having an ischemic stroke. However, the extent to which effects might vary in different types of patient is uncertain. Aims and Design We describe the protocol for an updated individual patient data meta-analysis of trials of intravenous alteplase, including results from the recently reported third International Stroke Trial, in which a wide range of patients enrolled up to six-hours after stroke onset were randomized to alteplase vs. control. Study Outcomes This protocol will specify the primary outcome for efficacy, specified prior to knowledge of the results from the third International Stroke Trial, as the proportion of patients having a 'favorable' stroke outcome, defined by modified Rankin Score 0-1 at final follow-up at three-to six-months. The primary analysis will be to estimate the extent to which the known benefit of alteplase on modified Rankin Score 0-1 diminishes with treatment delay, and the extent to which it is independently modified by age and stroke severity. Key secondary outcomes include effect of alteplase on death within 90 days; analyses of modified Rankin Score using ordinal, rather than dichotomous, methods; and effects of alteplase on symptomatic intracranial hemorrhage, fatal intracranial hemorrhage, symptomatic ischemic brain edema and early edema, effacement and/or midline shift. Discussion This collaborative meta-analysis of individual participant data from all randomized trials of intravenous alteplase vs. control will demonstrate how the known benefits of alteplase on ischemic stroke outcome vary across different types of patient. from treatment [bib_ref] Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS,..., Hacke [/bib_ref] , an analysis that was subsequently updated in 2010 to include the results of the ECASS-3 (2) and EPITHET [bib_ref] Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging..., Davis [/bib_ref] trials. These analyses demonstrated reliably that thrombolysis with iv rt-PA is both effective and safe when administered to particular types of patient within 4·5 h of having an ischemic stroke, and that treatment benefit diminishes with increasing treatment delay. However, several uncertainties remain regarding the potential effects of rt-PA when administered in different circumstances, as well as in different subgroups of patients [bib_ref] Thrombolysis for acute ischemic stroke, Wardlaw [/bib_ref]. In this third phase of the collaborative analysis of pooled individual patient data from the rt-PA trials, results from the third International Stroke Trial (IST- [bib_ref] Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging..., Davis [/bib_ref] [and, if possible, the Thrombolysis in Elderly Stroke Patients in Italy (TESPI) trial [bib_ref] TESPI (Thrombolysis in Elderly Stroke Patients in Italy): a randomized controlled trial..., Lorenzano [/bib_ref] ] will be included to help address these and other outstanding questions. This statistical analysis plan describes the analyses that were agreed by the Stroke Thrombolysis Treatment (STT) Collaborative Group prior to becoming unblinded to the results from IST-3. The main protocol can be downloaded from the study Web site (http://www.ctsu.ox.ac.uk/research/meta-trials/stt). ## Comparisons of baseline measures between trials Prior to performing analyses of estimated treatment effects (see below), we propose that descriptive and exploratory analyses will be performed to identify and display differences in baseline characteristics between the types of patient enrolled in the trials. In particular, statistical comparisons of baseline means (using t-tests) and prevalences (using chi-squared tests) between patients enrolled in IST-3 and patients enrolled in earlier trials will be performed. The baseline characteristics of patients in IST-3 who might have been expected to have been already eligible for treatment with rt-PA under guidelines at the time (e.g. patients presenting within 3 and within 4·5 h of stroke onset, particularly if aged <80 years), will also be presented because it is of interest to examine if reasons for the 'uncertainty' of benefit that prompted enrolment in IST-3 are evident. The rationale for performing these initial descriptive analyses is because an understanding of how IST-3 patients differ from those in the earlier trials might aid the interpretation of any apparent between-trial treatment differences that may arise (see section 'IST-3 compared with earlier trials'). ## Primary prespecified analyses It has already been established that thrombolysis with iv alteplase (rt-PA) is both effective and safe when administered to particular types of patient within 4·5 h of stroke onset, and that treatment benefit diminishes with increasing treatment delay [bib_ref] Time to treatment with intravenous alteplase and outcome in stroke: an updated..., Lees [/bib_ref]. Consequently, any estimate of the overall effect for all patients randomized to rt-PA within six-hours of stroke onset provided by the analyses described in this document should not necessarily be used to guide the future use of treatment (or to revisit efficacy in presently recommended subgroups) because of the possibility that such an estimate might be diluted substantially by the results from IST-3 (which, through use of the 'uncertainty principle' in its design, recruited substantial numbers of patients in whom the effect of treatment may be proportionally smaller than that observed in previous trials, or even nonexistent). Rather, the analyses described in this document seek to promote a better characterization of the extent to which rt-PA treatment effects vary in different types of patient, with a concomitant improvement in the identification of subgroups of patients in whom treatment may be particularly beneficial, nonexistent, or even harmful. ## Primary outcome The primary outcome will be the proportion of patients having a 'favorable' stroke outcome defined by modified Rankin Score (mRS) 0-1 at final follow-up at three-to six-months. If threemonth outcome is available for a specific study, this will be used as the primary outcome in analyses (regardless of whether it was used as the primary analysis in the original study report). If the three-month outcome is not available, the next available follow-up point will be used, as long as that point is no more than 190 days after randomization (i.e. one-week beyond the patient's scheduled six-month visit). In IST-3, there was no three-month follow-up, and follow-up at six-months was done by postal questionnaire. For many patients there was a delay of some days or weeks before the form was returned and received by the co-ordinating center. Therefore, following the prespecified approach taken in IST-3 (6), all completed six-month questionnaires in IST-3 will be included in analyses irrespective of when they were received by the co-ordinating center, with missing data imputed from the sevenday assessment using an algorithm that was found to work well among patients who had both measurements. In other trials, a conservative algorithm for imputing missing outcome data based on measurements made earlier than 90 days will also be used [as done previously [bib_ref] Time to treatment with intravenous alteplase and outcome in stroke: an updated..., Lees [/bib_ref] ]. This will assign a modified Rankin score of 5 if vital status is unknown or measurements were not available after baseline. If measurements are available after baseline in survivors, the last known score will be carried forward; otherwise for survivors a modified Rankin score of 5 will be imputed. ## Intention-to-treat (itt) analyses and missing data Wherever possible, analyses will include all randomized patients, irrespective of whether they subsequently received the intended treatment (i.e. according to the ITT principle). Patients with missing mRS at final follow-up will have a value imputed as described above. Any patients who withdrew their consent will contribute information only up to the point of withdrawal; thereafter, their missing data will be imputed. The frequency of missing baseline data for each trial will also be assessed. Depending on the extent of missing data, a range of statistical approaches will be used, including imputing missing values with mean values from other patients in that trial; using missing value indicators in analyses; multiple imputation (7); and complete case analyses. The range of approaches are needed because none of these methods are guaranteed to yield unbiased results for tests of interaction (see 'Primary analysis' below) should the data be 'missing not at random' [bib_ref] Multiple imputation for missing data in epidemiological and clinical research: potential and..., Sterne [/bib_ref]. In the unlikely scenario that these analyses give qualitatively different results the reasons for the differences will be explored and reported in publications. Otherwise, primary focus will be based on the simplest method of imputing missing data with the mean value seen among other patients in that trial. ## Primary analysis -after what treatment delay is benefit lost or does harm begin, and do age or stroke severity modify the proportional effect of rt-pa on stroke outcome? A key feature of the main analysis is to estimate the extent to which the effect of allocation to rt-PA on a favorable stroke outcome (i.e. mRS 0-1) depends on particular patient characteristics recorded at randomization (i.e. treatment effect 'modification'). To limit the potential for spurious results to arise from examination of multiple potential effect modifiers, the main analyses will be limited to three clinical characteristics that are anticipated to be particularly important: the time from stroke onset to treatment (hereon referred to as treatment delay), patient age, and stroke severity: (a) Treatment delay. Treatment delay is defined as the time from symptom onset to treatment delivery. [In the IST-3 trial, for patients recruited in the open phase of the study who were allocated control, it is not possible to specify a time interval from onset to 'treatment' that is comparable to the time from onset to delivery of the rt-PA bolus dose. Following the approach outlined in the prespecified statistical analysis plan (SAP) for that trial, the delay from randomization to delivery of the bolus among patients allocated placebo will therefore be set to 18 min (the mean delay observed in patients randomized to rt-PA in IST-3).] It has previously been shown that there is a decay in treatment benefit with increasing treatment delay and that the declining benefit may even translate to increased mortality if treatment is delayed beyond 4·5 h (1,2). However, confidence intervals around the time at which benefit is lost and/or mortality is first encountered are wide. Presently, there is no evidence to suggest that treatment initiation beyond 4·5 h confers any net benefit and, as a consequence, such patients are not routinely offered treatment in current clinical practice. The addition of IST-3 data to the existing subgroup of patients treated between 4·5 and 6 h therefore carries the lowest risk of effect dilution when combining IST-3 with the existing collaboration (since selection is less affected by existing treatment recommendations) and so this subgroup will be specifically examined. Regression analyses [see 'Using regression to test for effect modification (two-way interactions)'] will be performed to estimate the relationship between treatment delay (handled as a continuous variable) and the log-odds ratio for the effect of allocation to rt-PA on a favorable stroke outcome, after adjustment for any other modifying effects on treatment of age and stroke severity (see b and c below). Specifically, analyses will test for linearity in the log-odds ratio (i.e. 'log-linearity' in the odds ratio) with increasing treatment delay, and will estimate the size of such an effect. Assuming such a trend is observed, further analyses will estimate the time at which the estimated benefit crosses zero, as well as the time at which the 95% confidence interval for the odds ratio first crosses one. (See 'Key secondary analyses' for a description of analyses of mortality.) In addition to considering treatment delay as a continuous variable, the effect of allocation to rt-PA on stroke outcome in three subcategories of treatment delay will also be estimated: Յ3 h, >3 to Յ4·5 h; and >4·5 h. These estimates will also be adjusted for any modifying effects on treatment of age and stroke severity. (b) Patient age. It is hypothesized that, for a given treatment delay and stroke severity, the proportional benefits of rt-PA on a favorable stroke outcome do not reduce with increasing patient age. It is important to test this hypothesis because the marketing authorization for rt-PA in some European countries is currently restricted to patients aged 80 or less (due primarily to limited direct randomized evidence in older patients), whereas nonrandomized controlled data and clinical guidelines support the use of rt-PA in the elderly [bib_ref] VISTA Collaborators; SITS Collaborators. Thrombolysis in very elderly people: controlled comparison of..., Mishra [/bib_ref] [bib_ref] Influence of age on outcome from thrombolysis in acute stroke: a controlled..., Mishra [/bib_ref] [bib_ref] Intravenous alteplase for stroke in those older than 80 years old, Ford [/bib_ref]. Thus, a key question to answer is whether the current European marketing authorization restriction, based on an upper age limit of 80, is justified. Regression analyses will therefore be performed to test whether the proportional effect of allocation to rt-PA on a favorable stroke outcome varies (in a log-linear manner) with age at randomization (handled as a continuous variable), once adjustment is made for any treatment modifying effects of treatment delay and stroke severity. The effect of allocation to rt-PA on stroke outcome in patients Յ80 and >80 years of age will also be estimated (again, adjusted for other baseline covariates and treatment modifying effects of those covariates) and, if evidence of independent effect modification by age is observed, a test for difference in the two log-odds ratios will be performed (by comparing the difference in log odds ratios divided by its standard error against a standard normal distribution, a test that will be deemed nominally significant if the two-sided P-value is less than 0·05). (c) Stroke severity. Stroke severity is defined by the National Institutes of Health Stroke Scale (NIHSS) score determined before treatment. The Marketing Authorization for rt-PA in stroke cautions against use in severe and mild stroke (13). Regression analyses will therefore be performed to test whether the proportional effect of allocation to rt-PA on a favorable stroke outcome varies across the NIHSS scores. As indicated above, it is anticipated that a 'U-shaped' relationship might exist between the proportional effect of treatment allocation and NIHSS score, with a smaller proportional effect of treatment being seen among patients with the lowest and highest scores [bib_ref] Thrombolysis is associated with consistent functional improvement across baseline stroke severity: a..., Mishra [/bib_ref]. To test for such a relationship, regression analyses will be performed that allow the estimated treatment effect to vary with NIHSS score in such a manner (e.g. by inclusion of a quadratic interaction term in a model that additionally adjusts for any potential treatment modifying effects of treatment delay and patient age). If evidence of effect modification is determined from this analysis, five subcategories of severity (NIHSS score: 0-4, 5-10, 11-15, 16-21, and Ն22) will be defined, and further analyses will be done to estimate the proportional treatment effect in each of these groups (after adjustment for the other baseline variables of age and treatment delay). ## Using regression to test for effect modification (two-way interactions) As already stated, a key aspect of the main analysis is to estimate the extent to which treatment delay, age, and/or stroke severity modify the proportional effect of allocation to rt-PA on a favorable stroke outcome (i.e. mRS 0-1). Since these three baseline ## Protocols The Stroke Thrombolysis Trialists' Collaborative Group characteristics may be correlated with each other, if any one of them importantly modifies the proportional effect of treatment, then simple analyses of each in turn (e.g. through standard forest plots) might make it appear that the others do also even if the truth is that they do not (i.e. an apparent modifying effect on treatment may be artificially induced by a correlation existing with a 'true' effect modifier). Therefore, the main analyses will be done by fitting a logistic regression model (stratified by trial) with simultaneous adjustment for treatment allocation, the three key baseline characteristics (handled as appropriate for the particular hypothesis being tested; see above) and appropriate 'two-way' interaction terms with treatment allocation (i.e. treatment-bydelay, treatment-by-age, and treatment-by-severity). When handled as continuous variables, treatment delay, age, and stroke severity will be standardized prior to inclusion into any regression model (which will facilitate the interpretation of the 'main' effects in the presence of interaction terms but will not affect the statistical significance of any interaction terms). The statistical testing and estimation of the interaction terms will allow the following, hypothesis-driven, questions to be answered: - To what extent does treatment delay modify the proportional effect of rt-PA on stroke outcome (taking into account any other independent relationships between age/stroke severity and treatment effect)? - Does patient age modify the effect of rt-PA on stroke outcome (taking into account the independent relationships between treatment delay/stroke severity and treatment effect)? - Does stroke severity modify the effect of rt-PA on stroke outcome (taking into account the independent relationships between treatment delay/age and treatment effect)? As previously stated, the primary interest is not in the 'main effect' of treatment estimated across all the trials but rather the extent to which the treatment effect varies according to these three baseline characteristics. The most powerful test and reliable estimation of such effect modification is provided by an analysis that includes all IST-3 patients (irrespective of the overall results from IST-3). The results of these analyses for particular subgroups of patient defined by categories of treatment delay, age, and stroke severity will be shown graphically in forest plots that take their subgroup-specific relative risk estimates of the effect of allocation to rt-PA directly from the (relevant combination of) estimated regression coefficients from the appropriate regression models. Again, this is done most reliably by inclusion of all IST-3 patients into regression models that include the relevant interaction terms (which allow treatment effects to be estimated separately in each predefined subgroup). Two-way interaction tests will be regarded as nominally significant if the two-sided P-value is less than 0·05, before adjustment for multiplicity (see 'Interpretation of P-values for interaction'). ## Modification of effect modification (three-way interactions) On the assumption that the analyses described above do suggest that the proportional effect on stroke outcome of allocation to rt-PA is modified by some baseline feature, then a natural subsidiary clinical question would be whether this effect modification itself might vary depending on one of the other baseline features. In particular, if, as expected from the results of the earlier trials, treatment delay is found to importantly modify the proportional treatment effect (independently of age and stroke severity), then two natural subsidiary questions would be 1. Does age have any impact on the extent to which treatment delay modifies the effect of treatment? In particular, it may be hypothesized that older age would shorten the time window during which rt-PA may safely be given. 2. Does stroke severity have any impact on the extent to which treatment delay modifies the effect of treatment? In particular, it may be hypothesized that it would be less safe to treat very severe strokes late because increasing depth and duration of ischemia may increase subsequent risk of reperfusion injury. These questions can be answered using similar regression models to those described previously, but with the additional inclusion of appropriate 'three-way' interaction terms, one between age, treatment delay, and treatment allocation, and the other between stroke severity, treatment delay, and treatment allocation. (Note: the only other three-way interaction term that could be fitted, between age, stroke severity, and treatment allocation, would be included if either the interaction between age and treatment or the interaction between stroke severity and treatment were found to be independently significant.) Three-way interaction tests will be regarded as nominally significant if the two-sided P-value is less than 0·05, before adjustment for multiplicity (see 'Interpretation of P-values for interaction'). ## Interpretation of p-values for interaction Statistical tests for effect-modification (and modification of effect modification) will be provided by the P-values corresponding to the relevant two-or three-way interactions described above. In general, a two-sided P-value <0·05 will be considered as evidence supporting true effect modification. The rationale for using a P-value of 0·05, rather than 0·1 for instance (which would increase the power of the test), is that the probability of incorrectly claiming evidence for effect modification increases both with the nominal significance level and the number of tests being performed. For example, for any single regression model which includes three 2-way interaction terms, the probability of one or more 'false-positive' results is increased from about one in seven when using the 5% significance level to one in four when using the 10% significance level. Such a false-positive finding could be seriously damaging to clinical practice if it meant that inappropriate regulatory changes were made to the treatment indication as a result. Nonetheless, even with a P-value for interactions of 0·05, the probability of a false-positive result arising is not negligible. Thus, P-values will always be interpreted based on their actual value, rather than merely whether or not they are above or below a necessarily arbitrary value. ## Ist-3 compared with earlier trials One reason why the main analyses have been specified to allow assessment of how the effect of rt-PA varies depending on treatment delay, age, and stroke severity is because patients in whom rt-PA might be anticipated to have a reduced, or no, benefit (based on these criteria) are likely to be overrepresented in the IST-3 trial. Therefore, in a further regression model, an additional two-way interaction term between randomization into the IST-3 trial (a binary indicator) and treatment allocation will be fitted (in a model that also includes IST-3 as a main effect) to test whether or not, after allowing for the effect of treatment to vary according to treatment delay, patient age, and stroke severity, there remain any significant differences between the result of IST-3 and the pooled result from the other trials (i.e. are there unexplained differences). Specifically, the difference in minus twice the log-likelihood statistic between two nested models, one including an interaction term between enrollment in IST-3 and treatment with rt-PA and one not including such an interaction, will be tested against a chi-squared distribution with 1 degree of freedom. (Note: To allow estimation of main and interaction effects involving comparisons of IST-3 patients with patients recruited into other trials, this regression model will need to be unstratified, effectively resulting in the pooling of patients from the other trials into a single group.) ## Secondary analyses ## Key secondary analyses - Effect of treatment allocation on death within 90 days, analyzed using Cox proportional hazards regression, stratified by trial, with failure time set to time from randomization to death/censoring time. The potential for effect modification will be assessed by the addition of interaction terms to the model. - An analysis of the effect of treatment allocation on mRS using a 'sliding dichotomy approach' (also sometimes referred to as 'responder analysis' , 'prognosis-adjusted analysis' , or 'patientspecific analysis') [bib_ref] Design and analysis of phase III trials with ordered outcome scales: the..., Murray [/bib_ref]. For this approach, a favorable stroke outcome is defined individually for each patient based on their risk profile at randomization (rather than applying one rule for all patients). ## Other secondary outcomes Further analyses will be done to assess the effect of allocation to rt-PA on - Symptomatic intracranial hemorrhage, defined using PH2 or PH2 with the SITS-MOST criterion of a deterioration of Ն4 NIHSS points. - Fatal intracranial hemorrhage (PH2 and death within seven-days). - Symptomatic ischemic brain edema (brain tissue swelling associated with neurological deterioration by Ն4 NIHSS points). - Early edema, effacement and/or midline shift. Time to event outcomes will be analyzed using Cox proportional hazards regression, stratified by trial, with failure time set to time from randomization to outcome. Where there are a sufficient number of events (at least 10 per predictor variable), the potential for effect modification will be assessed by the addition of interaction terms to the model. ## Other analyses of mrs A number of other preplanned secondary analyses of stroke outcome will be conducted: - An analysis using an identical analytic approach of the dichotomous mRS outcome, but rather than modeling the probability of the outcome mRS 0-1, using instead the outcome mRS 0-2 (then, additionally, each of the outcomes mRS 0, mRS 0-3, mRS 0-4, and mRS 0-5). - An analysis of the distribution of mRS using an approach proposed by Howard et al. [bib_ref] A simple, assumption-free, and clinically interpretable approach for analysis of modified rankin..., Howard [/bib_ref] (Briefly, the approach is akin to the Mann-Whitney U-test in that it focuses on whether a randomly chosen actively treated patient is more or less likely to have a better outcome than a randomly chosen placebo-treated patient. This analysis will also be stratified by study and assess the potential for effect modification by the three prespecified baseline characteristics.) - Analyses of mRS across the whole spectrum using the Cochran-Mantel-Haenszel test followed by the proportional odds model. ## Modification of effects of rt-pa on the primary outcome by other baseline characteristics In addition to the three primary potential effect modifiers (treatment delay, age, and stroke severity), under a secondary set of hypotheses, further analysis of potential effect-modification will be performed for other baseline characteristics. Prioritized among these are blood pressure, blood glucose, and body temperature on admission. At a later stage other variables will also be examined, including sex, presence of atrial fibrillation on prerandomization electrocardiogram, baseline imaging features (e.g. presence of hyperdense middle cerebral artery, visible early ischemic tissue changes, ischemic leukoencephalopathy), stroke clinical syndrome, side of lesion (left vs. right hemisphere), concomitant treatments at baseline (e.g. antiplatelets, oral anticoagulants, statins), predicted prognosis, predicted risk of symptomatic intracranial hemorrhage, and tPA dose. Any apparently significant interactions arising from these analyses will be interpreted with appropriate caution (depending on the extent of their statistical significance), and, in general, may be considered as 'hypothesis generating' only. ## Other prespecified analyses In an additional analysis, the impact of affected hemisphere (left vs. right) on the log-odds ratio for the effect of allocation to rt-PA on a favorable stroke outcome in people with a low NIHSS score (Յ7) will be assessed. In particular, it is hypothesized that among people with a low NIHSS score, treatment with rt-PA will have little or no benefit among patients with stroke in the right hemisphere but substantial benefit among patients with stroke in the left hemisphere. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization 280 Vol 8, June 2013, 278-283 Collaborating trials	None	https://europepmc.org/articles/pmc3816333?pdf=render	Rationale Thrombolysis with intravenous alteplase is both effective and safe when administered to particular types of patient within 4·5 hours of having an ischemic stroke. However, the extent to which effects might vary in different types of patient is uncertain. Aims and Design We describe the protocol for an updated individual patient data meta-analysis of trials of intravenous alteplase, including results from the recently reported third International Stroke Trial, in which a wide range of patients enrolled up to six-hours after stroke onset were randomized to alteplase vs. control. Study Outcomes This protocol will specify the primary outcome for efficacy, specified prior to knowledge of the results from the third International Stroke Trial, as the proportion of patients having a ‘favorable’ stroke outcome, defined by modified Rankin Score 0–1 at final follow-up at three- to six-months. The primary analysis will be to estimate the extent to which the known benefit of alteplase on modified Rankin Score 0–1 diminishes with treatment delay, and the extent to which it is independently modified by age and stroke severity. Key secondary outcomes include effect of alteplase on death within 90 days; analyses of modified Rankin Score using ordinal, rather than dichotomous, methods; and effects of alteplase on symptomatic intracranial hemorrhage, fatal intracranial hemorrhage, symptomatic ischemic brain edema and early edema, effacement and/or midline shift. Discussion This collaborative meta-analysis of individual participant data from all randomized trials of intravenous alteplase vs. control will demonstrate how the known benefits of alteplase on ischemic stroke outcome vary across different types of patient.
0f7810978a500b9ccb130368210aabbbba4033d9	pubmed	The NICE COVID‐19 rapid guideline on haematopoietic stem cell transplantation: development, implementation and impact	The NICE COVID‐19 rapid guideline on haematopoietic stem cell transplantation: development, implementation and impact [bib_ref] Management of respiratory viral infections in hematopoietic cell transplant recipients and patients..., Chemaly [/bib_ref] [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref] ## Process and methods for guideline development NICE NG164 was developed jointly by NICE and NHS England and NHS Improvement (NHSE&I) in March 2020. The main stages of development included scoping, appointing an independent advisory expert panel, conducting evidence reviews, drafting recommendations, as well as targeted peer review through stakeholder consultation. The cross-speciality independent clinical advisory panel for HSCT included experts from the BSBMTCT, the NHSE&I Clinical Reference Group (CRG) for Blood and Marrow Transplantation (BMT), supported by the NICE guideline development team. The clinical review considered how the delivery of HSCT services should be managed for patients and donors during the COVID-19 pandemic and how to mitigate risks of COVID-19, at all stages of HSCT. An initial literature search was undertaken on 24 March 2020, in the early days of the pandemic when little information was available on COVID-19. A targeted approach was taken to identify published and preprint guidance and evidence. The recommendations were informed by a combination of evidence and expert panel consensus. The final guideline scope and equality impact assessment and the interim process and methods manual are published on the NICE website.An update of the NICE guideline was published, incorporating advice based on emerging evidence on the SARS-CoV-2 virus, the epidemiology and clinical impact. 7 A surveillance approach was implemented following publication involving frequent searches of literature and guidance, and a pragmatic intelligence gathering approach to identify other information which could impact on recommendations, such as changing COVID-19 alert levels and implementation feedback. ## Communicating with patients and minimising risk Patients undergoing HSCT experience significant anxiety and distress. [bib_ref] Routine screening for psychosocial distress following hematopoietic stem cell transplantation, Lee [/bib_ref] The Shielding Behavioural Survey undertaken by the Office for National Statistics (ONS) in June 2020 showed that 35% of people who are clinically extremely vulnerable reported that their mental health had become slightly worse (29%) or much worse (6%).A survey undertaken by Anthony Nolan, using the same wording as the ONS survey, showed that 79/139 (57%) of respondents reported that their mental health had become slightly worse (57/139, 41%) or much worse (22/139, 16%) as a result of the coronavirus pandemic (Anthony Nolan, personal communication). To support their mental wellbeing, the guideline recommends signposting of patients and families to charities and support groups. Documented examples include a local transplant teams support telephone line established during the pandemic by Anthony Nolan.NG164 recommends measures to mitigate risks of nosocomial transmission, including telephone or video consultations, avoiding non-essential clinic visits, coordinating blood tests and using alternative means of delivering medications. Many of these measures had been successfully implemented in centres across the UK. [bib_ref] Care of haematology patients in a COVID-19 epidemic, Willan [/bib_ref] Additionally, transplant centre healthcare workers are advised to follow UK guidance on infection prevention and control which includes the use of personal protective equipment (PPE) and recommendations on patient transfers, transport and options for outpatient settings.Patients with new symptoms of COVID-19 Patients undergoing HSCT are immunocompromised and may have atypical presentations of SARS-CoV-2 infection. [bib_ref] Clinical characteristics of hematological patients concomitant with COVID-19, Zhou [/bib_ref] They are also susceptible to other post-transplant complications which may have similar symptoms to COVID-19, including neutropenic sepsis or pneumonia caused by other pathogens. The expert panel was concerned that patients who feel unwell may be advised to isolate at home, which means that other types of infection or neutropenic sepsis-which is immediately life-threatening-could be missed. Consequently, the guideline recommends that patients with new symptoms suggestive of COVID-19 contact their transplant centre rather than the national NHS emergency telephone number, in order to receive specialist advice. The guidance also aligns with existing NICE guidance for people with cancer and suspected neutropenic sepsis, recommending assessment in secondary or tertiary care and offering immediate empirical antibiotic therapy (NICE CG151. Patients with symptoms suggestive of COVID-19 require testing for SARS-CoV-2. Isolation and the use of PPE are required until the test result is known.If a patient tests positive for SARS-CoV-2, NG164 recommends following UK guidance on the management of exposed healthcare workers and patients in hospital settings, which includes information on testing and isolating patients.Transplant recipients pre-transplant Transplant recipients are susceptible to viral infections, and evidence shows that respiratory viral infections can increase transplant-related mortality. [bib_ref] Management of respiratory viral infections in hematopoietic cell transplant recipients and patients..., Chemaly [/bib_ref] Recent evidence also suggests that this is true for HSCT patients who develop a SARS-CoV-2 infection, [bib_ref] Clinical characteristics and risk factors associated with COVID-19 severity in patients with..., Passamonti [/bib_ref] [bib_ref] COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter..., Ljungman [/bib_ref] [bib_ref] Poor outcome and prolonged persistence of SARS-CoV-2 RNA in COVID-19 patients with..., Shah [/bib_ref] [bib_ref] Risk factors and outcome of COVID-19 in patients with hematological malignancies, Piñana [/bib_ref] and advice includes social distancing, regular hand washing and self-isolation for the 14 days prior to admission. Patients should also be tested for SARS-CoV-2 prior to admission regardless of whether they have symptoms, due to the high rate of asymptomatic carriers of the virus (reviewed in Ref. [bib_ref] Asymptomatic transmission during the COVID-19 pandemic and implications for public health strategies, Huff [/bib_ref]. If patients have been in close contact with an individual infected with COVID-19 within the preceding week, deferral of transplant by three weeks was recommended. This recommendation was in line with EBMT guidance at that time, but since then the interval has been reduced to 'a minimum of 14 days' by the EBMT before the start of any transplant-related procedures and could be subject to further change. [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref] In patients with high-risk haematological disease progression, morbidity or mortality who test positive for SARS-CoV-2, it is recommended that transplant is deferred until they are asymptomatic and have three negative polymerase chain reaction (PCR) tests taken at least one week apart, similar to EBMT guidance which recommends two negative swabs, a deferral of 14 days from the first negative swab and a repeated swab prior to the start of conditioning. [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref] In patients with lower risk disease it is suggested that their transplant is delayed by three months. A repeat assessment of organ function including a chest X-ray, echocardiogram and pulmonary function tests is recommended as organ function may have deteriorated due to the SARS-CoV-2 infection. ## Transplant donors Following the initial rapid spread of SARS-CoV-2, the peak of infection in the general population occurred in mid-April 2020 21 with COVID-19 deaths peaking soon afterwards. Measures were required to reduce the risk and to mitigate the potential interruption to a planned transplant. For example, transplant centres and donor registries advised donors to follow government guidance on strict social distancing behaviour for at least four weeks before donating. Donors were advised to keep in contact with the harvest centre and to seek advice if they developed any symptoms suggestive of COVID-19. Due to the reported asymptomatic carriage of the virus by individuals, which ranges from 18%-88% depending upon the population studied, 22,23 screening by throat and nasal swabs for SARS-CoV-2 PCR at least once prior to donation and ideally on the day of donation was recommended. Screening on the day of donation was intended to provide an audit trail rather than inform the use of the harvested stem cells. In theory it was possible that a donor would be asymptomatic but positive for COVID-19 on the day of donation. There have been reports of SARS-CoV-2 RNA being detected in several organs and in blood; [bib_ref] Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in..., Zheng [/bib_ref] however, the presence of the potentially infectious virus in blood, and hence blood products, in an asymptomatic donor is remote. [bib_ref] SARS-CoV-2 asymptomatic and symptomatic patients and risk for transfusion transmission, Corman [/bib_ref] The swab test on the day of donation would allow tracing in the event that a transplant recipient became unwell with COVID-19 post-transplant. Similarly, donors were asked to inform harvest teams if they developed any COVID-19 symptoms within two weeks of donation.A major change in the allogeneic transplant procedure was a recommendation by some donor registries to cryopreserve stem cells prior to the start of conditioning for the recipient, based on BSBMTCT recommendations and expert consensus. [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref] The intention of this recommendation was to avoid the possibility that a donor was unable to donate due to developing COVID-19. Evidence from two retrospective studies indicated that the use of cryopreserved stem cells in allogeneic transplantation had no impact on transplant outcome. [bib_ref] Cryopreservation of allogeneic PBSC from related and unrelated donors is associated with..., Medd [/bib_ref] [bib_ref] Graft cryopreservation does not impact overall survival after allogeneic hematopoietic cell transplantation..., Hamadani [/bib_ref] If fresh cells were to be used, it was recommended that an alternative donor, including for haplo-identical or cord blood, was identified in case the selected donor was unable to donate. Donors who had tested positive for COVID-19, even if asymptomatic, were required to be deferred for three months after the resolution of symptoms. This is longer than the period of 28 days recommended by the EBMT 3,5 , but with evidence of long-term medical complications following COVID-19 the longer period of deferral seemed appropriate. However, it was recognised that in situations where the clinical urgency of the transplant was high then earlier donation would be possible with a risk assessment, an asymptomatic period and repeated negative swabs for SARS-CoV-2 prior to donation. ## Transplant recipients post-transplant Based on the increased risk of mortality from other respiratory viruses [bib_ref] Respiratory virus infections after stem cell transplantation: a prospective study from the..., Ljungman [/bib_ref] , it was highly probable that transplant recipients would be at increased risk of mortality from SARS-CoV-2. Emerging evidence supports this assumption with data from the EBMT COVID-19 survey reporting the outcome of confirmed COVID-19 infection in 272 patients, 175 allogeneic SCT and 97 autologous SCT. The mortality rate was 30% in allogeneic recipients and 25Á3% in autologous recipients. [bib_ref] COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter..., Ljungman [/bib_ref] A smaller report in 25 patients with haematological malignancies reported a mortality rate of 40% but only seven HSCT recipients were included in this study. [bib_ref] COVID-19 outcomes in patients with hematologic disease, Malard [/bib_ref] The CIBMTR registry has a cumulative reporting process and by the end of September 2020 a total of 554 cases of COVID-19 had been reported, with a mortality rate of 19Á1%.As with subgroups of patients with haematological malignancies, similar high mortality rates in HSCT recipients have been reported. [bib_ref] Poor outcome and prolonged persistence of SARS-CoV-2 RNA in COVID-19 patients with..., Shah [/bib_ref] [bib_ref] Risk factors and outcome of COVID-19 in patients with hematological malignancies, Piñana [/bib_ref] Strict social distancing behaviour was recommended in line with current guidelines. [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref] Supporting staff Depletion of experienced transplant teams was acknowledged with staff remaining away from work, either due to symptomatic infection, contact with proven cases, or personal reasons.The risk of nosocomial infection from staff was of great concern 34 ; in the report by Malard, a large number of infections in patients with haematological malignancies were thought to have been acquired in hospital. [bib_ref] COVID-19 outcomes in patients with hematologic disease, Malard [/bib_ref] It was therefore important to ensure that transplant programmes could provide 'COVID-19 safe' environments with a key component being education of staff on the symptoms of COVID-19, regular symptom checks and routine screening of asymptomatic staff whenever possible. During the preparation of the guideline it was clear that there was uncertainty regarding the period that an individual may remain potentially infective, with reports of prolonged positivity by PCR despite resolution of symptoms. [bib_ref] Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in..., Zheng [/bib_ref] [bib_ref] Transmission of 2019-nCoV infection from an asymptomatic contact in Germany, Rothe [/bib_ref] Return to work recommendations from the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC) and EBMT indicated that staff should be asymptomatic, fever being the main symptom to have been resolved, have a minimum time-period since onset of symptoms and ideally two negative swabs for SARS-CoV-2. The approach by the NICE guidelines group was pragmatic, acknowledging the rapidly changing evidence and limitations of testing. [bib_ref] Molecular diagnostic technologies for COVID-19: limitations and challenges, Afzal [/bib_ref] [bib_ref] False negative of RT-PCR and prolonged nucleic acid conversion in COVID-19: Rather..., Xiao [/bib_ref] [bib_ref] Elective surgery during SARS-Cov-2/COVID-19 pandemic: safety protocols with literature review, C Ardenas-Camarena [/bib_ref] [bib_ref] Universal testing for COVID-19 in essential orthopaedic surgery reveals a high percentage..., Gruskay [/bib_ref] [bib_ref] The theoretical mortality risk of an asymptomatic patient with a negative SARS-CoV-2..., Kader [/bib_ref] Rivett et al. reported the results of a screening programme for asymptomatic staff in a large teaching hospital in the UK, [bib_ref] Screening of healthcare workers for SARS-CoV-2 s the role of asymptomatic carriage..., Rivett [/bib_ref] indicating that the presence or absence of symptoms alone would miss individuals still potentially shedding virus. Similar to the 'test-based strategy' of the CDC, 42 a recommendation was made for staff to be asymptomatic for at least seven days plus a negative SARS-CoV-2 swab PCR test prior to returning to direct contact with transplant recipients. The creation of 'COVID-19 safe' environments for transplant recipients was based on the provision of regular swab testing of staff. As of September 2020, PCR testing for SARS-CoV-2 was limited and routine testing of asymptomatic staff was not achieved in all sites despite the NICE recommendation. A BSBMTCT survey of the 53 transplant units in the UK conducted in September 2020 received 42 responses; of these only 24 (57%) of centres were offering routine testing of asymptomatic staff with the majority (83%) using nose and throat swab tests for SARS-CoV-2 (Bloor et al., BJH 2020 accepted). ## Prioritising treatment Given the uncertainties during the early phase of the COVID pandemic, there was a need to prioritise HSCT procedures depending on risk of disease indication if untreated by HSCT, and potential risk of severe COVID-19 infection during and after HSCT. To inform shared decision-making with patients, NICE recommended that multidisciplinary teams (MDTs) consider using transplant outcome predictive tools such as the haematopoietic cell transplantation-specific comorbidity index (HCT-CI) [bib_ref] Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment..., Sorror [/bib_ref] [bib_ref] Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell..., Sorror [/bib_ref] or the refined disease risk index (DRI), [bib_ref] Validation and refinement of the Disease Risk Index for allogeneic stem cell..., Armand [/bib_ref] but also to be aware of the limitations of these tools. Prioritising treatment for people with high risk of haematological disease progression, morbidity or mortality enabled units to focus on critically urgent, curative HSCT procedures concentrated in larger units where COVID-19minimised pathways could be provided. Close liaison within local MDTs was recommended to consider suitable alternative treatments if the risks associated with COVID-19 were felt to be higher than the risk of continuing with the transplant. ## Modifications to usual care NICE recommended different ways of working within HSCT programmes, as well as regional (adults) and national (paediatrics) via 'clusters' of HSCT centres within operational delivery networks (ODNs) to provide a 'safety net' should any programmes fail to maintain quality standards and/or meet demands in activity. ODNs were extended to support devolved nations. Modifications to haematopoietic stem cell collection (apheresis and bone marrow harvest) practice and facilities were also recommended. Engagement between stakeholders was critical, [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref] along with reporting into the EBMT registry experience. [bib_ref] COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter..., Ljungman [/bib_ref] Impact of COVID-19 on HSCT activity in the UK [fig_ref] Table I: Day 0 transplant registrations received by the British Society of Blood and... [/fig_ref] andsummarise the autologous and allogeneic HSCT activity (adult and paediatric combined) as reported to the BSBMTCT registry during the period 1 Jan-31 July in 2019 and 2020. Both autologous and allogeneic HSCT activity fell in March 2020, reaching a nadir in April 2020, which corresponded with the peak of the COVID-19 crisis in the UK. Autologous HSCT was reduced to a greater extent than allogeneic HSCT, reaching 16Á4% of the 2019 activity, while allogeneic HSCT fell to 65%. These data show the total transplant activity in the UK but there was considerable heterogeneity of the impact around the country; some small autologous HSCT units ceased all activity, and some large programmes reduced autologous HSCT activity but maintained allogeneic activity close to 2019 levels, while some large programmes reduced both (BSBMTCT registry data). The impact of the COVID-19 crisis on individual centres was influenced by several factors, including local infection rates, staffing levels and risk assessments. The reduction of transplant activity, particularly for autologous HSCT, created a large 'backlog' of patients awaiting transplantation, and, by the time of the second wave of the pandemic, HSCT in the UK was still in recovery phase as activity had still not reached that of 2019. # Conclusion The COVID-19 pandemic has posed an exceptional challenge for the stem cell transplant community which responded quickly by publishing relevant guidance for the management of transplant recipients, advice on safe service delivery and donor issues 4 , and was updated in response to new evidence and government advice. The advice and experience from experts within EBMT was invaluable in formulating these guidelines. [bib_ref] The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management..., Ljungman [/bib_ref] The NHS also responded quickly to the complex issues posed by the pandemic to support patients, NHS trusts, clinicians and commissioners. The guidelines will require ongoing review as more clinical evidence emerges and government advice changes to address further 'waves' of the pandemic, and, ultimately, the challenge of 'endemic' COVID-19. ## Acknowledgements All the authors actively contributed as per ICMJE authorship requirements. NICE NG164 was developed, published (1 April 2020) and updated (29 July 2020) by EM, MD, AP and PS, with clinical input led by JAS, KO and FLD on behalf of NHSE&I Clinical Reference Group (CRG) for Blood and Marrow Transplantation and BSBMTCT. The BSBMTCT Head of Registry and Statistician (JL & RP) provided data, statistical analysis and interpretation of the registry data, with clinical input from KO, JAS and FD. All authors wrote, reviewed and approved the manuscript. NICE NG164 was produced by NICE as part of the response of NHSE&I to the COVID-19 pandemic. JAS and FLD receive remuneration from NHSE&I for chairing the CRG. BSBMTCT maintains the national registry with data management and statistical support (JL and RP). All patients have consented for data entry into the registry in accordance with data protection regulations. The authors wish to thank the executive committee of the BSBMTCT for their contribution to these guidelines: Deborah Richardson, Dominic Culligan, Kavita Raj, Maria Gilleece, Eduardo Olavarria, Marie Waller, Bim Laguda, Rachael Hough, Ram Malladi, Jennifer Byrne, Matthew Collin, Stephen Robinson. The authors would also like to thank the UK and Ireland Paediatric BMT Group (chair, Persis Amrolia), UK Myeloma Forum (John Ashcroft and Gordon Cook) and other stakeholder groups who contributed to development and updating of NG164. The authors also wish to thank Janette Harper and Rob Coster from NHSE&I for their contribution to these guidelines and all members of the NHSE&I Clinical Reference Group for Blood and Marrow Transplantation, and Henny Braund, Amelia Chong, Rob Danby and members of the Anthony Nolan team, who have supported regular video-conferenced discussions throughout the pandemic. ## Conflicts of interest JAS was chair of BMT-CRG from June 2016-June 2020, and FLD is chair from April 2020. They co-chaired the BMT-CRG from April-June 2020. KO was President of BSBMTCT from January 2018 to December 2020, and JS is President from January 2021-December 2022. No other conflicts of interest were declared. [fig] Fig 1: (A) Day 0 reported autologous HSCT activity in the period 1 January-31 July, comparing monthly totals for 2019 and 2020. P-values were determined from a linear regression model using monthly data for 2007-2019, assuming normally distributed variation. (B) Day 0 reported allogeneic HSCT activity in the period 1 January-31 July, comparing monthly totals for 2019 and 2020. P-values were determined from a linear regression model using monthly data for 2007-2019, assuming normally distributed variation. [Colour figure can be viewed at wileyonlinelibra ry.com] [/fig] [table] Table I: Day 0 transplant registrations received by the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT) Registry for the period 1 January-31 July in 2019 compared with 2020. The numbers include adult and paediatric transplant activity. January February March April May June July [/table]	None	https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bjh.17280	Kim Orchard,* Fiona L. Dignan,* Julia Lee, Rachel Pearce, Monica Desai, Emma McFarlane, Angela Parkin, Peter Shearn and John A. Snowden Department of Haematology, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire, Department of Clinical Haematology, Manchester University NHS Foundation Trust, Manchester, BSBMTCT Registry, Guy’s and St. Thomas’ NHS Foundation Trust, London, National Institute for Health and Care Excellence, Manchester, Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, and Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK

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